|
1
|
Gao Y, Tang Y. Emerging roles of prohibitins in cancer: an update. Cancer Gene Ther 2025; 32:357-370. [PMID: 40057573 DOI: 10.1038/s41417-025-00883-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2024] [Revised: 02/17/2025] [Accepted: 02/26/2025] [Indexed: 04/09/2025]
Abstract
The prohibitin (PHB) family, including PHB1 and its homolog PHB2, is ubiquitously located in different cellular compartments and plays roles in fundamental cellular processes such as proliferation, differentiation, and apoptosis. Accumulating evidence has indicated that this family contributes to the development of numerous diseases in particular cancers. Aberrant expressions of PHBs can been observed in diverse types of human cancer. Depending on their cell compartment-specific attributes and interacting proteins, PHBs are tightly linked to almost all aspects of cancer biology and have distinct bidirectional functions of tumor-suppression or tumor-promotion. However, the roles of PHBs in cancer have yet to be fully characterized and understood. This review provides an updated overview of the pleiotropic effects of PHBs and emphasizes their characteristic roles in each cancer respectively, with the great expectation to identify potential targets for therapeutic approaches and promising molecular biomarkers for cancer diagnosis and prognostic monitor.
Collapse
Affiliation(s)
- Yunliang Gao
- Department of Urology, the Second Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Mental Disorders, Changsha, China
- Hunan Clinical Research Center of Minimally Invasive Urology, Changsha, China
| | - Yuanyuan Tang
- Department of Oncology, the Second Xiangya Hospital, Central South University, Changsha, China.
| |
Collapse
|
|
2
|
Wan M, Pan S, Shan B, Diao H, Jin H, Wang Z, Wang W, Han S, Liu W, He J, Zheng Z, Pan Y, Han X, Zhang J. Lipid metabolic reprograming: the unsung hero in breast cancer progression and tumor microenvironment. Mol Cancer 2025; 24:61. [PMID: 40025508 PMCID: PMC11874147 DOI: 10.1186/s12943-025-02258-1] [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: 12/03/2024] [Accepted: 02/02/2025] [Indexed: 03/04/2025] Open
Abstract
Aberrant lipid metabolism is a well-recognized hallmark of cancer. Notably, breast cancer (BC) arises from a lipid-rich microenvironment and depends significantly on lipid metabolic reprogramming to fulfill its developmental requirements. In this review, we revisit the pivotal role of lipid metabolism in BC, underscoring its impact on the progression and tumor microenvironment. Firstly, we delineate the overall landscape of lipid metabolism in BC, highlighting its roles in tumor progression and patient prognosis. Given that lipids can also act as signaling molecules, we next describe the lipid signaling exchanges between BC cells and other cellular components in the tumor microenvironment. Additionally, we summarize the therapeutic potential of targeting lipid metabolism from the aspects of lipid metabolism processes, lipid-related transcription factors and immunotherapy in BC. Finally, we discuss the possibilities and problems associated with clinical applications of lipid‑targeted therapy in BC, and propose new research directions with advances in spatiotemporal multi-omics.
Collapse
Affiliation(s)
- Mengting Wan
- Department of Medical Oncology, The First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, China
| | - Shuaikang Pan
- Department of Medical Oncology, The First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, China
- School of Medical Oncology, Wan Nan Medical College, Wuhu, Anhui, China
| | - Benjie Shan
- Department of Medical Oncology, The First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, China
| | - Haizhou Diao
- Department of Medical Oncology, The First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, China
| | - Hongwei Jin
- Department of Medical Oncology, The First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, China
- School of Medical Oncology, Anhui Medical University, Hefei, China
| | - Ziqi Wang
- Department of Medical Oncology, The First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, China
| | - Wei Wang
- Department of Medical Oncology, The First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, China
- School of Medical Oncology, Wan Nan Medical College, Wuhu, Anhui, China
| | - Shuya Han
- Department of Medical Oncology, The First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, China
| | - Wan Liu
- Department of Medical Oncology, The First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, China
| | - Jiaying He
- Department of Medical Oncology, The First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, China
- Graduate School of Bengbu Medical University, Bengbu, Anhui Province, China
| | - Zihan Zheng
- Department of Medical Oncology, The First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, China
- School of Medical Oncology, Anhui Medical University, Hefei, China
| | - Yueyin Pan
- Department of Medical Oncology, The First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, China.
