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1
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Azizi L, Hausman H, Meyer AK, Wong M, Pajonk F. The Mevalonate Pathway in the Radiation Response of Cancer. Int J Radiat Oncol Biol Phys 2025:S0360-3016(25)00278-0. [PMID: 40194746 DOI: 10.1016/j.ijrobp.2025.03.059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Revised: 02/14/2025] [Accepted: 03/19/2025] [Indexed: 04/09/2025]
Abstract
The mevalonate (MVA) pathway plays a critical role in cholesterol biosynthesis, protein prenylation, and metabolic reprogramming, all of which contribute to cancer progression and therapy resistance. Targeting the MVA pathway with statins and other inhibitors has shown promise in preclinical studies; however, clinical outcomes remain controversial, raising concerns about translating these findings into effective treatments. Additionally, the interaction between the MVA pathway and radiation therapy (RT) is not yet fully understood, as RT upregulates the pathway, which can enhance tumor cell survival. This review summarizes the current literature on MVA pathway inhibition in cancer therapy, focusing on its potential to enhance the efficacy of RT. A better understanding of the pathway's role in radiation responses will be essential to translate combination therapies that target this pathway.
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Affiliation(s)
- Linda Azizi
- Department of Radiation Oncology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California.
| | - Hannah Hausman
- Department of Radiation Oncology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California
| | - Alexandra K Meyer
- Department of Radiation Oncology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California
| | - Matthew Wong
- Department of Radiation Oncology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California
| | - Frank Pajonk
- Department of Radiation Oncology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California; Department of Neurosurgery, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California; Jonsson Comprehensive Cancer Center at University of California, Los Angeles, Los Angeles, California
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2
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Wang Z, Xu C, Wang Q, Wang Y. Repurposing of nervous system drugs for cancer treatment: recent advances, challenges, and future perspectives. Discov Oncol 2025; 16:396. [PMID: 40133751 PMCID: PMC11936871 DOI: 10.1007/s12672-025-02067-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Accepted: 03/05/2025] [Indexed: 03/27/2025] Open
Abstract
The nervous system plays a critical role in developmental biology and oncology, influencing processes from ontogeny to the complex dynamics of cancer progression. Interactions between the nervous system and cancer significantly affect oncogenesis, tumor growth, invasion, metastasis, treatment resistance, inflammation that promotes tumors, and the immune response. A comprehensive understanding of the signal transduction pathways involved in cancer biology is essential for devising effective anti-cancer strategies and overcoming resistance to existing therapies. Recent advances in cancer neuroscience promise to establish a new cornerstone of cancer therapy. Repurposing drugs originally developed for modulating nerve signal transduction represent a promising approach to target oncogenic signaling pathways in cancer treatment. This review endeavors to investigate the potential of repurposing neurological drugs, which target neurotransmitters and neural pathways, for oncological applications. In this context, it aims to bridge the interdisciplinary gap between neurology, psychiatry, internal medicine, and oncology. By leveraging already approved drugs, researchers can utilize existing extensive safety and efficacy data, thereby reducing both the time and financial resources necessary for the development of new cancer therapies. This strategy not only promises to enhance patient outcomes but also to expand the array of available treatments, thereby enriching the therapeutic landscape in oncology.
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Affiliation(s)
- Zixun Wang
- Nanshan School, Guangzhou Medical University, Jingxiu Road, Panyu District, Guangzhou, 511436, China
| | - Chen Xu
- Department of Gynecologic Oncology, the International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Municipal Key Clinical Specialty, Female Tumor Reproductive Specialty, Shanghai Key Laboratory of Embryo Original Disease, Shanghai Jiao Tong University, Shanghai, 200025, China
| | - Qi Wang
- Department of Gynecologic Oncology, the International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Municipal Key Clinical Specialty, Female Tumor Reproductive Specialty, Shanghai Key Laboratory of Embryo Original Disease, Shanghai Jiao Tong University, Shanghai, 200025, China.
| | - Yudong Wang
- Department of Gynecologic Oncology, the International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Municipal Key Clinical Specialty, Female Tumor Reproductive Specialty, Shanghai Key Laboratory of Embryo Original Disease, Shanghai Jiao Tong University, Shanghai, 200025, China.
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3
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Chen Q, Jin J, Li P, Wang X, Wang Q. Navigating Glioma Complexity: The Role of Abnormal Signaling Pathways in Shaping Future Therapies. Biomedicines 2025; 13:759. [PMID: 40149733 PMCID: PMC11940491 DOI: 10.3390/biomedicines13030759] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2025] [Revised: 03/11/2025] [Accepted: 03/19/2025] [Indexed: 03/29/2025] Open
Abstract
Gliomas are a type of highly heterogeneous and invasive central nervous system tumor. Traditional treatment methods have limited efficacy, and the prognosis for patients remains poor. Recent studies have revealed the crucial roles of several abnormal signaling pathways in the pathogenesis of gliomas, including the Receptor Tyrosine Kinase/Rat Sarcoma Virus Oncogene/Phosphatidylinositol-3-Kinase (RTK/RAS/PI3K) pathway, the Wingless-Related Integration Site/β-Catenin (Wnt/β-Catenin) pathway, the Hippo/YAP (Hippo/Yes-associated protein) pathway, and the Slit/Robo (Slit Guidance Ligands/Roundabout) signaling pathway. These pathways play extremely vital roles in tumor proliferation, invasion, and treatment resistance. This article comprehensively and systematically reviews the molecular mechanisms of these signaling pathways, deeply summarizing the research progress of various treatment strategies, including targeted inhibitors, gene therapy, and nanomedicine against them. Moreover, the combination of targeted therapy and personalized treatment regimens is expected to overcome the current treatment bottleneck and provide a more favorable survival prognosis for glioblastoma patients.
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Affiliation(s)
- Qiang Chen
- Department of Pharmacy, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430077, China;
| | - Jin Jin
- Department of Rehabilitation, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430077, China;
| | - Pian Li
- Liyuan Cardiovascular Center, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430077, China;
| | - Xiuping Wang
- Department of Pharmacy, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430077, China;
| | - Qianyan Wang
- Liyuan Cardiovascular Center, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430077, China;
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4
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Lu L, Zhang Y, Yang Y, Jin M, Ma A, Wang X, Zhao Q, Zhang X, Zheng J, Zheng X. Lipid metabolism: the potential therapeutic targets in glioblastoma. Cell Death Discov 2025; 11:107. [PMID: 40097417 PMCID: PMC11914282 DOI: 10.1038/s41420-025-02390-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Revised: 02/19/2025] [Accepted: 03/06/2025] [Indexed: 03/19/2025] Open
Abstract
Glioblastoma is a highly malignant tumor of the central nervous system with a high mortality rate. The mechanisms driving glioblastoma onset and progression are complex, posing substantial challenges for developing precise therapeutic interventions to improve patient survival. Over a century ago, the discovery of the Warburg effect underscored the importance of abnormal glycolysis in tumors, marking a pivotal moment in cancer research. Subsequent studies have identified mitochondrial energy conversion as a fundamental driver of tumor growth. Recently, lipid metabolism has emerged as a critical factor in cancer cell survival, providing an alternative energy source. Research has shown that lipid metabolism is reprogrammed in glioblastoma, playing a vital role in shaping the biological behavior of tumor cells. In this review, we aim to elucidate the impact of lipid metabolism on glioblastoma tumorigenesis and explore potential therapeutic targets. Additionally, we provide insights into the regulatory mechanisms that govern lipid metabolism, emphasizing the critical roles of key genes and regulators involved in this essential metabolic process.
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Affiliation(s)
- Lu Lu
- Department of Pathology, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
| | - Yan Zhang
- Department of Pathology, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
| | - Yuzhong Yang
- Department of Pathology, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
| | - Meihua Jin
- Department of Pathology, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
| | - Aiyu Ma
- Department of Pathology, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
| | - Xu Wang
- Department of Pathology, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
| | - Qiuyu Zhao
- Department of Pathology, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
| | - Xuemei Zhang
- Department of Pathology, Liuzhou People's Hospital Affiliated to Guangxi Medical University, Liuzhou, Guangxi, China
| | - Jinhua Zheng
- Department of Pathology, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China.
| | - Xiang Zheng
- Department of Pathology, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China.
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Basso J, Matos AM, Ghavami S, Fortuna A, Vitorino R, Vitorino C. Are we better together? Addressing a combined treatment of pitavastatin and temozolomide for brain cancer. Eur J Pharmacol 2024; 985:177087. [PMID: 39491742 DOI: 10.1016/j.ejphar.2024.177087] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Revised: 10/29/2024] [Accepted: 10/30/2024] [Indexed: 11/05/2024]
Abstract
Pitavastatin is commonly prescribed to treat hypercholesterolemia through the regulation of cholesterol biosynthesis. Interestingly, it has also demonstrated a great potential for treating brain tumors, although the detailed cytotoxic mechanism, particularly in glioblastoma, remains incompletely understood. This work explores the activity of pitavastatin in 2D and 3D glioblastoma models, in an attempt to provide a more representative and robust overview of its anticancer potential in glioblastoma. The results show that not only is pitavastatin 10-1000 times-fold more effective in reducing tumoral metabolic activity than temozolomide, but also demonstrate a synergistic activity with this alkylating drug. In addition, low micromolar concentrations of this statin strongly impair the growth and the invasion ability of multicellular tumor spheroids. The obtained qRT-PCR and proteomics data highlight the modulation of cell death via apoptosis (BAX/BCL2, CASP9) and autophagy (BECN1, BNIP3, BNIP3L and LC3B), as well as an epithelial to mesenchymal transition blockage (HTRA1, SERPINE1, WNT5A, ALDH3B1 and EPHA2) and remodeling of the extracellular matrix (VCAN, SERPINE1 and TGFBI). Overall, these results lay the foundation for further investigations on the potential combinatory clinical treatment with temozolomide.
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Affiliation(s)
- João Basso
- Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal; Coimbra Chemistry Centre, Institute of Molecular Sciences-IMS, Faculty of Sciences and Technology, University of Coimbra, Coimbra, Portugal
| | - Ana Miguel Matos
- Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal; Chemical Engineering and Renewable Resources for Sustainability, CERES, Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal
| | - Saeid Ghavami
- Department of Human Anatomy and Cell Science, University of Manitoba College of Medicine, Winnipeg, MB, R3E 0J9, Canada; Research Institute of Oncology and Hematology, Cancer Care Manitoba-University of Manitoba, Winnipeg, MB, R3E 0V9, Canada; Biology of Breathing Theme, Children Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, MB, R3T 2N2, Canada
| | - Ana Fortuna
- Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal; Coimbra Institute for Biomedical Imaging and Translational Research, University of Coimbra, Coimbra, Portugal
| | - Rui Vitorino
- Department of Medical Sciences, Institute of Biomedicine-iBiMED, University of Aveiro, Aveiro, Portugal; UnIC@RISE, Department of Surgery and Physiology, Faculty of Medicine of the University of Porto, Porto, Portugal
| | - Carla Vitorino
- Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal; Coimbra Chemistry Centre, Institute of Molecular Sciences-IMS, Faculty of Sciences and Technology, University of Coimbra, Coimbra, Portugal.
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6
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Kobayashi K, Murakami K, Baba K. Effects of Lipophilic Statins on Cell Viability and Tissue Factor Expression in Canine Haemangiosarcoma Cells. Vet Comp Oncol 2024; 22:581-591. [PMID: 39319370 DOI: 10.1111/vco.13012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Revised: 08/18/2024] [Accepted: 09/06/2024] [Indexed: 09/26/2024]
Abstract
Canine haemangiosarcoma (HSA) is a highly aggressive cancer often associated with coagulation abnormalities. Statins, inhibitors of 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR) clinically prescribed for hypercholesterolemia, are also believed to possess antitumour and anticoagulant properties by inhibiting downstream Akt activation. Akt phosphorylation is involved in the mechanism of the antitumour and tissue factor (TF)-lowering effects of statins. In the present study, we aimed to investigate whether statins could inhibit cell viability while concurrently inducing anticoagulant properties by regulating the expression of TFs in canine HSA cells. Using reverse transcription-quantitative polymerase chain reaction (RT-qPCR), we initially exclusively detected HMGCR mRNA expression in canine HSA tissues and cell lines but not in normal cephalic vein and spleen tissues. Moreover, treatment with lipophilic statins, including atorvastatin, fluvastatin, and simvastatin, inhibited cell viability in a concentration-dependent manner and decreased TF expression both at the mRNA and protein levels, as evidenced by cell viability assays, RT-qPCR, and immunoblotting, respectively. Further investigation using cell viability assays and flow cytometry revealed that simvastatin decreased Akt phosphorylation, and MK-2206, a specific Akt inhibitor, mirrored the effect of simvastatin on cell viability and cell cycle arrest. However, MK-2206 exhibited different effects on TF expression depending on the cell type, indicating that Akt phosphorylation may not consistently regulate TF expression. Overall, this study provides insights into the potential therapeutic use of statins in targeting tumour growth and coagulation abnormalities in canine HSA. Further research is warranted to fully elucidate the underlying mechanisms and clinical applications of statins in canine HSA treatment.
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Affiliation(s)
- Kosuke Kobayashi
- Faculty of Veterinary Medicine, Okayama University of Science, Imabari, Japan
| | - Kohei Murakami
- Faculty of Veterinary Medicine, Okayama University of Science, Imabari, Japan
| | - Kenji Baba
- Laboratory of Veterinary Internal Medicine, The United Graduate School of Veterinary Science, Yamaguchi University, Yamaguchi, Japan
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Basso J, Fortuna A, Vitorino R, Vitorino C. Old drugs, new tricks: Delivering pitavastatin-loaded nanostructured lipid carriers for glioblastoma treatment. Colloids Surf B Biointerfaces 2024; 245:114253. [PMID: 39303387 DOI: 10.1016/j.colsurfb.2024.114253] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2024] [Revised: 09/01/2024] [Accepted: 09/16/2024] [Indexed: 09/22/2024]
Abstract
Glioblastoma (GB) is the most common and lethal primary form of malignant brain cancers. Its intrinsic aggressiveness and the blood-brain barrier (BBB) are two major factors that limit the efficacy of standard therapies. In recent years, nanostructured lipid carriers (NLCs) have established themselves as a promising avenue for improving drug delivery to the brain, overcoming the challenges associated with the low drug permeability of the BBB. This work delves into the systematic development of a novel carrier for pitavastatin delivery by establishing a "get it right at the first time" quality by design perspective, supported by multivariate analysis, computational modelling, and molecular docking. The manufacturing process was comprehensively evaluated at each step, from raw material selection to NLC purification, thus leading to a carrier with optimal colloidal, encapsulation and stability properties. The cytotoxic behaviour of the carrier was assessed in a panel of GB cell lines, which includes a low, a medium and a highly sensitive cell line to pitavastatin, providing a better discriminatory power and addressing the different potential in the therapeutic responses. The results obtained reflect a strong antiglioblastoma activity in concentrations where the standard of care lacks activity, as well as a swift and prominent internalization by GB cells. Overall, this work positions these long-term stable parenteral systems in line with the hypothesis of providing more effective surrogate therapeutics in the field of GB.
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Affiliation(s)
- João Basso
- Faculty of Pharmacy, University of Coimbra, Coimbra 3000-548, Portugal; Coimbra Chemistry Centre, Institute of Molecular Sciences-IMS, Faculty of Sciences and Technology, University of Coimbra, Coimbra 3004-535, Portugal
| | - Ana Fortuna
- Faculty of Pharmacy, University of Coimbra, Coimbra 3000-548, Portugal; Coimbra Institute for Biomedical Imaging and Translational Research, CIBIT, University of Coimbra, Coimbra 3000-548, Portugal
| | - Rui Vitorino
- Department of Medical Sciences, Institute of Biomedicine-iBiMED, University of Aveiro, Aveiro 3810-193, Portugal; UnIC@RISE, Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Porto 4200-319, Portugal; LAQV/REQUIMTE, Department of Chemistry, University of Aveiro, Aveiro 3810-193, Portugal
| | - Carla Vitorino
- Faculty of Pharmacy, University of Coimbra, Coimbra 3000-548, Portugal; Coimbra Chemistry Centre, Institute of Molecular Sciences-IMS, Faculty of Sciences and Technology, University of Coimbra, Coimbra 3004-535, Portugal.