| | - Xinghua Han
- Department of Medical Oncology, The First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, China.
| | - Jinguo Zhang
- Department of Medical Oncology, The First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, China.
| |
Collapse
|
|
3
|
Hosseini FS, Ahmadi A, Kesharwani P, Hosseini H, Sahebkar A. Regulatory effects of statins on Akt signaling for prevention of cancers. Cell Signal 2024; 120:111213. [PMID: 38729324 DOI: 10.1016/j.cellsig.2024.111213] [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: 03/11/2024] [Revised: 05/01/2024] [Accepted: 05/06/2024] [Indexed: 05/12/2024]
Abstract
Statins, which are primarily used as lipid-lowering drugs, have been found to exhibit anti-tumor effects through modulating and interfering with various signaling pathways. In observational studies, statin use has been associated with a significant reduction in the progression of various cancers, including colon, lung, prostate, pancreas, and esophagus cancer, as well as melanoma and B and T cell lymphoma. The mevalonate pathway, which is affected by statins, plays a crucial role in activating Rho, Ras, and Rab proteins, thereby impacting the proliferation and apoptosis of tumor cells. Statins block this pathway, leading to the inhibition of isoprenoid units, which are critical for the activation of these key proteins, thereby affecting cancer cell behavior. Additionally, statins affect MAPK and Cdk2, which in turn reduce the expression of p21 and p27 cyclin-dependent kinase inhibitors. Akt signaling plays a crucial role in key cancer cell features like proliferation, invasion, and apoptosis by activating multiple effectors in downstream pathways such as FOXO, PTEN, NF-κB, GSK3β, and mTOR. The PI3K/Akt signaling is necessary for many events in the metastatic pathway and has been implicated in the resistance to cytostatic drugs. The Akt/PTEN axis is currently attracting great interest for its role in carcinogenesis. Statins have been shown to activate the purinergic receptor P2X7 and affect Akt signaling, which may have important anti-cancer effects. Hence, targeting Akt shows promise as an effective approach to cancer prevention and therapy. This review aims to provide a comprehensive discussion on the specific impact of statins through Akt signaling in different types of cancer.
Collapse
Affiliation(s)
- Fatemeh Sadat Hosseini
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Abdolreza Ahmadi
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Prashant Kesharwani
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India.
| | - Hossein Hosseini
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Amirhossein Sahebkar
- Center for Global Health Research, Saveetha Medical College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India; Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
| |
Collapse
|
|
4
|
Zaki RM, Ramasamy K, Ahmad Alwi NA, Mohd Yusoff R, Lim SM. Pediococcus pentosaceus LAB6- and Lactiplantibacillus plantarum LAB12-Derived Cell Free Supernatant Inhibited RhoA Activation and Reduced Amyloid-Β In Vitro. Probiotics Antimicrob Proteins 2024; 16:62-75. [PMID: 36443559 DOI: 10.1007/s12602-022-10009-7] [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] [Accepted: 11/14/2022] [Indexed: 11/30/2022]
Abstract
Alzheimer's disease (AD) is characterized by aggregation of amyloid beta (Aβ) plaque. RhoA may serve as a potential target for prevention against AD given its role in the amyloidogenic pathway. The recent emergence of the gut-brain axis has linked lactic acid bacteria (LAB) to neuroprotection against AD. This study assessed the importance of RhoA inhibition in mediating the neuroprotective potential of LAB. To this end, de Man, Rogosa and Sharpe (MRS) broth fermented by lactobacilli or pediococci were tested against SK-N-SH (a human neuroblastoma cell line) in the presence of RhoA activator II for 24 h after which the RhoA activity was measured using the G-LISA Kit. Fluorescence staining of f-actin stress fibres was performed to validate RhoA inhibition. SK-N-SH was transfected with plasmid expressing amyloid precursor protein (APP) gene. The Aβ concentration in transfected cells exposed to LAB-derived cell free supernatant (CFS) in the presence of RhoA activator II was measured using the ELISA kit. Furthermore, this study measured organic acids in LAB-derived CFS using the gas chromatography. It was found that LAB-derived CFS yielded strain-dependent inhibition of RhoA, with LAB6- and LAB12-derived CFS being the most potent Pediococcal- and Lactiplantibacillus-based RhoA inhibitor, respectively. Lesser stress fibres were formed under treatment with LAB-derived CFS. The LAB-derived CFS also significantly inhibited Aβ in SK-N-SH transfected with APP gene in the presence of RhoA activator II. The LAB-derived CFS was presented with increased lactic acid, acetic acid, butyric acid and propionic acid. The present findings warrant in-depth study using animal models.