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8
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Guo H, Malone KE, Heckbert SR, Li CI. Statin use and risks of breast cancer recurrence and mortality. Cancer 2024; 130:3106-3114. [PMID: 38709898 DOI: 10.1002/cncr.35362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Revised: 04/05/2024] [Accepted: 04/23/2024] [Indexed: 05/08/2024]
Abstract
BACKGROUND Preclinical evidence suggests improved breast cancer survival associated with statin use, but findings from observational studies are conflicting and remain inconclusive. The objective of this study was to assess the association between statin use after cancer diagnosis and cancer outcomes among breast cancer patients. METHODS In this retrospective cohort study, 38,858 women aged ≥66 years who were diagnosed with localized and regional stage breast cancer from 2008 through 2017 were identified from the linked Surveillance, Epidemiology, and End Results Medicare database. Statin use was ascertained from Medicare Part D pharmacy claims data. Multivariable Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between post-diagnosis statin use and risks of breast cancer recurrence and breast cancer-specific mortality. RESULTS Over a median follow-up of 2.9 years for recurrence and 3.7 years for mortality, 1446 women experienced a recurrence, and 2215 died from breast cancer. The mean duration of post-diagnosis statin use was 2.2 years. Statin use post-diagnosis was not associated with recurrence risk (HR, 1.05; 95% CI, 0.91-1.21), but was associated with a reduced risk of cancer-specific mortality (HR, 0.85; 95% CI, 0.75-0.96). The reduction was more pronounced in women with hormone receptor-positive/human epidermal growth factor receptor 2-negative breast cancer (HR, 0.71; 95% CI, 0.57-0.88). CONCLUSIONS These findings suggest that post-diagnosis statin use is associated with improved cancer-specific survival in women with breast cancer and should be confirmed in randomized trials of statin therapy in breast cancer patients.
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Affiliation(s)
- Hanbing Guo
- Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, Washington, USA
- Department of Epidemiology, University of Washington, Seattle, Washington, USA
| | - Kathleen E Malone
- Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, Washington, USA
- Department of Epidemiology, University of Washington, Seattle, Washington, USA
| | - Susan R Heckbert
- Department of Epidemiology, University of Washington, Seattle, Washington, USA
| | - Christopher I Li
- Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, Washington, USA
- Department of Epidemiology, University of Washington, Seattle, Washington, USA
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9
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Kamal A, Boerner J, Assad H, Chen W, Simon MS. The Effect of Statins on Markers of Breast Cancer Proliferation and Apoptosis in Women with In Situ or Early-Stage Invasive Breast Cancer. Int J Mol Sci 2024; 25:9587. [PMID: 39273534 PMCID: PMC11395452 DOI: 10.3390/ijms25179587] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Revised: 08/20/2024] [Accepted: 08/27/2024] [Indexed: 09/15/2024] Open
Abstract
Statins, inhibitors of HMG-CoA reductase, have been shown to have potential anti-carcinogenic effects through the inhibition of the mevalonate pathway and their impact on Ras and RhoGTAases. Prior studies have demonstrated a reduction in breast tumor proliferation, as well as increased apoptosis, among women with early-stage breast cancer who received statins between the time of diagnosis and the time of surgery. The aim of this study was to evaluate the impact of short-term oral high-potency statin therapy on the expression of markers of breast tumor proliferation, apoptosis, and cell cycle arrest in a window-of-opportunity trial. This single-arm study enrolled 24 women with stage 0-II invasive breast cancer who were administered daily simvastatin (20 mg) for 2-4 weeks between diagnosis and surgical resection. Pre- and post-treatment tumor samples were analyzed for fold changes in Ki-67, cyclin D1, p27, and cleaved caspase-3 (CC3) expression. Out of 24 enrolled participants, 18 received statin treatment and 17 were evaluable for changes in marker expression. There was no significant change in Ki-67 expression (fold change = 1.4, p = 0.597). There were, however, significant increases in the expression of cyclin D1 (fold change = 2.8, p = 0.0003), p27 cytoplasmic (fold change = 3.2, p = 0.025), and CC3 (fold change = 2.1, p = 0.016). Statin treatment was well tolerated, with two reported grade-1 adverse events. These results align with previous window-of-opportunity studies suggesting a pro-apoptotic role of statins in breast cancer. The increased expression of markers of cell cycle arrest and apoptosis seen in this window-of-opportunity study supports further investigation into the anti-cancer properties of statins in larger-scale clinical trials.
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Affiliation(s)
- Anam Kamal
- Ascension Providence Hospital, Michigan State University, Southfield, MI 48075, USA
| | - Julie Boerner
- Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA
| | - Hadeel Assad
- Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA
| | - Wei Chen
- Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA
| | - Michael S Simon
- Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA
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10
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Buccioli G, Testa C, Jacchetti E, Pinoli P, Carelli S, Ceri S, Raimondi MT. The molecular basis of the anticancer effect of statins. Sci Rep 2024; 14:20298. [PMID: 39217242 PMCID: PMC11365972 DOI: 10.1038/s41598-024-71240-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Accepted: 08/26/2024] [Indexed: 09/04/2024] Open
Abstract
Statins, widely used cardiovascular drugs that lower cholesterol by inhibiting HMG-CoA reductase, have been increasingly recognized for their potential anticancer properties. This study elucidates the underlying mechanism, revealing that statins exploit Synthetic Lethality, a principle where the co-occurrence of two non-lethal events leads to cell death. Our computational analysis of approximately 37,000 SL pairs identified statins as potential drugs targeting genes involved in SL pairs with metastatic genes. In vitro validation on various cancer cell lines confirmed the anticancer efficacy of statins. This data-driven drug repurposing strategy provides a molecular basis for the anticancer effects of statins, offering translational opportunities in oncology.
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Affiliation(s)
- Giovanni Buccioli
- Department of Chemistry, Materials and Chemical Engineering "Giulio Natta", Politecnico di Milano, Milan, Italy
| | - Carolina Testa
- Department of Chemistry, Materials and Chemical Engineering "Giulio Natta", Politecnico di Milano, Milan, Italy
| | - Emanuela Jacchetti
- Department of Chemistry, Materials and Chemical Engineering "Giulio Natta", Politecnico di Milano, Milan, Italy
| | - Pietro Pinoli
- Department of Electronics, Information and Bioengineering, Politecnico di Milano, Milan, Italy
| | - Stephana Carelli
- Center of Functional Genomics and Rare Diseases, Buzzi Children's Hospital, Milan, Italy
| | - Stefano Ceri
- Department of Electronics, Information and Bioengineering, Politecnico di Milano, Milan, Italy.
| | - Manuela T Raimondi
- Department of Chemistry, Materials and Chemical Engineering "Giulio Natta", Politecnico di Milano, Milan, Italy.
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11
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Chen YH, Wu JX, Yang SF, Wu YC, Hsiao YH. Molecular Mechanisms Underlying the Anticancer Properties of Pitavastatin against Cervical Cancer Cells. Int J Mol Sci 2024; 25:7915. [PMID: 39063157 PMCID: PMC11277542 DOI: 10.3390/ijms25147915] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Revised: 06/27/2024] [Accepted: 07/10/2024] [Indexed: 07/28/2024] Open
Abstract
Cervical cancer ranks as the fourth most prevalent form of cancer and is a significant contributor to female mortality on a global scale. Pitavastatin is an anti-hyperlipidemic medication and has been demonstrated to exert anticancer and anti-inflammatory effects. Thus, the purpose of this study was to evaluate the anticancer effect of pitavastatin on cervical cancer and the underlying molecular mechanisms involved. The results showed that pitavastatin significantly inhibited cell viability by targeting cell-cycle arrest and apoptosis in Ca Ski, HeLa and C-33 A cells. Pitavastatin caused sub-G1- and G0/G1-phase arrest in Ca Ski and HeLa cells and sub-G1- and G2/M-phase arrest in C-33 A cells. Moreover, pitavastatin induced apoptosis via the activation of poly-ADP-ribose polymerase (PARP), Bax and cleaved caspase 3; inactivated the expression of Bcl-2; and increased mitochondrial membrane depolarization. Furthermore, pitavastatin induced apoptosis and slowed the migration of all three cervical cell lines, mediated by the PI3K/AKT and MAPK (JNK, p38 and ERK1/2) pathways. Pitavastatin markedly inhibited tumor growth in vivo in a cancer cell-originated xenograft mouse model. Overall, our results identified pitavastatin as an anticancer agent for cervical cancer, which might be expanded to clinical use in the future.
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Affiliation(s)
- Ya-Hui Chen
- Women’s Health Research Laboratory, Changhua Christian Hospital, Changhua 50006, Taiwan; (Y.-H.C.); (J.-X.W.)
- Institute of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan;
| | - Jyun-Xue Wu
- Women’s Health Research Laboratory, Changhua Christian Hospital, Changhua 50006, Taiwan; (Y.-H.C.); (J.-X.W.)
| | - Shun-Fa Yang
- Institute of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan;
- Department of Medical Research, Chung Shan Medical University Hospital, Taichung 40201, Taiwan
| | - Yun-Chia Wu
- Department of Obstetrics and Gynecology, Changhua Christian Hospital, Changhua 50006, Taiwan;
| | - Yi-Hsuan Hsiao
- Women’s Health Research Laboratory, Changhua Christian Hospital, Changhua 50006, Taiwan; (Y.-H.C.); (J.-X.W.)
- Institute of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan;
- Department of Obstetrics and Gynecology, Changhua Christian Hospital, Changhua 50006, Taiwan;
- School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan
- College of Medicine, Kaohsiung Medical University, Kaohsiung 807378, Taiwan
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung 40227, Taiwan
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Kounatidis D, Tentolouris N, Vallianou NG, Mourouzis I, Karampela I, Stratigou T, Rebelos E, Kouveletsou M, Stamatopoulos V, Tsaroucha E, Dalamaga M. The Pleiotropic Effects of Lipid-Modifying Interventions: Exploring Traditional and Emerging Hypolipidemic Therapies. Metabolites 2024; 14:388. [PMID: 39057711 PMCID: PMC11278853 DOI: 10.3390/metabo14070388] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Revised: 07/14/2024] [Accepted: 07/15/2024] [Indexed: 07/28/2024] Open
Abstract
Atherosclerotic cardiovascular disease poses a significant global health issue, with dyslipidemia standing out as a major risk factor. In recent decades, lipid-lowering therapies have evolved significantly, with statins emerging as the cornerstone treatment. These interventions play a crucial role in both primary and secondary prevention by effectively reducing cardiovascular risk through lipid profile enhancements. Beyond their primary lipid-lowering effects, extensive research indicates that these therapies exhibit pleiotropic actions, offering additional health benefits. These include anti-inflammatory properties, improvements in vascular health and glucose metabolism, and potential implications in cancer management. While statins and ezetimibe have been extensively studied, newer lipid-lowering agents also demonstrate similar pleiotropic effects, even in the absence of direct cardiovascular benefits. This narrative review explores the diverse pleiotropic properties of lipid-modifying therapies, emphasizing their non-lipid effects that contribute to reducing cardiovascular burden and exploring emerging benefits for non-cardiovascular conditions. Mechanistic insights into these actions are discussed alongside their potential therapeutic implications.
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Affiliation(s)
- Dimitris Kounatidis
- Diabetes Center, First Department of Propaedeutic Internal Medicine, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (D.K.); (N.T.); (E.R.); (M.K.)
| | - Nikolaos Tentolouris
- Diabetes Center, First Department of Propaedeutic Internal Medicine, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (D.K.); (N.T.); (E.R.); (M.K.)
| | - Natalia G. Vallianou
- First Department of Internal Medicine, Sismanogleio General Hospital, 15126 Athens, Greece;
| | - Iordanis Mourouzis
- Department of Pharmacology, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Irene Karampela
- Second Department of Critical Care, Attikon General University Hospital, Medical School, National and Kapodistrian University of Athens, 12462 Athens, Greece;
| | - Theodora Stratigou
- Department of Endocrinology and Metabolism, Evangelismos General Hospital, 10676 Athens, Greece;
| | - Eleni Rebelos
- Diabetes Center, First Department of Propaedeutic Internal Medicine, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (D.K.); (N.T.); (E.R.); (M.K.)
| | - Marina Kouveletsou
- Diabetes Center, First Department of Propaedeutic Internal Medicine, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (D.K.); (N.T.); (E.R.); (M.K.)
| | | | - Eleni Tsaroucha
- First Department of Internal Medicine, Sismanogleio General Hospital, 15126 Athens, Greece;
| | - Maria Dalamaga
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
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13
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He L, Ioannidis A, Hoffman CJ, Arambula E, Joshi P, Whitelegge J, Liau LM, Kornblum HI, Pajonk F. Activation of the Mevalonate Pathway in Response to Anti-cancer Treatments Drives Glioblastoma Recurrences Through Activation of Rac-1. CANCER RESEARCH COMMUNICATIONS 2024; 4:1566-1580. [PMID: 38837899 PMCID: PMC11197925 DOI: 10.1158/2767-9764.crc-24-0049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 03/26/2024] [Accepted: 05/31/2024] [Indexed: 06/07/2024]
Abstract
Glioblastoma (GBM) is the deadliest adult brain cancer. Under the current standard of care, almost all patients succumb to the disease and novel treatments are urgently needed. Recognizing that GBMs are addicted to cholesterol, past clinical trials have repurposed statins against GBM but failed. The purpose of this study was to test whether treatments that upregulate the cholesterol biosynthesis pathway in GBM would generate a metabolic vulnerability that can be exploited using statins and to determine the underlying mechanisms.Effects of radiotherapy and temozolomide or dopamine receptor antagonists on the mevalonate pathway in GBM were assessed in vitro and in vivo. The impact of statins on self-renewal of glioma stem cells and median survival was studied. Branches of the mevalonate pathway were probed to identify relevant effector proteins.Cells surviving combination treatments that converge in activating the immediate early response, universally upregulated the mevalonate pathway and increased stemness of GBM cells through activation of the Rho-GTPase Rac-1. Activation of the mevalonate pathway and Rac-1 was inhibited by statins, which led to improved survival in mouse models of glioblastoma when combined with radiation and drugs that target the glioma stem cell pool and plasticity of glioma cells.We conclude that a combination of dopamine receptor antagonists and statins could potentially improve radiotherapy outcome and warrants further investigation. SIGNIFICANCE Combination therapies that activate the mevalonate pathway in GBM cells after sublethal treatment enhance self-renewal and migratory capacity through Rac-1 activation, which creates a metabolic vulnerability that can be further potentially exploited using statins.
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Affiliation(s)
- Ling He
- Department of Radiation Oncology, David Geffen School of Medicine at UCLA, Los Angeles, California
- Jonsson Comprehensive Cancer Center at UCLA, Los Angeles, California
| | - Angeliki Ioannidis
- Department of Radiation Oncology, David Geffen School of Medicine at UCLA, Los Angeles, California
| | - Carter J. Hoffman
- Department of Radiation Oncology, David Geffen School of Medicine at UCLA, Los Angeles, California
| | - Evelyn Arambula
- Department of Radiation Oncology, David Geffen School of Medicine at UCLA, Los Angeles, California
| | - Purva Joshi
- Department of Radiation Oncology, David Geffen School of Medicine at UCLA, Los Angeles, California
| | - Julian Whitelegge
- Jonsson Comprehensive Cancer Center at UCLA, Los Angeles, California
- Department of Psychiatry and Human Behavior, David Geffen School of Medicine at UCLA, Los Angeles, California
| | - Linda M. Liau
- Jonsson Comprehensive Cancer Center at UCLA, Los Angeles, California
- Department of Neurosurgery, David Geffen School of Medicine at UCLA, Los Angeles, California
| | - Harley I. Kornblum
- Jonsson Comprehensive Cancer Center at UCLA, Los Angeles, California
- Department of Psychiatry and Human Behavior, David Geffen School of Medicine at UCLA, Los Angeles, California
| | - Frank Pajonk
- Department of Radiation Oncology, David Geffen School of Medicine at UCLA, Los Angeles, California
- Jonsson Comprehensive Cancer Center at UCLA, Los Angeles, California
- Department of Neurosurgery, David Geffen School of Medicine at UCLA, Los Angeles, California
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14
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Park JH, Hothi P, de Lomana ALG, Pan M, Calder R, Turkarslan S, Wu WJ, Lee H, Patel AP, Cobbs C, Huang S, Baliga NS. Gene regulatory network topology governs resistance and treatment escape in glioma stem-like cells. SCIENCE ADVANCES 2024; 10:eadj7706. [PMID: 38848360 PMCID: PMC11160475 DOI: 10.1126/sciadv.adj7706] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Accepted: 05/03/2024] [Indexed: 06/09/2024]
Abstract
Poor prognosis and drug resistance in glioblastoma (GBM) can result from cellular heterogeneity and treatment-induced shifts in phenotypic states of tumor cells, including dedifferentiation into glioma stem-like cells (GSCs). This rare tumorigenic cell subpopulation resists temozolomide, undergoes proneural-to-mesenchymal transition (PMT) to evade therapy, and drives recurrence. Through inference of transcriptional regulatory networks (TRNs) of patient-derived GSCs (PD-GSCs) at single-cell resolution, we demonstrate how the topology of transcription factor interaction networks drives distinct trajectories of cell-state transitions in PD-GSCs resistant or susceptible to cytotoxic drug treatment. By experimentally testing predictions based on TRN simulations, we show that drug treatment drives surviving PD-GSCs along a trajectory of intermediate states, exposing vulnerability to potentiated killing by siRNA or a second drug targeting treatment-induced transcriptional programs governing nongenetic cell plasticity. Our findings demonstrate an approach to uncover TRN topology and use it to rationally predict combinatorial treatments that disrupt acquired resistance in GBM.
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Affiliation(s)
| | - Parvinder Hothi
- Ivy Center for Advanced Brain Tumor Treatment, Swedish Neuroscience Institute, Seattle, WA, USA
| | | | - Min Pan
- Institute for Systems Biology, Seattle, WA, USA
| | | | | | - Wei-Ju Wu
- Institute for Systems Biology, Seattle, WA, USA
| | - Hwahyung Lee
- Ivy Center for Advanced Brain Tumor Treatment, Swedish Neuroscience Institute, Seattle, WA, USA
| | - Anoop P. Patel
- Department of Neurosurgery, Preston Robert Tisch Brain Tumor Center, Duke University, Durham, NC, USA
- Center for Advanced Genomic Technologies, Duke University, Durham, NC, USA
| | - Charles Cobbs
- Ivy Center for Advanced Brain Tumor Treatment, Swedish Neuroscience Institute, Seattle, WA, USA
| | - Sui Huang
- Institute for Systems Biology, Seattle, WA, USA
| | - Nitin S. Baliga
- Institute for Systems Biology, Seattle, WA, USA
- Departments of Microbiology, Biology, and Molecular Engineering Sciences, University of Washington, Seattle, WA, USA
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15
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Matsukawa A, Yanagisawa T, Bekku K, Parizi MK, Laukhtina E, Klemm J, Chiujdea S, Mori K, Kimura S, Miki J, Pradere B, Rivas JG, Gandaglia G, Kimura T, Kasivisvanathan V, Ploussard G, Cornford P, Shariat SF, Rajwa P. Nonsurgical Interventions to Prevent Disease Progression in Prostate Cancer Patients on Active Surveillance: A Systematic Review and Meta-analysis. Eur Urol Oncol 2024; 7:376-400. [PMID: 38277189 DOI: 10.1016/j.euo.2023.10.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Revised: 09/17/2023] [Accepted: 10/10/2023] [Indexed: 01/27/2024]
Abstract
CONTEXT Active surveillance (AS) is a standard of care for patients with low-risk and selected intermediate-risk prostate cancer (PCa). Nevertheless, there is a lack of summary evidence on how to impact disease trajectory during AS. OBJECTIVE To assess which interventions prevent PCa progression effectively during AS. EVIDENCE ACQUISITION We queried PubMed, Scopus, and Web of Science databases to identify studies examining the impact of interventions aimed at slowing disease progression during AS. The primary endpoint was PCa progression, the definition of which must have included pathological upgrading. The secondary endpoint included treatment toxicities. EVIDENCE SYNTHESIS We identified 22 studies, six randomized controlled trials and 16 observational studies, which analyzed the association between different interventions and PCa progression during AS. The interventions considered in the studies included 5-alpha reductase inhibitors (5-ARIs), statins, diet, exercise, chlormadinone, fexapotide triflutate (FT), enzalutamide, coffee, vitamin D3, and PROSTVAC. We found that administration of 5-ARIs was associated with improved progression-free survival (PFS; hazard ratio: 0.59; 95% confidence interval 0.48-0.72), with no increased toxicity signals. Therapies such as vitamin D3, chlormadinone, FT, and enzalutamide have shown some efficacy. However, these anticancer drugs have been associated with treatment-related adverse events in up to 88% of patients. CONCLUSIONS The use of 5-ARIs in PCa patients on AS is associated with longer PFS. However, for the other interventions, it is difficult to draw clear conclusions based on the weak available evidence. PATIENT SUMMARY Patients with prostate cancer managed with active surveillance (AS) who are treated with 5-alpha reductase inhibitors have a lower risk of disease progression, with minimal adverse events. Other interventions require more studies to determine their efficacy and safety profile in men on AS.
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Affiliation(s)
- Akihiro Matsukawa
- Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; Department of Urology, The Jikei University School of Medicine, Tokyo, Japan
| | - Takafumi Yanagisawa
- Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; Department of Urology, The Jikei University School of Medicine, Tokyo, Japan
| | - Kensuke Bekku
- Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Mehdi Kardoust Parizi
- Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; Department of Urology, Shariati Hospital, Tehran University of Medical Science, Tehran, Iran
| | - Ekaterina Laukhtina
- Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; Institute for Urology and Reproductive Health, Sechenov University, Moscow, Russia
| | - Jakob Klemm
- Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; Department of Urology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Sever Chiujdea
- Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; Department of Urology, Spitalul Clinic Judetean Murures, University of Medicine, Pharmacy, Science, and Technology of Targu Mures, Mures, Romania
| | - Keiichiro Mori
- Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; Department of Urology, The Jikei University School of Medicine, Tokyo, Japan
| | - Shoji Kimura
- Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; Department of Urology, The Jikei University School of Medicine, Tokyo, Japan
| | - Jun Miki
- Department of Urology, The Jikei University School of Medicine, Tokyo, Japan
| | - Benjamin Pradere
- Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; Department of Urology, La Croix Du Sud Hospital, Quint Fonsegrives, France
| | - Juan Gomez Rivas
- Department of Urology, Clinico San Carlos Hospital, Madrid, Spain
| | | | - Takahiro Kimura
- Department of Urology, The Jikei University School of Medicine, Tokyo, Japan
| | - Veeru Kasivisvanathan
- Department of Urology, University College London Hospital NHS Foundation Trust, London, UK; Division of Surgery and Interventional Science, University College London, London, UK
| | | | - Philip Cornford
- Department of Urology, Liverpool University Hospitals, Liverpool, UK
| | - Shahrokh F Shariat
- Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; Institute for Urology and Reproductive Health, Sechenov University, Moscow, Russia; Hourani Center for Applied Scientific Research, Al-Ahliyya Amman University, Amman, Jordan; Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Urology, Second Faculty of Medicine, Charles University, Prague, Czech Republic; Department of Urology, Weill Cornell Medical College, New York, NY, USA; Karl Landsteiner Institute of Urology and Andrology, Vienna, Austria.
| | - Pawel Rajwa
- Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; Department of Urology, Medical University of Silesia, Zabrze, Poland
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16
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Jaiswal V, Ang SP, Deb N, Hanif M, Batra N, Kanagala SG, Vojjala N, Rajak K, Roy P, Sharath M, Waleed MS, Wajid Z, Mattumpuram J. Association between Statin Use and Chemotherapy-Induced Cardiotoxicity: A Meta-Analysis. MEDICINA (KAUNAS, LITHUANIA) 2024; 60:580. [PMID: 38674227 PMCID: PMC11052115 DOI: 10.3390/medicina60040580] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Accepted: 03/08/2024] [Indexed: 04/28/2024]
Abstract
Background: Chemotherapy-induced cardiac dysfunction (CIC) is a significant and concerning complication observed among cancer patients. Despite the demonstrated cardioprotective benefits of statins in various cardiovascular diseases, their effectiveness in mitigating CIC remains uncertain. Objective: This meta-analysis aims to comprehensively evaluate the potential cardioprotective role of statins in patients with CIC. Methods: A systematic literature search was conducted using PubMed, Embase, and Scopus databases to identify relevant articles published from inception until 10th May 2023. The outcomes were assessed using pooled odds ratio (OR) for categorical data and mean difference (MD) for continuous data, with corresponding 95% confidence intervals (95% CIs). Results: This meta-analysis comprised nine studies involving a total of 5532 patients, with 1904 in the statin group and 3628 in the non-statin group. The pooled analysis of primary outcome shows that patients who did not receive statin suffer a greater decline in the LVEF after chemotherapy compared to those who receive statin (MD, 3.55 (95% CI: 1.04-6.05), p = 0.01). Likewise, we observed a significantly higher final mean LVEF among chemotherapy patients with statin compared to the non-statin group of patients (MD, 2.08 (95% CI: 0.86-3.30), p > 0.001). Additionally, there was a lower risk of incident heart failure in the statin group compared to the non-statin group of patients (OR, 0.41 (95% CI: 0.27-0.62), p < 0.001). Lastly, the change in the mean difference for LVEDV was not statistically significant between the statin and non-statin groups (MD, 1.55 (95% CI: -5.22-8.33), p = 0.65). Conclusion: Among patients of CIC, statin use has shown cardioprotective benefits by improving left ventricular function and reducing the risk of heart failure.
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Affiliation(s)
- Vikash Jaiswal
- Department of Cardiovascular Research, Larkin Community Hospital, South Miami, FL 33143, USA
| | - Song Peng Ang
- Department of Internal Medicine, Rutgers Health/Community Medical Center, Toms River, NJ 08755, USA
| | - Novonil Deb
- North Bengal Medical College and Hospital, Darjeeling 734012, West Bengal, India
| | - Muhammad Hanif
- Department of Internal Medicine, SUNY Upstate Medical University, 750 E Adams St., Syracuse, NY 13210, USA
| | - Nitya Batra
- Department of Internal Medicine, Beaumont Hospital, Royal Oak, MI 48073, USA
| | - Sai Gautham Kanagala
- Department of Internal Medicine, Metropolitan Hospital Center, New York, NY 10029, USA
| | - Nikhil Vojjala
- Internal Medicine Department, Trinity Health Oakland/Wayne State University, Detroit, MI 48341, USA
| | - Kripa Rajak
- Department of Internal Medicine, UPMC Harrisburgh, 111 S Front St., Harrisburg, PA 17101, USA
| | - Poulami Roy
- North Bengal Medical College and Hospital, Darjeeling 734012, West Bengal, India
| | - Medha Sharath
- Bangalore Medical College and Research Institute, Kalasipalya, Bengaluru 560002, Karnataka, India
| | - Madeeha Subhan Waleed
- Department of Internal Medicine, Lower Bucks Hospital, Bristo, 501 Bath Rd., Bristol, PA 19007, USA
| | - Zarghoona Wajid
- Department of Internal Medicine, Wayne State University School of Medicine, 540 E. Canfield Ave., Detroit, MI 48201, USA
| | - Jishanth Mattumpuram
- Division of Cardiology, Department of Medicine, University of Louisville School of Medicine, Louisville, KY 40202, USA
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17
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Ishikawa T, Irie N, Tashiro J, Osaki T, Warita T, Warita K, Naito M. Comparison of the anticancer effects of various statins on canine oral melanoma cells. Vet Comp Oncol 2024; 22:156-161. [PMID: 38044042 DOI: 10.1111/vco.12946] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2023] [Revised: 10/29/2023] [Accepted: 11/17/2023] [Indexed: 12/05/2023]
Abstract
Canine oral melanoma is a highly malignant cancer with a poor prognosis. Statins, commonly used drugs for treating dyslipidemia, exhibit pleiotropic anticancer effects and marked anti-proliferative effects against melanoma cells. The anticancer effects among statins vary; in human cancers, lipophilic statins have shown stronger anticancer effects compared with hydrophilic statins. However, data on the differences in the effects of various statins on canine cancer cells are lacking, hence the optimal statins for treating canine melanoma remain unknown. Therefore, this study aimed to clarify the most effective statin by comparing the anticancer effects of hydrophilic rosuvastatin and lipophilic atorvastatin, simvastatin, fluvastatin and pitavastatin on three canine oral melanoma cell lines. Time-dependent measurement of cell confluence showed that lipophilic statins had a stronger anti-proliferative effect on all cell lines than hydrophilic rosuvastatin. Quantification of lactate dehydrogenase release, an indicator of cytotoxicity, showed that lipophilic statins more effectively induced cell death than hydrophilic rosuvastatin. Lipophilic statins affected both inhibition of cell proliferation and induction of cell death. The anticancer effects of statins on canine oral melanoma cells differed in the following ascending order of IC50 values: pitavastatin < fluvastatin = simvastatin < atorvastatin < rosuvastatin. The required concentration of pitavastatin was approximately 1/20th that of rosuvastatin. Among the statins used in this study, pitavastatin had the highest anticancer effect. Our results suggest lipophilic pitavastatin as the optimal statin for treating canine oral melanoma.
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Affiliation(s)
- Takuro Ishikawa
- Department of Anatomy, School of Medicine, Aichi Medical University, Nagakute, Aichi, Japan
| | - Nanami Irie
- Graduate School of Science and Technology, Kwansei Gakuin University, Sanda, Hyogo, Japan
| | - Jiro Tashiro
- Department of Veterinary Anatomy, School of Veterinary Medicine, Tottori University, Tottori, Japan
| | - Tomohiro Osaki
- Department of Veterinary Clinical Medicine, School of Veterinary Medicine, Tottori University, Tottori, Japan
| | - Tomoko Warita
- Graduate School of Science and Technology, Kwansei Gakuin University, Sanda, Hyogo, Japan
| | - Katsuhiko Warita
- Department of Veterinary Anatomy, School of Veterinary Medicine, Tottori University, Tottori, Japan
| | - Munekazu Naito
- Department of Anatomy, School of Medicine, Aichi Medical University, Nagakute, Aichi, Japan
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18
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Park JH, Hothi P, Lopez Garcia de Lomana A, Pan M, Calder R, Turkarslan S, Wu WJ, Lee H, Patel AP, Cobbs C, Huang S, Baliga NS. Gene regulatory network topology governs resistance and treatment escape in glioma stem-like cells. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.02.02.578510. [PMID: 38370784 PMCID: PMC10871280 DOI: 10.1101/2024.02.02.578510] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/20/2024]
Abstract
Poor prognosis and drug resistance in glioblastoma (GBM) can result from cellular heterogeneity and treatment-induced shifts in phenotypic states of tumor cells, including dedifferentiation into glioma stem-like cells (GSCs). This rare tumorigenic cell subpopulation resists temozolomide, undergoes proneural-to-mesenchymal transition (PMT) to evade therapy, and drives recurrence. Through inference of transcriptional regulatory networks (TRNs) of patient-derived GSCs (PD-GSCs) at single-cell resolution, we demonstrate how the topology of transcription factor interaction networks drives distinct trajectories of cell state transitions in PD-GSCs resistant or susceptible to cytotoxic drug treatment. By experimentally testing predictions based on TRN simulations, we show that drug treatment drives surviving PD-GSCs along a trajectory of intermediate states, exposing vulnerability to potentiated killing by siRNA or a second drug targeting treatment-induced transcriptional programs governing non-genetic cell plasticity. Our findings demonstrate an approach to uncover TRN topology and use it to rationally predict combinatorial treatments that disrupts acquired resistance in GBM.