Collapse
Affiliation(s)
- Ramli Muhammad Zaki
- Collaborative Drug Discovery Research (CDDR) Group, Faculty of Pharmacy, Universiti Teknologi MARA (UiTM), Cawangan Selangor, Kampus Puncak Alam, 42300, Bandar Puncak Alam, Selangor Darul Ehsan, Malaysia
- Faculty of Pharmacy and Health Sciences, Royal College of Medicine Perak, Universiti Kuala Lumpur , Ipoh, 30450, Perak, Malaysia
| | - Kalavathy Ramasamy
- Collaborative Drug Discovery Research (CDDR) Group, Faculty of Pharmacy, Universiti Teknologi MARA (UiTM), Cawangan Selangor, Kampus Puncak Alam, 42300, Bandar Puncak Alam, Selangor Darul Ehsan, Malaysia
| | - Nor Amalina Ahmad Alwi
- Collaborative Drug Discovery Research (CDDR) Group, Faculty of Pharmacy, Universiti Teknologi MARA (UiTM), Cawangan Selangor, Kampus Puncak Alam, 42300, Bandar Puncak Alam, Selangor Darul Ehsan, Malaysia
| | - Rosmadi Mohd Yusoff
- Collaborative Drug Discovery Research (CDDR) Group, Faculty of Pharmacy, Universiti Teknologi MARA (UiTM), Cawangan Selangor, Kampus Puncak Alam, 42300, Bandar Puncak Alam, Selangor Darul Ehsan, Malaysia
| | - Siong Meng Lim
- Collaborative Drug Discovery Research (CDDR) Group, Faculty of Pharmacy, Universiti Teknologi MARA (UiTM), Cawangan Selangor, Kampus Puncak Alam, 42300, Bandar Puncak Alam, Selangor Darul Ehsan, Malaysia.
| |
Collapse
|
|
5
|
Sadowska A, Osiński P, Roztocka A, Kaczmarz-Chojnacka K, Zapora E, Sawicka D, Car H. Statins-From Fungi to Pharmacy. Int J Mol Sci 2023; 25:466. [PMID: 38203637 PMCID: PMC10779115 DOI: 10.3390/ijms25010466] [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: 11/30/2023] [Revised: 12/22/2023] [Accepted: 12/23/2023] [Indexed: 01/12/2024] Open
Abstract
Statins have been used in the treatment of hyperlipidemia, both as monotherapy and in combination therapy. Natural fermentation processes of fungi such as Monascus spp., Penicillium spp., Aspergillus terreus, and Pleurotus ostreatus have given rise to natural statins. Compactin (mevastatin), the original naturally occurring statin, is the primary biotransformation substrate in the manufacturing process of marketed drugs. Statins are classified into natural, semi-synthetic derivatives of natural statins, and synthetic ones. Synthetic statins differ from natural statins in their structural composition, with the only common feature being the HMG-CoA-like moiety responsible for suppressing HMG-CoA reductase. Statins do not differ significantly regarding their pleiotropic and adverse effects, but their characteristics depend on their pharmacokinetic parameters and chemical properties. This paper focuses on describing the processes of obtaining natural statins, detailing the pharmacokinetics of available statins, divided into natural and synthetic, and indicating their pleiotropic effects.
Collapse
Affiliation(s)
- Anna Sadowska
- Department of Experimental Pharmacology, Medical University of Bialystok, Szpitalna 37, 15-295 Bialystok, Poland; (D.S.); (H.C.)
| | - Patryk Osiński
- Student’s Pharmacological Club, Lazarski University, Świeradowska 43, 02-662 Warsaw, Poland; (P.O.); (A.R.); (K.K.-C.)
| | - Alicja Roztocka
- Student’s Pharmacological Club, Lazarski University, Świeradowska 43, 02-662 Warsaw, Poland; (P.O.); (A.R.); (K.K.-C.)