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Affiliation(s)
| | - Parvinder Hothi
- Ivy Center for Advanced Brain Tumor Treatment, Swedish Neuroscience Institute, Seattle, WA
| | | | - Min Pan
- Institute for Systems Biology, Seattle, WA
| | | | | | - Wei-Ju Wu
- Institute for Systems Biology, Seattle, WA
| | - Hwahyung Lee
- Ivy Center for Advanced Brain Tumor Treatment, Swedish Neuroscience Institute, Seattle, WA
| | - Anoop P Patel
- Department of Neurosurgery, Preston Robert Tisch Brain Tumor Center, Duke University, Durham, NC
- Center for Advanced Genomic Technologies, Duke University, Durham, NC
| | - Charles Cobbs
- Ivy Center for Advanced Brain Tumor Treatment, Swedish Neuroscience Institute, Seattle, WA
| | - Sui Huang
- Institute for Systems Biology, Seattle, WA
| | - Nitin S Baliga
- Institute for Systems Biology, Seattle, WA
- Departments of Microbiology, Biology, and Molecular Engineering Sciences, University of Washington, Seattle, WA
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19
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Zhang X, Lou D, Fu R, Wu F, Zheng D, Ma X. Association between Statins Types with Incidence of Liver Cancer: An Updated Meta-analysis. Curr Med Chem 2024; 31:762-775. [PMID: 37393552 PMCID: PMC10661961 DOI: 10.2174/0929867330666230701000400] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Revised: 03/21/2023] [Accepted: 04/23/2023] [Indexed: 07/04/2023]
Abstract
BACKGROUND Previous studies have found a potential role for statins in liver cancer prevention. OBJECTIVE This study aimed to explore the effect of different types of statins on the incidence of liver cancer. METHODS Relevant articles were systematically retrieved from PubMed, EBSCO, Web of Science, and Cochrane Library databases from inception until July 2022 to explore the relationship between lipophilic statins or hydrophilic statins exposure and the incidence of liver cancer. The main outcome was the incidence of liver cancer. RESULTS Eleven articles were included in this meta-analysis. The pooled results showed a reduced incidence of liver cancer in patients exposed to lipophilic statins (OR=0.54, p < 0.001) and hydrophilic statins (OR=0.56, p < 0.001) compared with the non-exposed cohort. Subgroup analysis showed that both exposures to lipophilic (Eastern countries: OR=0.51, p < 0.001; Western countries: OR=0.59, p < 0.001) and hydrophilic (Eastern countries: OR=0.51, p < 0.001; Western countries: OR=0.66, p=0.019) statins reduced the incidence of liver cancer in Eastern and Western countries, and the reduction was most significant in Eastern countries. Moreover, atorvastatin (OR=0.55, p < 0.001), simvastatin (OR=0.59, p < 0.001), lovastatin (OR=0.51, p < 0.001), pitavastatin (OR=0.36, p=0.008) and rosuvastatin (OR=0.60, p=0.027) could effectively reduce the incidence of liver cancer, unlike fluvastatin, cerivastatin and pravastatin. CONCLUSION Both lipophilic and hydrophilic statins contribute to the prevention of liver cancer. Moreover, the efficacy was influenced by the region and the specific type of statins used.
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Affiliation(s)
- Xingfen Zhang
- Department of Liver Disease, Ningbo No. 2 Hospital, Ningbo, Zhejiang, China
- Key Laboratory of Diagnosis and Treatment of Digestive System Tumors of Zhejiang Province, Ningbo No. 2 Hospital, Ningbo, Zhejiang, China
| | - Dandi Lou
- The First Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Rongrong Fu
- The First Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Feng Wu
- Department of General Surgery, Ningbo No. 2 Hospital, Ningbo, Zhejiang, China
| | - Dingcheng Zheng
- Department of General Surgery, Ningbo No. 2 Hospital, Ningbo, Zhejiang, China
| | - Xueqiang Ma
- Department of Hepatobiliary Surgery, Zhuji People's Hospital, Shaoxing, Zhejiang, China
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20
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Tashiro J, Warita T, Sugiura A, Mizoguchi K, Ishikawa T, Warita K. Exploration of Novel Metabolic Features Reflecting Statin Sensitivity in Lung Cancer Cells. Biol Pharm Bull 2024; 47:1992-2002. [PMID: 39647902 DOI: 10.1248/bpb.b24-00346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/10/2024]
Abstract
Statins are cholesterol-lowering drugs often used for the treatment of dyslipidemia. Statins also exert anti-cancer effects by inhibiting hydroxymethylglutaryl-CoA reductase (HMGCR), a rate-limiting enzyme in cholesterol synthesis. We previously reported that the susceptibility to statin treatment differs among cancer cells and that functional E-cadherin expression on the plasma membrane could be a biomarker of statin sensitivity in cancer cells. However, the detailed qualitative and molecular differences between statin-sensitive and statin-resistant cancer cells remain unclear. Here, we explored novel parameters related to statin sensitivity by comparing gene expression profiles and metabolite contents between statin-sensitive and statin-resistant lung cancer cell lines. We found that the expression of most cholesterol synthesis genes was lower in the statin-sensitive cancer cell line, HOP-92, than in the statin-resistant cancer cell line, NCI-H322M. Moreover, HOP-92 cells originally exhibited lower levels of CoA and HMG-CoA. Additionally, atorvastatin decreased the mRNA expression of PANK2, a rate-limiting enzyme in CoA synthesis. Atorvastatin also reduced the mRNA levels of the cholesterol esterification enzyme SOAT1, which was consistent with a decrease in the ratio of cholesterol ester to total cholesterol in HOP-92 cells. Our data suggest that the cholesterol synthetic flow and CoA content may be limited in statin-sensitive cancer cells. We also suggest that CoA synthesis and cholesterol storage may fluctuate with atorvastatin treatment in statin-sensitive cancer cells.
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Affiliation(s)
- Jiro Tashiro
- Department of Veterinary Anatomy, School of Veterinary Medicine, Tottori University
| | - Tomoko Warita
- Department of Biomedical Sciences, School of Biological and Environmental Sciences, Kwansei Gakuin University
| | - Akihiro Sugiura
- Department of Veterinary Anatomy, School of Veterinary Medicine, Tottori University
| | - Kana Mizoguchi
- Graduate School of Science and Technology, Kwansei Gakuin University
| | - Takuro Ishikawa
- Department of Veterinary Anatomy, School of Veterinary Medicine, Tottori University
| | - Katsuhiko Warita
- Department of Veterinary Anatomy, School of Veterinary Medicine, Tottori University
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21
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Zhai Y, Du Y, Li G, Yu M, Hu H, Pan C, Wang D, Shi Z, Yan X, Li X, Jiang T, Zhang W. Trogocytosis of CAR molecule regulates CAR-T cell dysfunction and tumor antigen escape. Signal Transduct Target Ther 2023; 8:457. [PMID: 38143263 PMCID: PMC10749292 DOI: 10.1038/s41392-023-01708-w] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Revised: 10/19/2023] [Accepted: 11/15/2023] [Indexed: 12/26/2023] Open
Abstract
Chimeric antigen receptor (CAR) T-cell therapy has demonstrated clinical response in treating both hematologic malignancies and solid tumors. Although instances of rapid tumor remissions have been observed in animal models and clinical trials, tumor relapses occur with multiple therapeutic resistance mechanisms. Furthermore, while the mechanisms underlying the long-term therapeutic resistance are well-known, short-term adaptation remains less understood. However, more views shed light on short-term adaptation and hold that it provides an opportunity window for long-term resistance. In this study, we explore a previously unreported mechanism in which tumor cells employ trogocytosis to acquire CAR molecules from CAR-T cells, a reversal of previously documented processes. This mechanism results in the depletion of CAR molecules and subsequent CAR-T cell dysfunction, also leading to short-term antigen loss and antigen masking. Such type of intercellular communication is independent of CAR downstream signaling, CAR-T cell condition, target antigen, and tumor cell type. However, it is mainly dependent on antigen density and CAR sensitivity, and is associated with tumor cell cholesterol metabolism. Partial mitigation of this trogocytosis-induced CAR molecule transfer can be achieved by adaptively administering CAR-T cells with antigen density-individualized CAR sensitivities. Together, our study reveals a dynamic process of CAR molecule transfer and refining the framework of clinical CAR-T therapy for solid tumors.
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Affiliation(s)
- You Zhai
- Department of Molecular Neuropathology, Beijing Neurosurgical Institute, Capital Medical University, Beijing, PR China
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, PR China
| | - Yicong Du
- Department of Urology, Peking University First Hospital, Institute of Urology, Peking University, National Urological Cancer Center, Beijing, PR China
| | - Guanzhang Li
- Department of Molecular Neuropathology, Beijing Neurosurgical Institute, Capital Medical University, Beijing, PR China
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, PR China
| | - Mingchen Yu
- Department of Molecular Neuropathology, Beijing Neurosurgical Institute, Capital Medical University, Beijing, PR China
| | - Huimin Hu
- Department of Molecular Neuropathology, Beijing Neurosurgical Institute, Capital Medical University, Beijing, PR China
| | - Changqing Pan
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, PR China
| | - Di Wang
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, PR China
| | - Zhongfang Shi
- Department of Pathophysiology, Beijing Neurosurgical Institute, Capital Medical University, Beijing, PR China
| | - Xu Yan
- Department of Pathophysiology, Beijing Neurosurgical Institute, Capital Medical University, Beijing, PR China
| | - Xuesong Li
- Department of Urology, Peking University First Hospital, Institute of Urology, Peking University, National Urological Cancer Center, Beijing, PR China
| | - Tao Jiang
- Department of Molecular Neuropathology, Beijing Neurosurgical Institute, Capital Medical University, Beijing, PR China.
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, PR China.
- China National Clinical Research Center for Neurological Diseases, Beijing, PR China.
- Center of Brain Tumor, Beijing Institute for Brain Disorders, Beijing, PR China.
- Research Unit of Accurate Diagnosis, Treatment, and Translational Medicine of Brain Tumors, Chinese Academy of Medical Sciences, Beijing, PR China.
- Chinese Glioma Genome Atlas Network (CGGA) and Asian Glioma Genome Atlas Network (AGGA), Beijing, PR China.
| | - Wei Zhang
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, PR China.
- China National Clinical Research Center for Neurological Diseases, Beijing, PR China.
- Center of Brain Tumor, Beijing Institute for Brain Disorders, Beijing, PR China.
- Chinese Glioma Genome Atlas Network (CGGA) and Asian Glioma Genome Atlas Network (AGGA), Beijing, PR China.
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22
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Tennakoon M, Thotamune W, Payton JL, Karunarathne A. CaaX-motif-adjacent residues influence G protein gamma (Gγ) prenylation under suboptimal conditions. J Biol Chem 2023; 299:105269. [PMID: 37739036 PMCID: PMC10590752 DOI: 10.1016/j.jbc.2023.105269] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Revised: 09/06/2023] [Accepted: 09/09/2023] [Indexed: 09/24/2023] Open
Abstract
Prenylation is an irreversible post-translational modification that supports membrane interactions of proteins involved in various cellular processes, including migration, proliferation, and survival. Dysregulation of prenylation contributes to multiple disorders, including cancers and vascular and neurodegenerative diseases. Prenyltransferases tether isoprenoid lipids to proteins via a thioether linkage during prenylation. Pharmacological inhibition of the lipid synthesis pathway by statins is a therapeutic approach to control hyperlipidemia. Building on our previous finding that statins inhibit membrane association of G protein γ (Gγ) in a subtype-dependent manner, we investigated the molecular reasoning for this differential inhibition. We examined the prenylation of carboxy-terminus (Ct) mutated Gγ in cells exposed to Fluvastatin and prenyl transferase inhibitors and monitored the subcellular localization of fluorescently tagged Gγ subunits and their mutants using live-cell confocal imaging. Reversible optogenetic unmasking-masking of Ct residues was used to probe their contribution to prenylation and membrane interactions of the prenylated proteins. Our findings suggest that specific Ct residues regulate membrane interactions of the Gγ polypeptide, statin sensitivity, and extent of prenylation. Our results also show a few hydrophobic and charged residues at the Ct are crucial determinants of a protein's prenylation ability, especially under suboptimal conditions. Given the cell and tissue-specific expression of different Gγ subtypes, our findings indicate a plausible mechanism allowing for statins to differentially perturb heterotrimeric G protein signaling in cells depending on their Gγ-subtype composition. Our results may also provide molecular reasoning for repurposing statins as Ras oncogene inhibitors and the failure of using prenyltransferase inhibitors in cancer treatment.
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Affiliation(s)
- Mithila Tennakoon
- Department of Chemistry, Saint Louis University, Saint Louis, Missouri, USA; Department of Chemistry and Biochemistry, The University of Toledo, Toledo, Ohio, USA; Institute for Drug and Biotherapeutic Innovation, Saint Louis University, Saint Louis, Missouri, USA
| | - Waruna Thotamune
- Department of Chemistry, Saint Louis University, Saint Louis, Missouri, USA; Department of Chemistry and Biochemistry, The University of Toledo, Toledo, Ohio, USA; Institute for Drug and Biotherapeutic Innovation, Saint Louis University, Saint Louis, Missouri, USA
| | - John L Payton
- Department of Chemistry, Kenyon College, Gambier, Ohio, USA
| | - Ajith Karunarathne
- Department of Chemistry, Saint Louis University, Saint Louis, Missouri, USA; Department of Chemistry and Biochemistry, The University of Toledo, Toledo, Ohio, USA; Institute for Drug and Biotherapeutic Innovation, Saint Louis University, Saint Louis, Missouri, USA.
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23
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Bailleul J, Vlashi E. Glioblastomas: Hijacking Metabolism to Build a Flexible Shield for Therapy Resistance. Antioxid Redox Signal 2023; 39:957-979. [PMID: 37022791 PMCID: PMC10655009 DOI: 10.1089/ars.2022.0088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Revised: 02/01/2023] [Accepted: 02/20/2023] [Indexed: 02/25/2023]
Abstract
Significance: Glioblastomas (GBMs) are among the most lethal tumors despite the almost exclusive localization to the brain. This is largely due to therapeutic resistance. Radiation and chemotherapy significantly increase the survival for GBM patients, however, GBMs always recur, and the median overall survival is just over a year. Proposed reasons for such intractable resistance to therapy are numerous and include tumor metabolism, in particular, the ability of tumor cells to reconfigure metabolic fluxes on demand (metabolic plasticity). Understanding how the hard-wired, oncogene-driven metabolic tendencies of GBMs intersect with flexible, context-induced metabolic rewiring promises to reveal novel approaches for combating therapy resistance. Recent Advances: Personalized genome-scale metabolic flux models have recently provided evidence that metabolic flexibility promotes radiation resistance in cancer and identified tumor redox metabolism as a major predictor for resistance to radiation therapy (RT). It was demonstrated that radioresistant tumors, including GBM, reroute metabolic fluxes to boost the levels of reducing factors of the cell, thus enhancing clearance of reactive oxygen species that are generated during RT and promoting survival. Critical Issues: The current body of knowledge from published studies strongly supports the notion that robust metabolic plasticity can act as a (flexible) shield against the cytotoxic effects of standard GBM therapies, thus driving therapy resistance. The limited understanding of the critical drivers of such metabolic plasticity hampers the rational design of effective combination therapies. Future Directions: Identifying and targeting regulators of metabolic plasticity, rather than specific metabolic pathways, in combination with standard-of-care treatments have the potential to improve therapeutic outcomes in GBM. Antioxid. Redox Signal. 39, 957-979.
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Affiliation(s)
- Justine Bailleul
- Department of Radiation Oncology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA
| | - Erina Vlashi
- Department of Radiation Oncology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA
- Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, California, USA
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24
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Sinn DH, Kang D, Park Y, Kim H, Hong YS, Cho J, Gwak GY. Statin use and the risk of hepatocellular carcinoma among patients with chronic hepatitis B: an emulated target trial using longitudinal nationwide population cohort data. BMC Gastroenterol 2023; 23:366. [PMID: 37880589 PMCID: PMC10601275 DOI: 10.1186/s12876-023-02996-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Accepted: 10/13/2023] [Indexed: 10/27/2023] Open
Abstract
BACKGROUND No randomized controlled trials have been completed to see whether statin can decrease hepatocellular carcinoma (HCC) risk in chronic hepatitis B (CHB) patients. We used large-scale, population-based, observational data to emulate a target trial with two groups, statin user and statin non-user. METHODS Among 1,379,708 nonunique individuals from the Korean National Health Insurance Service data, 2,915 CHB patients with serum cholesterol level of 200 mg/dL or higher who started statin therapy and 8,525 propensity-score matched CHB patients with serum cholesterol level of 200 mg/dL or higher who did not start statin therapy were analyzed for the development of HCC. In addition, liver cancer or liver-related mortality and all-cause mortality were assessed. RESULTS During follow-up, 207 participants developed HCC. Incidence rate of HCC was 0.2 per 1,000 person-years in the statin user group and 0.3 per 1,000 person-years in the statin non-user group. Fully adjusted hazard ratio (HR) for incident HCC comparing statin user group to statin nonuser group was 0.56 (95% confidence interval [CI]: 0.39 to 0.80). The association between statin use and decreased HCC risk was consistent in all subgroups analyzed. Fully adjusted HR comparing statin user to statin nonuser was 0.59 (95% CI: 0.35 to 0.99) for liver cancer or liver-related mortality and 0.93 (95% CI: 0.78 to 1.11) for all-cause mortality. CONCLUSIONS Statin might have a benefit for preventing HCC in CHB patients with elevated cholesterol levels. Statin should be actively considered for CHB patients with dyslipidemia.