| | - Karolina Kaczmarz-Chojnacka
- Student’s Pharmacological Club, Lazarski University, Świeradowska 43, 02-662 Warsaw, Poland; (P.O.); (A.R.); (K.K.-C.)
| | - Ewa Zapora
- Department of Silviculture and Forest Use, Institute of Forest Sciences, Bialystok University of Technology, Wiejska 45E, 15351 Bialystok, Poland;
| | - Diana Sawicka
- Department of Experimental Pharmacology, Medical University of Bialystok, Szpitalna 37, 15-295 Bialystok, Poland; (D.S.); (H.C.)
| | - Halina Car
- Department of Experimental Pharmacology, Medical University of Bialystok, Szpitalna 37, 15-295 Bialystok, Poland; (D.S.); (H.C.)
| |
Collapse
|
|
6
|
Gao J, Hu J, Yu F, Wang C, Sheng D, Liu W, Hu A, Yu K, Xiao X, Kuang Y, Zacksenhaus E, Gajendran B, Ben-David Y. Lovastatin inhibits erythroleukemia progression through KLF2-mediated suppression of MAPK/ERK signaling. BMC Cancer 2023; 23:306. [PMID: 37016335 PMCID: PMC10071686 DOI: 10.1186/s12885-023-10742-4] [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: 10/04/2022] [Accepted: 03/15/2023] [Indexed: 04/06/2023] Open
Abstract
BACKGROUND Lovastatin, an HMG-CoA inhibitor and an effective cholesterol lowering drug, exhibits anti-neoplastic activity towards several types of cancer, although the underlying mechanism is still not fully understood. Herein, we investigated mechanism of growth inhibition of leukemic cells by lovastatin. METHODS RNAseq analysis was used to explore the effect of lovastatin on gene expression in leukemic cells. An animal model of leukemia was used to test the effect of this statin in vivo. FAM83A and DDIT4 expression was knocked-downed in leukemia cells via lentivirus-shRNA. Western blotting, RT-qPCR, cell cycle analysis and apoptosis assays were used to determine the effect of lovastatin-induced growth suppression in leukemic cells in vitro. RESULTS Lovastatin treatment strongly inhibited cancer progression in a mouse model of erythroleukemia induced by Friend virus. In tissue culture, lovastatin inhibited cell proliferation through induction of G1 phase cell cycle arrest and apoptosis. Interestingly, lovastatin induced most known genes associated with cholesterol biosynthesis in leukemic cells. Moreover, it suppressed ERK1/2 phosphorylation by downregulating FAM83A and DDIT4, two mediators of MAP-Kinase signaling. RNAseq analysis of lovastatin treated leukemic cells revealed a strong induction of the tumor suppressor gene KLF2. Accordingly, lentivirus-mediated knockdown of KLF2 antagonized leukemia cell suppression induced by lovastatin, associated with higher ERK1/2 phosphorylation compared to control. We further show that KLF2 induction by lovastatin is responsible for lower expression of the FAM83A and DDIT4 oncogenes, involved in the activation of ERK1/2. KLF2 activation by lovastatin also activated a subset of cholesterol biosynthesis genes that may further contribute to leukemia suppression. CONCLUSIONS These results implicate KLF2-mediated FAM83A/DDIT4/MAPK suppression and activation of cholesterol biosynthesis as the mechanism of leukemia cell growth inhibition by lovastatin.
Collapse
Affiliation(s)
- Jian Gao
- State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, Guizhou, 550014, People's Republic of China
- The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese, Academic of Sciences, Guiyang, Guizhou, People's Republic of China
| | - Jifen Hu
- State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, Guizhou, 550014, People's Republic of China
- The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese, Academic of Sciences, Guiyang, Guizhou, People's Republic of China
| | - Fang Yu
- State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, Guizhou, 550014, People's Republic of China
- The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese, Academic of Sciences, Guiyang, Guizhou, People's Republic of China
| | - Chunlin Wang
- State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, Guizhou, 550014, People's Republic of China
- The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese, Academic of Sciences, Guiyang, Guizhou, People's Republic of China
| | - Danmei Sheng
- State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, Guizhou, 550014, People's Republic of China
- The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese, Academic of Sciences, Guiyang, Guizhou, People's Republic of China
| | - Wuling Liu
- State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, Guizhou, 550014, People's Republic of China
- The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese, Academic of Sciences, Guiyang, Guizhou, People's Republic of China
| | - Anling Hu
- State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, Guizhou, 550014, People's Republic of China
- The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese, Academic of Sciences, Guiyang, Guizhou, People's Republic of China
| | - Kunling Yu
- State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, Guizhou, 550014, People's Republic of China
- The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese, Academic of Sciences, Guiyang, Guizhou, People's Republic of China
| | - Xiao Xiao
- State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, Guizhou, 550014, People's Republic of China
- The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese, Academic of Sciences, Guiyang, Guizhou, People's Republic of China
| | - Yi Kuang
- State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, Guizhou, 550014, People's Republic of China
- The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese, Academic of Sciences, Guiyang, Guizhou, People's Republic of China
| | - Eldad Zacksenhaus
- Department of Medicine, University of Toronto, Toronto, ON, Canada
- Division of Advanced Diagnostics, Toronto General Research Institute, University Health Network, Toronto, ON, Canada
| | - Babu Gajendran
- State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, Guizhou, 550014, People's Republic of China.
- The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese, Academic of Sciences, Guiyang, Guizhou, People's Republic of China.
- School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang, Guizhou Province, 550025, People's Republic of China.
| | - Yaacov Ben-David
- State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, Guizhou, 550014, People's Republic of China.
- The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese, Academic of Sciences, Guiyang, Guizhou, People's Republic of China.
| |
Collapse
|
|
7
|
Samdani MN, Reza R, Morshed N, Asaduzzaman M, Islam ABMMK. Ligand-based modelling for screening natural compounds targeting Minichromosome Maintenance Complex Component-7 for potential anticancer effects. INFORMATICS IN MEDICINE UNLOCKED 2023. [DOI: 10.1016/j.imu.2022.101152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
|
|
8
|
Araújo D, Ribeiro E, Amorim I, Vale N. Repurposed Drugs in Gastric Cancer. MOLECULES (BASEL, SWITZERLAND) 2022; 28:molecules28010319. [PMID: 36615513 PMCID: PMC9822219 DOI: 10.3390/molecules28010319] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/01/2022] [Revised: 12/21/2022] [Accepted: 12/25/2022] [Indexed: 01/04/2023]
Abstract
Gastric cancer (GC) is one of the major causes of death worldwide, ranking as the fifth most incident cancer in 2020 and the fourth leading cause of cancer mortality. The majority of GC patients are in an advanced stage at the time of diagnosis, presenting a poor prognosis and outcome. Current GC treatment approaches involve endoscopic detection, gastrectomy and chemotherapy or chemoradiotherapy in an adjuvant or neoadjuvant setting. Drug development approaches demand extreme effort to identify molecular mechanisms of action of new drug candidates. Drug repurposing is based on the research of new therapeutic indications of drugs approved for other pathologies. In this review, we explore GC and the different drugs repurposed for this disease.
Collapse
Affiliation(s)
- Diana Araújo
- OncoPharma Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Doutor Plácido da Costa, 4200-450 Porto, Portugal
- Institute of Biomedical Sciences Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal
- Institute for Research and Innovation in Health (i3S), Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal
- Institute of Molecular Pathology and Immunology, University of Porto (IPATIMUP), Rua Júlio Amaral de Carvalho, 45, 4200-135 Porto, Portugal
| | - Eduarda Ribeiro
- OncoPharma Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Doutor Plácido da Costa, 4200-450 Porto, Portugal
- Institute of Biomedical Sciences Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal
| | - Irina Amorim
- Institute of Biomedical Sciences Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal
- Institute for Research and Innovation in Health (i3S), Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal
- Institute of Molecular Pathology and Immunology, University of Porto (IPATIMUP), Rua Júlio Amaral de Carvalho, 45, 4200-135 Porto, Portugal
| | - Nuno Vale
- OncoPharma Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Doutor Plácido da Costa, 4200-450 Porto, Portugal
- CINTESIS@RISE, Faculty of Medicine, University of Porto, Alameda Professor Hernâni Monteiro, 4200-319 Porto, Portugal
- Department of Community Medicine, Health Information and Decision (MEDCIDS), Faculty of Medicine, University of Porto, Rua Doutor Plácido da Costa, 4200-450 Porto, Portugal
- Correspondence: ; Tel.: +351-220426537
| |
Collapse
|
|
9
|
Liu Z, Zhang R, Zhang W, Xu Y. Structure-based rational design of hydroxysteroid dehydrogenases for improving and diversifying steroid synthesis. Crit Rev Biotechnol 2022:1-17. [PMID: 35834355 DOI: 10.1080/07388551.2022.2054770] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
A group of steroidogenic enzymes, hydroxysteroid dehydrogenases are involved in steroid metabolism which is very important in the cell: signaling, growth, reproduction, and energy homeostasis. The enzymes show an inherent function in the interconversion of ketosteroids and hydroxysteroids in a position- and stereospecific manner on the steroid nucleus and side-chains. However, the biocatalysis of steroids reaction is a vital and demanding, yet challenging, task to produce the desired enantiopure products with non-natural substrates or non-natural cofactors, and/or in non-physiological conditions. This has driven the use of protein design strategies to improve their inherent biosynthetic efficiency or activate their silent catalytic ability. In this review, the innate features and catalytic characteristics of enzymes based on sequence-structure-function relationships of steroidogenic enzymes are reviewed. Combining structure information and catalytic mechanisms, progress in protein redesign to stimulate potential function, for example, substrate specificity, cofactor dependence, and catalytic stability are discussed.