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Affiliation(s)
- Dong Hyun Sinn
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-Gu, Seoul, 06351, South Korea
- Department of Clinical Research Design and Evaluation, SAIHST, Sungkyunkwan University, 81 Irwon-ro, Gangnam-Gu, Seoul, 06351, South Korea
| | - Danbee Kang
- Department of Clinical Research Design and Evaluation, SAIHST, Sungkyunkwan University, 81 Irwon-ro, Gangnam-Gu, Seoul, 06351, South Korea
- Center for Clinical Epidemiology, Samsung Medical Center, Sungkyunkwan University, Seoul, South Korea
| | - Yewan Park
- Department of Internal Medicine, Kyung Hee University Hospital, Seoul, Korea
| | - Hyunsoo Kim
- Center for Clinical Epidemiology, Samsung Medical Center, Sungkyunkwan University, Seoul, South Korea
| | - Yun Soo Hong
- Departments of Epidemiology and Medicine, Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins Medical Institutions, Baltimore, MD, USA
| | - Juhee Cho
- Department of Clinical Research Design and Evaluation, SAIHST, Sungkyunkwan University, 81 Irwon-ro, Gangnam-Gu, Seoul, 06351, South Korea.
- Center for Clinical Epidemiology, Samsung Medical Center, Sungkyunkwan University, Seoul, South Korea.
- Departments of Epidemiology and Medicine, Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
| | - Geum-Youn Gwak
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-Gu, Seoul, 06351, South Korea.
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25
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Schelz Z, Muddather HF, Zupkó I. Repositioning of HMG-CoA Reductase Inhibitors as Adjuvants in the Modulation of Efflux Pump-Mediated Bacterial and Tumor Resistance. Antibiotics (Basel) 2023; 12:1468. [PMID: 37760764 PMCID: PMC10525194 DOI: 10.3390/antibiotics12091468] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Revised: 09/15/2023] [Accepted: 09/18/2023] [Indexed: 09/29/2023] Open
Abstract
Efflux pump (EP)-mediated multidrug resistance (MDR) seems ubiquitous in bacterial infections and neoplastic diseases. The diversity and lack of specificity of these efflux mechanisms raise a great obstacle in developing drugs that modulate efflux pumps. Since developing novel chemotherapeutic drugs requires large investments, drug repurposing offers a new approach that can provide alternatives as adjuvants in treating resistant microbial infections and progressive cancerous diseases. Hydroxy-methyl-glutaryl coenzyme-A (HMG-CoA) reductase inhibitors, also known as statins, are promising agents in this respect. Originally, statins were used in the therapy of dyslipidemia and for the prevention of cardiovascular diseases; however, extensive research has recently been performed to elucidate the functions of statins in bacterial infections and cancers. The mevalonate pathway is essential in the posttranslational modification of proteins related to vital eukaryotic cell functions. In this article, a comparative review is given about the possible role of HMG-CoA reductase inhibitors in managing diseases of bacterial and neoplastic origin. Molecular research and clinical studies have proven the justification of statins in this field. Further well-designed clinical trials are urged to clarify the significance of the contribution of statins to the lower risk of disease progression in bacterial infections and cancerous diseases.
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Affiliation(s)
| | | | - István Zupkó
- Institute of Pharmacodynamics and Biopharmacy, Faculty of Pharmacy, University of Szeged, Eötvös u. 6, 6720 Szeged, Hungary; (Z.S.); (H.F.M.)
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26
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Kim DG, Yim SH, Min EK, Choi MC, Kim MS, Joo DJ, Lee JG. Effect of statins on the recurrence of hepatocellular carcinoma after liver transplantation: An illusion revealed by exposure density sampling. Liver Int 2023; 43:2017-2025. [PMID: 37365992 DOI: 10.1111/liv.15653] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 05/09/2023] [Accepted: 06/11/2023] [Indexed: 06/28/2023]
Abstract
BACKGROUND Statins have been reported to reduce overall death and hepatocellular carcinoma (HCC) recurrence in liver transplantation (LT) recipients. However, previous retrospective studies have significant flaws in immortal time bias. METHODS Using data from 658 patients who received LT for HCC, we matched 140 statin users with statin nonusers in a 1:2 ratio at the time of the first statin administration after LT using the exposure density sampling (EDS). The propensity score, calculated using baseline variables (including explant pathology), was used for EDS to equilibrate both groups. HCC recurrence and overall death were compared after adjusting for information at the time of sampling. RESULTS Among statin users, the median time to statin start was 219 (IQR 98-570) days, and intensity of statins was mainly moderate (87.1%). Statin users and nonusers sampled using EDS showed well-balanced baseline characteristics, including detailed tumour pathology, and similar HCC recurrence with cumulative incidences of 11.3% and 11.8% at 5 years, respectively (p = .861). In multivariate Cox models (HR 1.04, p = .918) and subgroup analyses, statins did not affect HCC recurrence. Conversely, statin users showed a significantly lower risk of overall death than nonusers (HR 0.28, p < .001). There was no difference in the type and intensity of statin usage between statin users who experienced HCC recurrence and those who did not. CONCLUSION Upon controlling immortal time bias by EDS, statins did not affect HCC recurrence but reduced mortality after LT. Statin usage is encouraged for survival benefits but not for preventing HCC recurrence in LT recipients.
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Affiliation(s)
- Deok-Gie Kim
- Department of Surgery, The Research Institute for Transplantation, Yonsei University College of Medicine, Seoul, South Korea
| | - Seung Hyuk Yim
- Department of Surgery, The Research Institute for Transplantation, Yonsei University College of Medicine, Seoul, South Korea
| | - Eun-Ki Min
- Department of Surgery, The Research Institute for Transplantation, Yonsei University College of Medicine, Seoul, South Korea
| | - Mun Chae Choi
- Department of Surgery, The Research Institute for Transplantation, Yonsei University College of Medicine, Seoul, South Korea
| | - Myoung Soo Kim
- Department of Surgery, The Research Institute for Transplantation, Yonsei University College of Medicine, Seoul, South Korea
| | - Dong Jin Joo
- Department of Surgery, The Research Institute for Transplantation, Yonsei University College of Medicine, Seoul, South Korea
| | - Jae Geun Lee
- Department of Surgery, The Research Institute for Transplantation, Yonsei University College of Medicine, Seoul, South Korea
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27
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Chang CC, Jiang SS, Tsai FY, Hsu PJ, Hsieh CC, Wang LT, Yen ML, Yen BL. Targeting Conserved Pathways in 3D Spheroid Formation of Diverse Cell Types for Translational Application: Enhanced Functional and Antioxidant Capacity. Cells 2023; 12:2050. [PMID: 37626861 PMCID: PMC10453086 DOI: 10.3390/cells12162050] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2023] [Revised: 08/03/2023] [Accepted: 08/09/2023] [Indexed: 08/27/2023] Open
Abstract
Three-dimensional (3D) in vitro spheroid/organoid culture increasingly appears to better mimic physiological states than standard 2D systems. The biological consequence of 3D spheroids, however, differs for different cell types: for pluripotent embryonic stem cells (ESCs), differentiation and loss of stemness occur, while the converse is true for somatic and cancer cells. Despite such diverse consequences, there are likely conserved mechanisms governing 3D spheroid formation across cell types that are unknown but could be efficiently targeted for translational application. To elucidate such processes, we performed transcriptome analysis with functional validation on 2D- and 3D-cultured mouse ESCs, mesenchymal stromal/stem cells (MSCs), and cancer cells. At both the transcriptomic and functional levels, 3D spheroid formation resulted in commitment towards known cell-specific functional outcomes. Surprisingly in all cell types, downregulation of the cholesterol synthesis pathway was found during 3D spheroid formation, with modulation concomitantly affecting 3D spheroid formation and cell-specific consequences; similar results were seen with human cell types. Furthermore, improved antioxidant capacity after 3D spheroid formation across cell types was further enhanced with modulation of the pathway. These findings demonstrate the profound cell-specific consequences and the translational value of understanding conserved mechanisms across diverse cell types after 3D spheroid formation.
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Affiliation(s)
- Chia-Chi Chang
- Graduate Institute of Life Sciences, National Defense Medical Center (NDMC), Taipei 114, Taiwan
- Regenerative Medicine Research Group, Institute of Cellular & System Medicine, National Health Research Institutes (NHRI), Zhunan 350, Taiwan
| | | | - Fang-Yu Tsai
- National Institute of Cancer Research, NHRI, Zhunan 350, Taiwan
| | - Pei-Ju Hsu
- Regenerative Medicine Research Group, Institute of Cellular & System Medicine, National Health Research Institutes (NHRI), Zhunan 350, Taiwan
| | - Chen-Chan Hsieh
- Regenerative Medicine Research Group, Institute of Cellular & System Medicine, National Health Research Institutes (NHRI), Zhunan 350, Taiwan
| | - Li-Tzu Wang
- Department of Obstetrics/Gynecology, National Taiwan University (NTU) Hospital & College of Medicine, Taipei 100, Taiwan
| | - Men-Luh Yen
- Department of Obstetrics/Gynecology, National Taiwan University (NTU) Hospital & College of Medicine, Taipei 100, Taiwan
| | - B. Linju Yen
- Graduate Institute of Life Sciences, National Defense Medical Center (NDMC), Taipei 114, Taiwan
- Regenerative Medicine Research Group, Institute of Cellular & System Medicine, National Health Research Institutes (NHRI), Zhunan 350, Taiwan
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Ricco N, Kron SJ. Statins in Cancer Prevention and Therapy. Cancers (Basel) 2023; 15:3948. [PMID: 37568764 PMCID: PMC10417177 DOI: 10.3390/cancers15153948] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 07/29/2023] [Accepted: 07/30/2023] [Indexed: 08/13/2023] Open
Abstract
Statins, a class of HMG-CoA reductase inhibitors best known for their cholesterol-reducing and cardiovascular protective activity, have also demonstrated promise in cancer prevention and treatment. This review focuses on their potential applications in head and neck cancer (HNC), a common malignancy for which established treatment often fails despite incurring debilitating adverse effects. Preclinical and clinical studies have suggested that statins may enhance HNC sensitivity to radiation and other conventional therapies while protecting normal tissue, but the underlying mechanisms remain poorly defined, likely involving both cholesterol-dependent and -independent effects on diverse cancer-related pathways. This review brings together recent discoveries concerning the anticancer activity of statins relevant to HNC, highlighting their anti-inflammatory activity and impacts on DNA-damage response. We also explore molecular targets and mechanisms and discuss the potential to integrate statins into conventional HNC treatment regimens to improve patient outcomes.
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Affiliation(s)
- Natalia Ricco
- Basic Sciences Department, Faculty of Medicine and Health Sciences, Universitat Internacional de Catalunya, 08195 Barcelona, Spain;
| | - Stephen J. Kron
- Department of Molecular Genetics and Cell Biology and Ludwig Center for Metastasis Research, The University of Chicago, Chicago, IL 60637, USA
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29
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Bintener T, Pacheco MP, Philippidou D, Margue C, Kishk A, Del Mistro G, Di Leo L, Moscardó Garcia M, Halder R, Sinkkonen L, De Zio D, Kreis S, Kulms D, Sauter T. Metabolic modelling-based in silico drug target prediction identifies six novel repurposable drugs for melanoma. Cell Death Dis 2023; 14:468. [PMID: 37495601 PMCID: PMC10372000 DOI: 10.1038/s41419-023-05955-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Revised: 06/12/2023] [Accepted: 07/05/2023] [Indexed: 07/28/2023]
Abstract
Despite high initial response rates to targeted kinase inhibitors, the majority of patients suffering from metastatic melanoma present with high relapse rates, demanding for alternative therapeutic options. We have previously developed a drug repurposing workflow to identify metabolic drug targets that, if depleted, inhibit the growth of cancer cells without harming healthy tissues. In the current study, we have applied a refined version of the workflow to specifically predict both, common essential genes across various cancer types, and melanoma-specific essential genes that could potentially be used as drug targets for melanoma treatment. The in silico single gene deletion step was adapted to simulate the knock-out of all targets of a drug on an objective function such as growth or energy balance. Based on publicly available, and in-house, large-scale transcriptomic data metabolic models for melanoma were reconstructed enabling the prediction of 28 candidate drugs and estimating their respective efficacy. Twelve highly efficacious drugs with low half-maximal inhibitory concentration values for the treatment of other cancers, which are not yet approved for melanoma treatment, were used for in vitro validation using melanoma cell lines. Combination of the top 4 out of 6 promising candidate drugs with BRAF or MEK inhibitors, partially showed synergistic growth inhibition compared to individual BRAF/MEK inhibition. Hence, the repurposing of drugs may enable an increase in therapeutic options e.g., for non-responders or upon acquired resistance to conventional melanoma treatments.
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Affiliation(s)
- Tamara Bintener
- Department of Life Sciences and Medicine, University of Luxembourg, Belvaux, Luxembourg
| | - Maria Pires Pacheco
- Department of Life Sciences and Medicine, University of Luxembourg, Belvaux, Luxembourg
| | - Demetra Philippidou
- Department of Life Sciences and Medicine, University of Luxembourg, Belvaux, Luxembourg
| | - Christiane Margue
- Department of Life Sciences and Medicine, University of Luxembourg, Belvaux, Luxembourg
| | - Ali Kishk
- Department of Life Sciences and Medicine, University of Luxembourg, Belvaux, Luxembourg
| | - Greta Del Mistro
- Experimental Dermatology, Department of Dermatology, TU-Dresden, Dresden, Germany
- National Center for Tumour Diseases, TU-Dresden, Dresden, Germany
| | - Luca Di Leo
- Melanoma Research Team, Danish Cancer Society Research Center, Copenhagen, Denmark
| | - Maria Moscardó Garcia
- Department of Life Sciences and Medicine, University of Luxembourg, Belvaux, Luxembourg
| | - Rashi Halder
- Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belvaux, Luxembourg
| | - Lasse Sinkkonen
- Department of Life Sciences and Medicine, University of Luxembourg, Belvaux, Luxembourg
| | - Daniela De Zio
- Melanoma Research Team, Danish Cancer Society Research Center, Copenhagen, Denmark
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Stephanie Kreis
- Department of Life Sciences and Medicine, University of Luxembourg, Belvaux, Luxembourg
| | - Dagmar Kulms
- Experimental Dermatology, Department of Dermatology, TU-Dresden, Dresden, Germany
- National Center for Tumour Diseases, TU-Dresden, Dresden, Germany
| | - Thomas Sauter
- Department of Life Sciences and Medicine, University of Luxembourg, Belvaux, Luxembourg.
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He L, Ioannidis A, Arambula E, Hoffman CJ, Joshi P, Kathiravan A, Whitelegge J, Liau LM, Kornblum HI, Pajonk F. Activation of the mevalonate pathway in response to anti-cancer treatments drives glioblastoma recurrences through activation of Rac-1. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.07.23.550205. [PMID: 37546917 PMCID: PMC10402033 DOI: 10.1101/2023.07.23.550205] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/08/2023]
Abstract
Glioblastoma is the deadliest adult brain cancer. Under the current standard of care almost all patients succumb to the disease and novel treatments are urgently needed. Dopamine receptor antagonists have been shown to target cancer cell plasticity in GBM and repurposing these FDA-approved drugs in combination with radiation improves the efficacy of radiotherapy in glioma models. In cells surviving this combination treatment the mevalonate pathway is upregulated at the transcriptional and functional level. Here we report that glioblastoma treatments that converge in the immediate early response to radiation through activation of the MAPK cascade universally upregulate the mevalonate pathway and increase stemness of GBM cells through activation of the Rho-GTPase Rac-1. Activation of the mevalonate pathway and Rac-1 is inhibited by statins, which leads to improved survival in mouse models of glioblastoma when combined with radiation and drugs that target the glioma stem cell pool and plasticity of glioma cells.