Collapse
Affiliation(s)
- Zhiyong Liu
- Lab of Brewing Microbiology and Applied Enzymology, School of Biotechnology and Key Laboratory of Industrial Biotechnology of Ministry of Education, Jiangnan University, Wuxi, China
| | - Rongzhen Zhang
- Lab of Brewing Microbiology and Applied Enzymology, School of Biotechnology and Key Laboratory of Industrial Biotechnology of Ministry of Education, Jiangnan University, Wuxi, China
| | - Wenchi Zhang
- Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Yan Xu
- Lab of Brewing Microbiology and Applied Enzymology, School of Biotechnology and Key Laboratory of Industrial Biotechnology of Ministry of Education, Jiangnan University, Wuxi, China
| |
Collapse
|
|
10
|
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: 7] [Impact Index Per Article: 2.3] [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.
Collapse
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
| |
Collapse
|
|
11
|
Co-Application of Statin and Flavonoids as an Effective Strategy to Reduce the Activity of Voltage-Gated Potassium Channels Kv1.3 and Induce Apoptosis in Human Leukemic T Cell Line Jurkat. Molecules 2022; 27:molecules27103227. [PMID: 35630703 PMCID: PMC9145895 DOI: 10.3390/molecules27103227] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 05/14/2022] [Accepted: 05/16/2022] [Indexed: 11/17/2022] Open
Abstract
Voltage-gated potassium channels of the Kv1.3 type are considered a potential new molecular target in several pathologies, including some cancer disorders and COVID-19. Lipophilic non-toxic organic inhibitors of Kv1.3 channels, such as statins and flavonoids, may have clinical applications in supporting the therapy of some cancer diseases, such as breast, pancreas, and lung cancer; melanoma; or chronic lymphocytic leukemia. This study focuses on the influence of the co-application of statins-simvastatin (SIM) or mevastatin (MEV)-with flavonoids 8-prenylnaringenin (8-PN), 6-prenylnarigenin (6-PN), xanthohumol (XANT), acacetin (ACAC), or chrysin on the activity of Kv1.3 channels, viability, and the apoptosis of cancer cells in the human T cell line Jurkat. We showed that the inhibitory effect of co-application of the statins with flavonoids was significantly more potent than the effects exerted by each compound applied alone. Combinations of simvastatin with chrysin, as well as mevastatin with 8-prenylnaringenin, seem to be the most promising. We also found that these results correlate with an increased ability of the statin-flavonoid combination to reduce viability and induce apoptosis in cancer cells compared to single compounds. Our findings suggest that the co-application of statins and flavonoids at low concentrations may increase the effectiveness and safety of cancer therapy. Thus, the simultaneous application of statins and flavonoids may be a new and promising anticancer strategy.
Collapse
|
|
12
|
Fahham N, Zandi F, Ghahremani MH, Ostad SN, Vaziri B, Shahraeini SS, Sardari S. Unraveling Potential Candidate Targets Associated with Expression of
p16INK4a or p16 Truncated Fragment by Comparative Proteomics Analysis. CURR PROTEOMICS 2022. [DOI: 10.2174/1570164618666210728121529] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Background:
p16 is a tumor suppressor protein that is significantly involved in cycle
regulation through the reduction of cell progression from the G1 phase to the S phase via CDK-cyclin
D/p16INK4a/pRb/E2F cascade. The minimum functional domain of p16 has been uncovered that
may function comparable to wild type p16.