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Affiliation(s)
- Ling He
- Department of Radiation Oncology, David Geffen School of Medicine at UCLA
| | - Angeliki Ioannidis
- Department of Radiation Oncology, David Geffen School of Medicine at UCLA
| | - Evelyn Arambula
- Department of Radiation Oncology, David Geffen School of Medicine at UCLA
| | - Carter J. Hoffman
- Department of Radiation Oncology, David Geffen School of Medicine at UCLA
| | - Purva Joshi
- Department of Radiation Oncology, David Geffen School of Medicine at UCLA
| | | | - Julian Whitelegge
- Jonsson Comprehensive Cancer Center at UCLA
- Department of Psychiatry and Human Behavior, David Geffen School of Medicine at UCLA
| | - Linda M. Liau
- Jonsson Comprehensive Cancer Center at UCLA
- Department of Neurosurgery, David Geffen School of Medicine at UCLA
| | - Harley I. Kornblum
- Jonsson Comprehensive Cancer Center at UCLA
- Department of Psychiatry and Human Behavior, David Geffen School of Medicine at UCLA
| | - Frank Pajonk
- Department of Radiation Oncology, David Geffen School of Medicine at UCLA
- Jonsson Comprehensive Cancer Center at UCLA
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Tennakoon M, Thotamune W, Payton JL, Karunarathne A. CaaX-motif adjacent residues control G protein prenylation under suboptimal conditions. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.07.04.547731. [PMID: 37461501 PMCID: PMC10349941 DOI: 10.1101/2023.07.04.547731] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 07/30/2023]
Abstract
Prenylation is a universal and irreversible post-translational modification that supports membrane interactions of proteins involved in various cellular processes, including migration, proliferation, and survival. Thus, dysregulation of prenylation contributes to multiple disorders, including cancers, vascular diseases, and neurodegenerative diseases. During prenylation, prenyltransferase enzymes tether metabolically produced isoprenoid lipids to proteins via a thioether linkage. Pharmacological inhibition of the lipid synthesis pathway by statins has long been a therapeutic approach to control hyperlipidemia. Building on our previous finding that statins inhibit membrane association of G protein γ (Gγ) in a subtype-dependent manner, we investigated the molecular reasoning for this differential. We examined the prenylation efficacy of carboxy terminus (Ct) mutated Gγ in cells exposed to Fluvastatin and prenyl transferase inhibitors and monitored the subcellular localization of fluorescently tagged Gγ subunits and their mutants using live-cell confocal imaging. Reversible optogenetic unmasking-masking of Ct residues was used to probe their contribution to the prenylation process and membrane interactions of the prenylated proteins. Our findings suggest that specific Ct residues regulate membrane interactions of the Gγ polypeptide statin sensitivity, and prenylation efficacy. Our results also show that a few hydrophobic and charged residues at the Ct are crucial determinants of a protein's prenylation ability, especially under suboptimal conditions. Given the cell and tissue-specific expression of different Gγ subtypes, our findings explain how and why statins differentially perturb heterotrimeric G protein signaling in specific cells and tissues. Our results may provide molecular reasoning for repurposing statins as Ras oncogene inhibitors and the failure of using prenyltransferase inhibitors in cancer treatment.
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Affiliation(s)
- Mithila Tennakoon
- Department of Chemistry, Saint Louis University, Saint Louis, MO 63103, USA
- Department of Chemistry and Biochemistry, The University of Toledo, Toledo, OH 43606, USA
- Institute for Drug and Biotherapeutic Innovation, Saint Louis University, Saint Louis, MO 63103, USA
| | - Waruna Thotamune
- Department of Chemistry, Saint Louis University, Saint Louis, MO 63103, USA
- Department of Chemistry and Biochemistry, The University of Toledo, Toledo, OH 43606, USA
- Institute for Drug and Biotherapeutic Innovation, Saint Louis University, Saint Louis, MO 63103, USA
| | - John L. Payton
- Department of Chemistry, Kenyon College, Gambier, Ohio 43022, USA
| | - Ajith Karunarathne
- Department of Chemistry, Saint Louis University, Saint Louis, MO 63103, USA
- Department of Chemistry and Biochemistry, The University of Toledo, Toledo, OH 43606, USA
- Institute for Drug and Biotherapeutic Innovation, Saint Louis University, Saint Louis, MO 63103, USA
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Liang J, Yu D, Luo C, Bennett C, Jedrychowski M, Gygi SP, Widlund HR, Puigserver P. Epigenetic suppression of PGC1α (PPARGC1A) causes collateral sensitivity to HMGCR-inhibitors within BRAF-treatment resistant melanomas. Nat Commun 2023; 14:3251. [PMID: 37277330 PMCID: PMC10241879 DOI: 10.1038/s41467-023-38968-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2022] [Accepted: 05/22/2023] [Indexed: 06/07/2023] Open
Abstract
While targeted treatment against BRAF(V600E) improve survival for melanoma patients, many will see their cancer recur. Here we provide data indicating that epigenetic suppression of PGC1α defines an aggressive subset of chronic BRAF-inhibitor treated melanomas. A metabolism-centered pharmacological screen further identifies statins (HMGCR inhibitors) as a collateral vulnerability within PGC1α-suppressed BRAF-inhibitor resistant melanomas. Lower PGC1α levels mechanistically causes reduced RAB6B and RAB27A expression, whereby their combined re-expression reverses statin vulnerability. BRAF-inhibitor resistant cells with reduced PGC1α have increased integrin-FAK signaling and improved extracellular matrix detached survival cues that helps explain their increased metastatic ability. Statin treatment blocks cell growth by lowering RAB6B and RAB27A prenylation that reduces their membrane association and affects integrin localization and downstream signaling required for growth. These results suggest that chronic adaptation to BRAF-targeted treatments drive novel collateral metabolic vulnerabilities, and that HMGCR inhibitors may offer a strategy to treat melanomas recurring with suppressed PGC1α expression.
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Affiliation(s)
- Jiaxin Liang
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Cell Biology, Harvard Medical School, Boston, MA, USA
| | - Deyang Yu
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Cell Biology, Harvard Medical School, Boston, MA, USA
| | - Chi Luo
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Cell Biology, Harvard Medical School, Boston, MA, USA
- Parthenon Therapeutics, Boston, MA, 02135, USA
| | - Christopher Bennett
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Cell Biology, Harvard Medical School, Boston, MA, USA
- Atavistik Bio, Cambridge, MA, 02139, USA
| | - Mark Jedrychowski
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Cell Biology, Harvard Medical School, Boston, MA, USA
| | - Steve P Gygi
- Department of Cell Biology, Harvard Medical School, Boston, MA, USA
| | - Hans R Widlund
- Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
| | - Pere Puigserver
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
- Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
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Habeshian TS, Shu YH, Cannavale KL, Slezak JM, Chien GW, Vandeneeden SK, Chao CR. Exposure to statins post localized prostate cancer diagnosis and risk of metastasis among men who did not receive curative prostate cancer treatment. Cancer Rep (Hoboken) 2023; 6:e1749. [PMID: 36349511 PMCID: PMC10026299 DOI: 10.1002/cnr2.1749] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Revised: 10/10/2022] [Accepted: 10/13/2022] [Indexed: 11/11/2022] Open
Abstract
BACKGROUND Few studies have evaluated the effect of statin exposure on metastasis risk among prostate cancer patients not receiving curative treatment. METHODS We included men diagnosed with localized prostate cancer at an integrated health care system between 1997 and 2006 who did not receive curative treatment within 6 months of diagnosis. We followed these men until a metastatic event, disenrollment, death, or 12/31/2016. We collected all data from electronic health records supplemented by chart review. We used Cox regressions to examine the association between post-diagnostic statin exposure and metastasis, controlling for clinical characteristics and pre-diagnostic statin exposure. RESULTS There were 4245 men included. Mean age of diagnosis was 68.02 years. 46.6% of men used statins after prostate cancer diagnosis. During follow-up, 192 men developed metastasis (cumulative incidence rate: 14.5%). In the adjusted Cox model, statin use post-prostate cancer diagnosis was not significantly associated with a metastatic event (HR = 0.97, 95% CI = 0.69, 1.36). Pre-diagnostic statin use was also not associated with development of metastasis (HR = 0.76, 95% CI = 0.53, 1.10). We did not observe a dose-response for the proportion of person-time at-risk post-prostate cancer diagnosis on statins (HR = 0.98 per 10% increase in person-time exposed [95% CI = 0.93, 1.03]). CONCLUSIONS We did not find an inverse association between post-diagnosis statin exposure and metastasis development in localized prostate cancer patients who did not receive active treatment. Our results did not offer support to the chemopreventive potential of post-diagnostic statin use among men on active surveillance.
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Affiliation(s)
- Talar S Habeshian
- Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, California, USA
| | - Yu-Hsiang Shu
- Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, California, USA
| | - Kimberly L Cannavale
- Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, California, USA
| | - Jeff M Slezak
- Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, California, USA
| | - Gary W Chien
- Department of Urology, Los Angeles Medical Center, Kaiser Permanente Southern California, Los Angeles, California, USA
| | - Stephen K Vandeneeden
- Division of Research, Kaiser Permanente Northern California, Oakland, California, USA
| | - Chun R Chao
- Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, California, USA
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Selvin T, Berglund M, Lenhammar L, Jarvius M, Nygren P, Fryknäs M, Larsson R, Andersson CR. Phenotypic screening platform identifies statins as enhancers of immune cell-induced cancer cell death. BMC Cancer 2023; 23:164. [PMID: 36803614 PMCID: PMC9938546 DOI: 10.1186/s12885-023-10645-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Accepted: 02/14/2023] [Indexed: 02/19/2023] Open
Abstract
BACKGROUND High-throughput screening (HTS) of small molecule drug libraries has greatly facilitated the discovery of new cancer drugs. However, most phenotypic screening platforms used in the field of oncology are based solely on cancer cell populations and do not allow for the identification of immunomodulatory agents. METHODS We developed a phenotypic screening platform based on a miniaturized co-culture system with human colorectal cancer- and immune cells, providing a model that recapitulates part of the tumor immune microenvironment (TIME) complexity while simultaneously being compatible with a simple image-based readout. Using this platform, we screened 1,280 small molecule drugs, all approved by the Food and Drug Administration (FDA), and identified statins as enhancers of immune cell-induced cancer cell death. RESULTS The lipophilic statin pitavastatin had the most potent anti-cancer effect. Further analysis demonstrated that pitavastatin treatment induced a pro-inflammatory cytokine profile as well as an overall pro-inflammatory gene expression profile in our tumor-immune model. CONCLUSION Our study provides an in vitro phenotypic screening approach for the identification of immunomodulatory agents and thus addresses a critical gap in the field of immuno-oncology. Our pilot screen identified statins, a drug family gaining increasing interest as repurposing candidates for cancer treatment, as enhancers of immune cell-induced cancer cell death. We speculate that the clinical benefits described for cancer patients receiving statins are not simply caused by a direct effect on the cancer cells but rather are dependent on the combined effect exerted on both cancer and immune cells.
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Affiliation(s)
- Tove Selvin
- Department of Medical Sciences, Division of Cancer Pharmacology and Computational Medicine, Uppsala University, SE-75185, Uppsala, Sweden.
| | - Malin Berglund
- Department of Medical Sciences, Division of Cancer Pharmacology and Computational Medicine, Uppsala University, SE-75185, Uppsala, Sweden
| | - Lena Lenhammar
- Department of Medical Sciences, Division of Cancer Pharmacology and Computational Medicine, Uppsala University, SE-75185, Uppsala, Sweden
| | - Malin Jarvius
- Department of Medical Sciences, Division of Cancer Pharmacology and Computational Medicine, Uppsala University, SE-75185, Uppsala, Sweden
- Department of Pharmaceutical Biosciences and Science for Life Laboratory, Uppsala University, Box 591, SE-751 24, Uppsala, Sweden
| | - Peter Nygren
- Department of Immunology, Genetics and Pathology, Uppsala University, SE-75185, Rudbecklaboratoriet, Uppsala, Sweden
| | - Mårten Fryknäs
- Department of Medical Sciences, Division of Cancer Pharmacology and Computational Medicine, Uppsala University, SE-75185, Uppsala, Sweden
| | - Rolf Larsson
- Department of Medical Sciences, Division of Cancer Pharmacology and Computational Medicine, Uppsala University, SE-75185, Uppsala, Sweden
| | - Claes R Andersson
- Department of Medical Sciences, Division of Cancer Pharmacology and Computational Medicine, Uppsala University, SE-75185, Uppsala, Sweden.
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35
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Rossi FM, McBee DP, Trybala TN, Hulsey ZN, Gonzalez Curbelo C, Mazur W, Baccile JA. Membrane Permeant Analogs for Independent Cellular Introduction of the Terpene Precursors Isopentenyl- and Dimethylallyl-Pyrophosphate. Chembiochem 2023; 24:e202200512. [PMID: 36354788 DOI: 10.1002/cbic.202200512] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 11/09/2022] [Indexed: 11/12/2022]
Abstract
Isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP) are the central five-carbon precursors to all terpenes. Despite their significance, exogenous, independent delivery of IPP and DMAPP to cells is impossible as the negatively charged pyrophosphate makes these molecules membrane impermeant. Herein, we demonstrate a facile method to circumvent this challenge through esterification of the β-phosphate with two self-immolative esters (SIEs) that neutralize the negatively charged pyrophosphate to yield membrane-permeant analogs of IPP and DMAPP. Following cellular incorporation, general esterase activity initiates cleavage of the SIEs, resulting in traceless release of IPP and DMAPP for metabolic utilization. Addition of the synthesized IPP and DMAPP precursor analogs rescued cell growth of glioblastoma (U-87MG) cancer cells concurrently treated with the HMG-CoA reductase inhibitor pitavastatin, which otherwise abrogates cell growth via blocking production of IPP and DMAPP. This work demonstrates a new application of a prodrug strategy to incorporate a metabolic intermediate and promises to enable future interrogation of the distinct biological roles of IPP and DMAPP.
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Affiliation(s)
- Francis M Rossi
- Department of Chemistry, University of Tennessee, Knoxville, TN, USA.,Department of Chemistry SUNY Cortland, Cortland, NY, USA
| | - Dillon P McBee
- Department of Chemistry, University of Tennessee, Knoxville, TN, USA
| | - Thomas N Trybala
- Department of Chemistry, University of Tennessee, Knoxville, TN, USA
| | - Zackary N Hulsey
- Department of Chemistry, University of Tennessee, Knoxville, TN, USA
| | | | - William Mazur
- Department of Chemistry, University of Tennessee, Knoxville, TN, USA
| | - Joshua A Baccile
- Department of Chemistry, University of Tennessee, Knoxville, TN, USA
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36
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Subedi L, Pandey P, Khadka B, Shim JH, Cho SS, Kweon S, Byun Y, Kim KT, Park JW. Enhancement of the anticancer effect of atorvastatin-loaded nanoemulsions by improving oral absorption via multivalent intestinal transporter-targeting lipids. Drug Deliv 2022; 29:3397-3413. [DOI: 10.1080/10717544.2022.2149896] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Affiliation(s)
- Laxman Subedi
- Department of Biomedicine, Health & Life Convergence Sciences, BK21 Four, Biomedical and Healthcare Research Institute, Mokpo National University, Jeonnam, Republic of Korea
| | - Prashant Pandey
- Department of Biomedicine, Health & Life Convergence Sciences, BK21 Four, Biomedical and Healthcare Research Institute, Mokpo National University, Jeonnam, Republic of Korea
| | - Bikram Khadka
- Department of Biomedicine, Health & Life Convergence Sciences, BK21 Four, Biomedical and Healthcare Research Institute, Mokpo National University, Jeonnam, Republic of Korea
| | - Jung-Hyun Shim
- Department of Biomedicine, Health & Life Convergence Sciences, BK21 Four, Biomedical and Healthcare Research Institute, Mokpo National University, Jeonnam, Republic of Korea
- College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Jeonnam, Republic of Korea
| | - Seung-Sik Cho
- Department of Biomedicine, Health & Life Convergence Sciences, BK21 Four, Biomedical and Healthcare Research Institute, Mokpo National University, Jeonnam, Republic of Korea
- College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Jeonnam, Republic of Korea
| | - Seho Kweon
- Department of Molecular Medicine and Biopharmaceutical Science, Graduate School of Convergence Science and Technology, College of Pharmacy, Seoul National University, Seoul, Republic of Korea
| | - Youngro Byun
- Department of Molecular Medicine and Biopharmaceutical Science, Graduate School of Convergence Science and Technology, College of Pharmacy, Seoul National University, Seoul, Republic of Korea
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Republic of Korea
| | - Ki-Taek Kim
- Department of Biomedicine, Health & Life Convergence Sciences, BK21 Four, Biomedical and Healthcare Research Institute, Mokpo National University, Jeonnam, Republic of Korea
- College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Jeonnam, Republic of Korea
| | - Jin Woo Park
- Department of Biomedicine, Health & Life Convergence Sciences, BK21 Four, Biomedical and Healthcare Research Institute, Mokpo National University, Jeonnam, Republic of Korea
- College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Jeonnam, Republic of Korea
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37
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Wang Q, Zhi Z, Han H, Zhao Q, Wang X, Cao S, Zhao J. Statin use improves the prognosis of ovarian cancer: An updated and comprehensive meta-analysis. Oncol Lett 2022; 25:65. [PMID: 36644149 PMCID: PMC9827460 DOI: 10.3892/ol.2022.13648] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Accepted: 11/16/2022] [Indexed: 12/24/2022] Open
Abstract
Statins are lipid-lowering agents that have also been found to have anticancer effects. The relationship between statin use and clinical outcomes in ovarian cancer (OC) remains controversial, as previous assessments of the relationship between statin use and OC prognosis have yielded inconsistent results. Therefore, a comprehensive meta-analysis was performed in the present study to investigate this association. Studies were systematically retrieved by searching the PubMed, Embase and Cochrane Library databases, and consulting reference lists of the related studies. The search timeframe was from database creation to September 1, 2022. Pooled hazard ratios (HRs) with corresponding 95% confidence intervals (CIs) were calculated to assess the association. In the present meta-analysis, 16 studies with 37,660 patients with OC were included, of which 11,296 patients had been prescribed statins. The results showed that statin use markedly improved the overall survival time (OS; HR, 0.79; 95% CI, 0.73-0.85; P<0.00001) and OC-specific survival time (HR, 0.84; 95% CI, 0.80-0.89; P<0.00001), especially the OS time in patients with serous OC (HR, 0.81; 95% CI, 0.74-0.89; P<0.0001) and endometrioid OC (HR, 0.80; 95% CI, 0.66-0.98; P=0.03). In addition, survival rate was higher in patients who used statins after OC diagnosis (HR, 0.79; 95% CI, 0.73-0.85; P<0.00001). However, there was no statistically significant association between statin use and the prognosis of mucinous and clear cell OC. The results suggested that statin use markedly improved the OS in patients with OC, including in those with serous and endometrioid OC. Statins were also found to improve the prognosis of patients of both Asian and non-Asian ethnicities. In addition, both lipophilic and hydrophilic statins improved the survival in patients with OC, especially in patients using statins after OC diagnosis. However, the effect may vary depending on the statin type, duration of use and cancer type, and more well-designed studies are needed to further evaluate this.
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Affiliation(s)
- Qingxue Wang
- Graduate School, Hebei North University, Zhangjiakou, Hebei 075000, P.R. China,Department of Oncology, Hebei General Hospital, Shijiazhuang, Hebei 050051, P.R. China
| | - Zheng Zhi
- Department of Basic Medicine, Hebei University of Chinese Medicine, Shijiazhuang, Hebei 050200, P.R. China
| | - Hua Han
- Department of Gynecology, Hebei General Hospital, Shijiazhuang, Hebei 050051, P.R. China
| | - Qingtao Zhao
- Department of Thoracic Surgery, Hebei General Hospital, Shijiazhuang, Hebei 050051, P.R. China
| | - Xing Wang
- Department of Clinical Medical Research Center and Geriatric Key Laboratory, Hebei General Hospital, Shijiazhuang, Hebei 050051, P.R. China
| | - Shumin Cao
- Department of Internal Medicine, Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China
| | - Jing Zhao
- Department of Oncology, Hebei General Hospital, Shijiazhuang, Hebei 050051, P.R. China,Correspondence to: Dr Jing Zhao, Department of Oncology, Hebei General Hospital, 348 Heping West Road, Xinhua, Shijiazhuang, Hebei 050051, P.R. China, E-mail:
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38
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Ediriweera MK. Use of cholesterol metabolism for anti-cancer strategies. Drug Discov Today 2022; 27:103347. [PMID: 36087905 DOI: 10.1016/j.drudis.2022.103347] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 08/08/2022] [Accepted: 09/02/2022] [Indexed: 11/03/2022]
Abstract
Irregularities in cholesterol metabolism occur in a range of human cancers. Cholesterol precursors and derivatives support tumorigenesis and weaken immune responses. Intriguing preclinical and clinical findings demonstrate that cholesterol biosynthesis inhibition achieved by targeting major events and metabolites in cholesterol metabolism is an ideal anti-tumor strategy. Investigations addressing the effects of β-hydroxy β-methylglutaryl-CoA (HMG-CoA) reductase (HMGCR), 2,3-oxidosqualene cyclase (OSC), squalene synthase (SQS), liver X receptors (LXR), and cholesterol trafficking and esterification inhibition on cancer progression have shown encouraging results. Notably, manipulation of cholesterol metabolism strengthens the function of immune cells in the tumor microenvironment (TME). In this review, I discuss the role of cholesterol metabolism in cancer progression and the latest research related to cholesterol metabolism-based anti-cancer therapies and intend to bring this stylish biochemistry topic to the Sri Lankan research landscape.
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Affiliation(s)
- Meran Keshawa Ediriweera
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Colombo, Colombo 08, Sri Lanka.
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39
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Choi YS, Cho HJ, Jung HJ. Atorvastatin inhibits the proliferation of MKN45-derived gastric cancer stem cells in a mevalonate pathway-independent manner. THE KOREAN JOURNAL OF PHYSIOLOGY & PHARMACOLOGY 2022; 26:367-375. [PMID: 36039737 PMCID: PMC9437372 DOI: 10.4196/kjpp.2022.26.5.367] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Revised: 07/22/2022] [Accepted: 07/27/2022] [Indexed: 11/17/2022]
Abstract
Gastric cancer stem cells (GCSCs) are a major cause of radioresistance and chemoresistance in gastric cancer (GC). Therefore, targeting GCSCs is regarded as a powerful strategy for the effective treatment of GC. Atorvastatin is a widely prescribed cholesterol-lowering drug that inhibits 3-hydroxy-3-methylglutaryl-coenzyme A reductase, a rate-limiting enzyme in the mevalonate pathway. The anticancer activity of atorvastatin, a repurposed drug, is being investigated; however, its therapeutic effect and molecular mechanism of action against GCSCs remain unknown. In this study, we evaluated the anticancer effects of atorvastatin on MKN45-derived GCSCs. Atorvastatin significantly inhibited the proliferative and tumorsphere-forming abilities of MKN45 GCSCs in a mevalonate pathway-independent manner. Atorvastatin induced cell cycle arrest at the G0/G1 phase and promoted apoptosis by activating the caspase cascade. Furthermore, atorvastatin exerted an antiproliferative effect against MKN45 GCSCs by inhibiting the expression of cancer stemness markers, such as CD133, CD44, integrin α6, aldehyde dehydrogenase 1A1, Oct4, Sox2, and Nanog, through the downregulation of β-catenin, signal transducer and activator of transcription 3, and protein kinase B activities. Additionally, the combined treatment of atorvastatin and sorafenib, a multi-kinase targeted anticancer drug, synergistically suppressed not only the proliferation and tumorsphere formation of MKN45 GCSCs but also the in vivo tumor growth in a chick chorioallantoic membrane model implanted with MKN45 GCSCs. These findings suggest that atorvastatin can therapeutically eliminate GCSCs.
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Affiliation(s)
- Ye Seul Choi
- Department of Pharmaceutical Engineering and Biotechnology, Genome-Based BioIT Convergence Institute, Sun Moon University, Asan 31460, Korea
| | - Hee Jeong Cho
- Department of Pharmaceutical Engineering and Biotechnology, Genome-Based BioIT Convergence Institute, Sun Moon University, Asan 31460, Korea
| | - Hye Jin Jung
- Department of Pharmaceutical Engineering and Biotechnology, Genome-Based BioIT Convergence Institute, Sun Moon University, Asan 31460, Korea
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40
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Choe EJ, Lee CH, Bae JH, Park JM, Park SS, Baek MC. Atorvastatin Enhances the Efficacy of Immune Checkpoint Therapy and Suppresses the Cellular and Extracellular Vesicle PD-L1. Pharmaceutics 2022; 14:pharmaceutics14081660. [PMID: 36015287 PMCID: PMC9414447 DOI: 10.3390/pharmaceutics14081660] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 07/29/2022] [Accepted: 08/07/2022] [Indexed: 12/12/2022] Open
Abstract
According to clinical studies, statins improve the efficacy of programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) blockade therapy for breast cancer; however, the underlying mechanisms are unclear. Herein, we showed that atorvastatin (ATO) decreased the content of PD-L1 in extracellular vesicles (EVs) by reducing cellular PD-L1 expression and inhibiting EV secretion in breast cancer cells, thereby enhancing the efficacy of anti-PD-L1 therapy. ATO reduced EV secretion by regulating the Rab proteins involved in EV biogenesis and secretion. ATO-mediated inhibition of the Ras-activated MAPK signaling pathway downregulated PD-L1 expression. In addition, ATO strongly promoted antitumor efficacy by inducing T cell-mediated tumor destruction when combined with an anti-PD-L1 antibody. Moreover, suppression of EV PD-L1 by ATO improved the reactivity of anti-PD-L1 therapy by enhancing T-cell activity in draining lymph nodes of EMT6-bearing immunocompetent mice. Therefore, ATO is a potential therapeutic drug that improves antitumor immunity by inhibiting EV PD-L1, particularly in response to immune escape during cancer.
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Dewidar SA, Hamdy O, Eltantawy A, El-Mesery M, El Gayar AM, Soliman MM. Effect of concomitant use of pitavastatin with neoadjuvant chemotherapy protocols in breast cancer patients: A randomized controlled clinical trial. Saudi Pharm J 2022; 30:1486-1496. [PMID: 36387337 PMCID: PMC9649354 DOI: 10.1016/j.jsps.2022.07.011] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2022] [Accepted: 07/19/2022] [Indexed: 12/02/2022] Open
Abstract
Introduction Preclinical studies have demonstrated the possible anticancer effects of statins, but the synergistic effect of concomitant statin use with standard chemotherapy protocols in patients with breast cancer has not yet been investigated. Aim The current study aimed to evaluate the efficacy of concomitant pitavastatin use with neoadjuvant chemotherapy protocols in patients with breast cancer. Methods This study was a randomized controlled clinical trial. A total of 70 adult female patients with pathologically-proven invasive breast cancer were randomized to receive or not receive pitavastatin (2 mg) oral tablets once daily concomitantly with standard neoadjuvant chemotherapy protocols for 6 months. The primary outcomes of this study were changes in tumor size and changes to the Ki67 index. In addition, secondary outcomes were changes in cyclin D1 and cleaved caspase-3 serum levels. This study was registered at ClinicalTrials.gov (Identifier: NCT04705909). Results Patients in the pitavastatin group showed significantly higher median (IQR) reductions in tumor size [−19.8 (−41.5, 9.5)] compared to those in the control group [−5.0 (−15.5, 0.0), p = 0.0009]. The change in Ki67 from baseline to the end of therapy was similar between the two groups (p = 0.12). By the end of therapy, the cyclin D1 levels in the pitavastatin group were significantly decreased [median (IQR) change of − 10.0 (−20.2, −2.9) from baseline], whereas the control group showed an increase in cyclin D1 levels [14.8 (4.1, 56.4)]. The median (IQR) caspase−3 was elevated in the pitavastatin group 1.6 (0.2, 2.2), and decreased in the control group (−0.2 (−1.1, 0.0), p = 0.0002). Subgroup analysis of the pitavastatin group revealed that patients with positive human epidermal growth receptor 2 (HER2) had higher median (IQR) reductions in Ki67 [−35.0 (−70.0, −12.5)] than those with negative HER2 [2.5 (−15.0, 10.0), p = 0.04]. All patients who achieved a complete pathological response (n = 9) exhibited an HER2-neu positive receptor at baseline. Conclusion Concomitant use of pitavastatin with standard neoadjuvant chemotherapy protocols may improve neoadjuvant chemotherapy responses in patients with breast cancer.
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Affiliation(s)
- Samar A. Dewidar
- Clinical Pharmacy and Pharmacy Practice Department, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
| | - Omar Hamdy
- Surgical Oncology Department, Oncology Center, Mansoura University, Mansoura University, Mansoura, Egypt
| | - Ahmed Eltantawy
- Medical Oncology Unit, Oncology Center, Mansoura University, Mansoura, Egypt
| | - Mohamed El-Mesery
- Biochemistry Department, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
| | - Amal M. El Gayar
- Biochemistry Department, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
| | - Moetaza M. Soliman
- Clinical Pharmacy and Pharmacy Practice Department, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
- Corresponding author at: Clinical Pharmacy and Pharmacy Practice Department, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
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Lastakchi S, Olaloko MK, McConville C. A Potential New Treatment for High-Grade Glioma: A Study Assessing Repurposed Drug Combinations against Patient-Derived High-Grade Glioma Cells. Cancers (Basel) 2022; 14:2602. [PMID: 35681582 PMCID: PMC9179370 DOI: 10.3390/cancers14112602] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Revised: 05/06/2022] [Accepted: 05/17/2022] [Indexed: 02/05/2023] Open
Abstract
Repurposed drugs have demonstrated in vitro success against high-grade gliomas; however, their clinical success has been limited due to the in vitro model not truly representing the clinical scenario. In this study, we used two distinct patient-derived tumour fragments (tumour core (TC) and tumour margin (TM)) to generate a heterogeneous, clinically relevant in vitro model to assess if a combination of repurposed drugs (irinotecan, pitavastatin, disulfiram, copper gluconate, captopril, celecoxib, itraconazole and ticlopidine), each targeting a different growth promoting pathway, could successfully treat high-grade gliomas. To ensure the clinical relevance of our data, TC and TM samples from 11 different patients were utilized. Our data demonstrate that, at a concentration of 100µm or lower, all drug combinations achieved lower LogIC50 values than temozolomide, with one of the combinations almost eradicating the cancer by achieving cell viabilities below 4% in five of the TM samples 6 days after treatment. Temozolomide was unable to stop tumour growth over the 14-day assay, while combination 1 stopped tumour growth, with combinations 2, 3 and 4 slowing down tumour growth at higher doses. To validate the cytotoxicity data, we used two distinct assays, end point MTT and real-time IncuCyte life analysis, to evaluate the cytotoxicity of the combinations on the TC fragment from patient 3, with the cell viabilities comparable across both assays. The local administration of combinations of repurposed drugs that target different growth promoting pathways of high-grade gliomas have the potential to be translated into the clinic as a novel treatment strategy for high-grade gliomas.
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Affiliation(s)
| | | | - Christopher McConville
- School of Pharmacy, Institute of Clinical Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK; (S.L.); (M.K.O.)
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The mevalonate pathway in breast cancer biology. Cancer Lett 2022; 542:215761. [DOI: 10.1016/j.canlet.2022.215761] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 05/25/2022] [Accepted: 05/26/2022] [Indexed: 02/07/2023]
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Tilija Pun N, Lee N, Song SH, Jeong CH. Pitavastatin Induces Cancer Cell Apoptosis by Blocking Autophagy Flux. Front Pharmacol 2022; 13:854506. [PMID: 35387352 PMCID: PMC8977529 DOI: 10.3389/fphar.2022.854506] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Accepted: 02/28/2022] [Indexed: 11/25/2022] Open
Abstract
Statins, a class of lipid-lowering drugs, are used in drug repositioning for treatment of human cancer. However, the molecular mechanisms underlying statin-induced cancer cell death and autophagy are not clearly defined. In the present study, we showed that pitavastatin could increase apoptosis in a FOXO3a-dependent manner in the oral cancer cell line, SCC15, and the colon cancer cell line, SW480, along with the blockade of autophagy flux. The inhibition of autophagy by silencing the LC3B gene reduced apoptosis, while blockade of autophagy flux using its inhibitor, Bafilomycin A1, further induced apoptosis upon pitavastatin treatment, which suggested that autophagy flux blockage was the cause of apoptosis by pitavastatin. Further, the FOXO3a protein accumulated due to the blockade of autophagy flux which in turn was associated with the induction of ER stress by transcriptional upregulation of PERK-CHOP pathway, subsequently causing apoptosis due to pitavastatin treatment. Taken together, pitavastatin-mediated blockade of autophagy flux caused an accumulation of FOXO3a protein, thereby leading to the induction of PERK, ultimately causing CHOP-mediated apoptosis in cancer cells. Thus, the present study highlighted the additional molecular mechanism underlying the role of autophagy flux blockade in inducing ER stress, eventually leading to apoptosis by pitavastatin.
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Affiliation(s)
- Nirmala Tilija Pun
- College of Pharmacy, Keimyung University, Daegu, South Korea.,Boston Children's Hospital, Boston, MA, United States
| | - Naeun Lee
- College of Pharmacy, Keimyung University, Daegu, South Korea
| | - Sang-Hoon Song
- College of Pharmacy, Keimyung University, Daegu, South Korea
| | - Chul-Ho Jeong
- College of Pharmacy, Keimyung University, Daegu, South Korea
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Statins and prostate cancer-hype or hope? The biological perspective. Prostate Cancer Prostatic Dis 2022; 25:650-656. [PMID: 35768578 DOI: 10.1038/s41391-022-00557-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Revised: 03/14/2022] [Accepted: 05/27/2022] [Indexed: 01/14/2023]
Abstract
Growing evidence suggests that men prescribed a statin for cholesterol control have a lower risk of advanced prostate cancer (PCa) and improved treatment outcomes; however, the mechanism by which statins elicit their anti-neoplastic effects is not well understood and is likely multifaceted. Statins are potent and specific inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), the rate-limiting enzyme of the mevalonate (MVA) metabolic pathway. This two-part series is a review of the observational and experimental data on statins as anti-cancer agents in PCa. In this article, we describe the functional role that deregulated MVA metabolism plays in PCa progression and summarize the biological evidence and rationale for targeting the MVA pathway, with statins and other agents, for the treatment of PCa.
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Elimam H, Hussein J, Abdel-Latif Y, Abdel-Aziz AK, El-Say KM. Preclinical activity of fluvastatin-loaded self-nanoemulsifying delivery system against breast cancer models: Emphasis on apoptosis. J Cell Biochem 2022; 123:947-963. [PMID: 35342983 DOI: 10.1002/jcb.30238] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 01/27/2022] [Accepted: 03/08/2022] [Indexed: 12/22/2022]
Abstract
Statins trigger apoptotic cell death in some types of growing tumor cells in a cholesterol-lowering-independent manner. Self-nanoemulsifying delivery systems (SNEDs) are potentially effective for the suppression of breast cancer development. This study aims to investigate the potential anticancer activity of fluvastatin (FLV)-SNEDs in breast cancer while comparing it with FLV in vitro as well as in vivo exploiting/using MDA-MB-231 and Erhlich ascites carcinoma (EAC)-bearing mice, respectively. Biochemical analysis of liver and kidney functions, oxidative stress markers, and histopathological examinations of such tumor tissues were performed showing the potentiality of SNEDs as a nanocarrier for antitumor agents. FLV-SNEDs demonstrated more potent anticancer activity compared to FLV on MDA-MB-231 and hepatocellular carcinoma (HepG2) cells. In vivo experiments on the EAC-bearing mice model indicated that FLV and-to a greater extent-FLV-SNEDs ameliorated EAC-induced hepatotoxicity and nephrotoxicity. FLV or FLV-SNEDs evidently reduced the percent of Ki-67 +ve EAC cells by 57.5% and 86.5% in comparison to the vehicle-treated EAC group. In addition, FLV or FLV-SNEDs decreased Bcl-2 levels in serum and liver specimens. In contrast, FLV or FLV-SNEDs significantly activated the executioner caspase-3. Simultaneously, both FLV and FLV-SNEDs stimulated p53 signaling and modulated Bcl-2 protein levels in treated cells. Collectively, these results support the contribution of apoptotic cell death in mediating the anticancer activities of FLV and FLV-SNEDs against murine EAC model in vivo. This study provides new understandings of how FLV and FLV-SNEDs regulate EAC cell viability via upregulation of p53 signaling, and through modulation of cleaved caspase-3 as well as antiapoptotic Bcl-2 marker.
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Affiliation(s)
- Hanan Elimam
- Department of Biochemistry, Faculty of Pharmacy, University of Sadat City, Sadat City, Egypt.,Department of Biochemistry, Faculty of Pharmacy, Sinai University, Kantara, Egypt
| | - Jihan Hussein
- Department of Medical Biochemistry, National Research Centre, Giza, Egypt
| | - Yasmin Abdel-Latif
- Department of Medical Biochemistry, National Research Centre, Giza, Egypt.,Faculty of Biotechnology, October University for Modern Sciences and Arts (MSA), 6th of October, Giza, Egypt
| | - Amal Kamal Abdel-Aziz
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
| | - Khalid M El-Say
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia
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Yang J, Sun M, Cheng R, Tan H, Liu C, Chen R, Zhang J, Yang Y, Gao X, Huang L. Pitavastatin activates mitophagy to protect EPC proliferation through a calcium-dependent CAMK1-PINK1 pathway in atherosclerotic mice. Commun Biol 2022; 5:124. [PMID: 35145192 PMCID: PMC8831604 DOI: 10.1038/s42003-022-03081-w] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Accepted: 01/28/2022] [Indexed: 01/08/2023] Open
Abstract
Statins play a major role in reducing circulating cholesterol levels and are widely used to prevent coronary artery disease. Although they are recently confirmed to up-regulate mitophagy, little is known about the molecular mechanisms and its effect on endothelial progenitor cell (EPC). Here, we explore the role and mechanism underlying statin (pitavastatin, PTV)-activated mitophagy in EPC proliferation. ApoE−/− mice are fed a high-fat diet for 8 weeks to induce atherosclerosis. In these mice, EPC proliferation decreases and is accompanied by mitochondrial dysfunction and mitophagy impairment via the PINK1-PARK2 pathway. PTV reverses mitophagy and reduction in proliferation. Pink1 knockout or silencing Atg7 blocks PTV-induced proliferation improvement, suggesting that mitophagy contributes to the EPC proliferation increase. PTV elicits mitochondrial calcium release into the cytoplasm and further phosphorylates CAMK1. Phosphorylated CAMK1 contributes to PINK1 phosphorylation as well as mitophagy and mitochondrial function recover in EPCs. Together, our findings describe a molecular mechanism of mitophagy activation, where mitochondrial calcium release promotes CAMK1 phosphorylation of threonine177 before phosphorylation of PINK1 at serine228, which recruits PARK2 and phosphorylates its serine65 to activate mitophagy. Our results further account for the pleiotropic effects of statins on the cardiovascular system and provide a promising and potential therapeutic target for atherosclerosis. Endothelial progenitor cell (EPCs) proliferation decreased, accompanied by mitochondrial dysfunction and mitophagy impairment via the PINK1-PARK2 pathway in atherosclerosis. Statins induce mitophagy to protect EPCs by mitochondrial calcium release and CAMK1-mediated PINK1 phosphorylation.
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Affiliation(s)
- Jie Yang
- Institute of Cardiovascular Diseases of PLA, the Second Affiliated Hospital, Army Medical University (Third Military Medical University), Chongqing, China.,Department of Cardiology, the Second Affiliated Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Mengjia Sun
- Institute of Cardiovascular Diseases of PLA, the Second Affiliated Hospital, Army Medical University (Third Military Medical University), Chongqing, China.,Department of Cardiology, the Second Affiliated Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Ran Cheng
- Institute of Cardiovascular Diseases of PLA, the Second Affiliated Hospital, Army Medical University (Third Military Medical University), Chongqing, China.,Department of Cardiology, the Second Affiliated Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Hu Tan
- Institute of Cardiovascular Diseases of PLA, the Second Affiliated Hospital, Army Medical University (Third Military Medical University), Chongqing, China.,Department of Cardiology, the Second Affiliated Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Chuan Liu
- Institute of Cardiovascular Diseases of PLA, the Second Affiliated Hospital, Army Medical University (Third Military Medical University), Chongqing, China.,Department of Cardiology, the Second Affiliated Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Renzheng Chen
- Institute of Cardiovascular Diseases of PLA, the Second Affiliated Hospital, Army Medical University (Third Military Medical University), Chongqing, China.,Department of Cardiology, the Second Affiliated Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Jihang Zhang
- Institute of Cardiovascular Diseases of PLA, the Second Affiliated Hospital, Army Medical University (Third Military Medical University), Chongqing, China.,Department of Cardiology, the Second Affiliated Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Yuanqi Yang
- Institute of Cardiovascular Diseases of PLA, the Second Affiliated Hospital, Army Medical University (Third Military Medical University), Chongqing, China.,Department of Cardiology, the Second Affiliated Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Xubin Gao
- Institute of Cardiovascular Diseases of PLA, the Second Affiliated Hospital, Army Medical University (Third Military Medical University), Chongqing, China.,Department of Cardiology, the Second Affiliated Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Lan Huang
- Institute of Cardiovascular Diseases of PLA, the Second Affiliated Hospital, Army Medical University (Third Military Medical University), Chongqing, China. .,Department of Cardiology, the Second Affiliated Hospital, Army Medical University (Third Military Medical University), Chongqing, China.
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Bruinsmann FA, de Cristo Soares Alves A, de Fraga Dias A, Lopes Silva LF, Visioli F, Raffin Pohlmann A, Figueiró F, Sonvico F, Stanisçuaski Guterres S. Nose-to-brain delivery of simvastatin mediated by chitosan-coated lipid-core nanocapsules allows for the treatment of glioblastoma in vivo. Int J Pharm 2022; 616:121563. [PMID: 35151819 DOI: 10.1016/j.ijpharm.2022.121563] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 02/03/2022] [Accepted: 02/05/2022] [Indexed: 12/12/2022]
Abstract
Glioblastoma is the most common and lethal malignant brain tumor. Despite simvastatin (SVT) showing potential anticancer properties, its antitumoral effect against glioblastoma appears limited when the conventional oral administration route is selected. As a consequence, nose-to-brain delivery has been proposed as an alternative route to deliver SVT into the brain. This study aimed to prepare chitosan-coated simvastatin-loaded lipid-core nanocapsules (LNCSVT-chit) suitable for nose-to-brain delivery and capable of fostering antitumor effects against glioblastoma both in vitro and in vivo. Results showed that the nanocapsules present adequate particle size (mean diameter below 200 nm), narrow particle size distribution (PDI < 0.2), positive zeta potential and high encapsulation efficiency (nearly 100%). In vitro cytotoxicity of LNCSVT-chit was comparable to non-encapsulated SVT in C6 rat glioma cells, whereas LNCSVT-chit were more cytotoxic than non-encapsulated SVT after 72 h of incubation against U-138 MG human glioblastoma cell line. In studies carried out in rats, LNCSVT-chit significantly enhanced the amount of drug in rat brain tissue after intranasal administration (2.4-fold) when compared with free SVT. Moreover, LNCSVT-chit promoted a significant decrease in tumor growth and malignancy in glioma-bearing rats in comparison to control and free SVT groups. Additionally, LNCSVT-chit did not cause any toxicity in treated rats. Considered overall, the results demonstrated that the nose-to-brain administration of LNCSVT-chit represents a novel potential strategy for glioblastoma treatment.
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Affiliation(s)
- Franciele Aline Bruinsmann
- Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Federal do Rio Grande do Sul, Porto Alegre 90610-000, Brazil
| | - Aline de Cristo Soares Alves
- Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Federal do Rio Grande do Sul, Porto Alegre 90610-000, Brazil
| | - Amanda de Fraga Dias
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Universidade Federal do Rio Grande do Sul, Porto Alegre 90035 000, Brazil
| | - Luiz Fernando Lopes Silva
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Universidade Federal do Rio Grande do Sul, Porto Alegre 90035 000, Brazil
| | - Fernanda Visioli
- Programa de Pós-Graduação em Odontologia, Faculdade de Odontologia, Universidade Federal do Rio Grande do Sul, Porto Alegre 90035-003, Brazil
| | - Adriana Raffin Pohlmann
- Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Federal do Rio Grande do Sul, Porto Alegre 90610-000, Brazil
| | - Fabrício Figueiró
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Universidade Federal do Rio Grande do Sul, Porto Alegre 90035 000, Brazil; Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre 90035-003, Brazil
| | - Fabio Sonvico
- Food and Drug Department, University of Parma, Parco Area delle Scienze 27/a, 43124 Parma, Italy; Interdepartmental Centre for Innovation in Health Products - Biopharmanet-TEC, University of Parma, Padiglione 33, Campus Universitario, 43124 Parma, PR, Italy.
| | - Silvia Stanisçuaski Guterres
- Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Federal do Rio Grande do Sul, Porto Alegre 90610-000, Brazil.
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Statins and Gliomas: A Systematic Review of the Preclinical Studies and Meta-Analysis of the Clinical Literature. Drugs 2022; 82:293-310. [PMID: 35122635 DOI: 10.1007/s40265-021-01668-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/17/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND Gliomas represent most common primary brain tumors. Glioblastoma (GBM) is the most common subtype and carries a poor prognosis. There is growing interest in the anti-glioma properties of statins. The aim of this study was to conduct a systematic review of the preclinical literature and to meta-analyze existing clinical studies to determine what benefit, if any, statins may confer in the context of glioma. METHODS The PubMed, Embase, Cochrane, and Web of Science libraries were queried in May 2021. Preclinical studies were included if they investigated the anti-cancer effects of statins in glioma in vitro and in vivo. Clinical studies were included if they reported incidence rates of glioma by statin use, or mortality outcomes among GBM patients by statin use. Pooled point estimates were calculated using a random-effects model. RESULTS In total, 64 publications, 51 preclinical and 13 clinical, were included. Preclinical studies indicated that statins inhibited glioma cell proliferation, migration, and invasion. These effects were time- and concentration-dependent. Synergistic anti-glioma effects were observed when statins were combined with other anti-cancer therapies. Clinical observational studies showed an inverse, albeit non-statistically significant, association between statin use and incidence rate of glioma (HR = 0.84, 95% CI 0.62-1.13, I2 = 72%, p-heterogeneity = 0.003, 6 studies). Statin use was not associated with better overall survival following GBM surgery (HR = 1.05, 95% CI 0.85-1.30, I2 = 30%, p-heterogeneity = 0.23, 4 studies). CONCLUSION Statins were potent anti-cancer drugs that suppressed glioma growth through various mechanisms in vitro; these effects have translated into the clinical realm, clinically but not statistically, in terms of glioma incidence but not GBM survival.
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Barzegar Behrooz A, Talaie Z, Jusheghani F, Łos MJ, Klonisch T, Ghavami S. Wnt and PI3K/Akt/mTOR Survival Pathways as Therapeutic Targets in Glioblastoma. Int J Mol Sci 2022; 23:ijms23031353. [PMID: 35163279 PMCID: PMC8836096 DOI: 10.3390/ijms23031353] [Citation(s) in RCA: 134] [Impact Index Per Article: 44.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 01/14/2022] [Accepted: 01/17/2022] [Indexed: 02/06/2023] Open
Abstract
Glioblastoma (GBM) is a devastating type of brain tumor, and current therapeutic treatments, including surgery, chemotherapy, and radiation, are palliative at best. The design of effective and targeted chemotherapeutic strategies for the treatment of GBM require a thorough analysis of specific signaling pathways to identify those serving as drivers of GBM progression and invasion. The Wnt/β-catenin and PI3K/Akt/mTOR (PAM) signaling pathways are key regulators of important biological functions that include cell proliferation, epithelial–mesenchymal transition (EMT), metabolism, and angiogenesis. Targeting specific regulatory components of the Wnt/β-catenin and PAM pathways has the potential to disrupt critical brain tumor cell functions to achieve critical advancements in alternative GBM treatment strategies to enhance the survival rate of GBM patients. In this review, we emphasize the importance of the Wnt/β-catenin and PAM pathways for GBM invasion into brain tissue and explore their potential as therapeutic targets.
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Affiliation(s)
- Amir Barzegar Behrooz
- Brain Cancer Department, Asu vanda Gene Industrial Research Company, Tehran 1533666398, Iran; (A.B.B.); (Z.T.)
| | - Zahra Talaie
- Brain Cancer Department, Asu vanda Gene Industrial Research Company, Tehran 1533666398, Iran; (A.B.B.); (Z.T.)
| | - Fatemeh Jusheghani
- Department of Biotechnology, Asu vanda Gene Industrial Research Company, Tehran 1533666398, Iran;
| | - Marek J. Łos
- Biotechnology Center, Silesian University of Technology, 44-100 Gliwice, Poland;
| | - Thomas Klonisch
- Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB R3E 0V9, Canada;
- Department of Pathology, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB R3E 0V9, Canada
- Department of Surgery, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB R3E 0V9, Canada
- Department of Medical Microbiology and Infectious Diseases, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB R3E 0V9, Canada
- Research Institute of Oncology and Hematology, Cancer Care Manitoba, Winnipeg, MB R3E 0V9, Canada
| | - Saeid Ghavami
- Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB R3E 0V9, Canada;
- Research Institute of Oncology and Hematology, Cancer Care Manitoba, Winnipeg, MB R3E 0V9, Canada
- Biology of Breathing Theme, Children Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, MB R3E 0V9, Canada
- Faculty of Medicine, Katowice School of Technology, 40-555 Katowice, Poland
- Correspondence:
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