Objective:
To expand the knowledge on molecules and mechanisms by which p16 or p1666-156 fragment
suppresses human fibrosarcoma cell line growth, differential proteome profiles of fibrosarcoma
cells following p16 full length or the functional domain overexpression, were analyzed.
Methods:
Following transfecting HT-1080 fibrosarcoma cells with p16 full length, p1666-156 truncated
form, and pcDNA3.1 empty vector, protein extract of each sample was harvested and clarified
by centrifugation, and then the protein content was determined via Bradford assay. All protein extract
of each sample was analyzed by two-dimensional gel electrophoresis. Immunoblot analysis
was performed as further validation of the expression status of identified proteins.
Results:
Expression of p16 or p1666-156 fragment could induce mostly the common alterations (up/-
down-regulation) of proteome profile of HT-1080 cells. Mass spectrometry identification of the differentially
expressed protein spots revealed several proteins that were grouped in functional clusters,
including cell cycle regulation and proliferation, cell migration and structure, oxidative stress,
protein metabolism, epigenetic regulation, and signal transduction.
Conclusion:
The minimum functional domain of p16 could act in the same way as p16 full length.
Also, these new findings can significantly enrich the understanding of p16 growth-suppressive
function at the molecular level by the introduction of potential candidate targets for new treatment
strategies. Furthermore, the present study provides strong evidence on the functional efficacy of
the identified fragment of p16 for further attempts toward peptidomimetic drug design or gene
transfer to block cancer cell proliferation.
Collapse
Affiliation(s)
- Najmeh Fahham
- Protein Chemistry and Proteomics Laboratory, Biotechnology Research Center, Pasteur Institute of Iran, Tehran,
Iran
| | - Fatemeh Zandi
- Protein Chemistry and Proteomics Laboratory, Biotechnology Research Center, Pasteur Institute of Iran, Tehran,
Iran
| | - Mohammad Hossein Ghahremani
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tehran University of Medical Sciences,
Tehran, Iran
| | - Seyed Nasser Ostad
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tehran University of Medical Sciences,
Tehran, Iran
| | - Behrouz Vaziri
- Protein Chemistry and Proteomics Laboratory, Biotechnology Research Center, Pasteur Institute of Iran, Tehran,
Iran
| | - Seyed Sadegh Shahraeini
- Drug Design and Bioinformatics Unit, Department of Medical Biotechnology, Biotechnology Research
Centre, Pasteur Institute of Iran, Tehran, Iran
| | - Soroush Sardari
- Drug Design and Bioinformatics Unit, Department of Medical Biotechnology, Biotechnology Research
Centre, Pasteur Institute of Iran, Tehran, Iran
| |
Collapse
|
|
13
|
Kumar N, Mandal CC. Cholesterol-Lowering Drugs on Akt Signaling for Prevention of Tumorigenesis. Front Genet 2021; 12:724149. [PMID: 34603386 PMCID: PMC8483559 DOI: 10.3389/fgene.2021.724149] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2021] [Accepted: 08/23/2021] [Indexed: 12/12/2022] Open
Abstract
Cholesterol has been reported to be accumulated in cancer cells. The metabolic dysregulation of the cholesterol is associated with tumor development and progression. The cholesterol-lowering drugs have been found to be involved in the prevention and treatment of various cancers. Akt, a serine/threonine kinase, can modulate the role of several downstream proteins involved in cell proliferation, migration, invasion, metabolism, and apoptosis. Since its involvement in several signaling pathways, its dysregulation is commonly reported in several cancers. Thus, targeting Akt could be an effective approach for cancer prevention and therapy. Cholesterol-lowering drugs have been found to affect the expression of Akt, and its activation in the cancer cells and thus have shown anticancer activity in different type of cancers. These drugs act on various signaling pathways such as PTEN/Akt, PI3k/Akt, Akt/NF-κB, Akt/FOXO1, Akt/mTOR, etc., which will be discussed in this article. This review article will discuss the significance of cholesterol in cancer cells, cholesterol-lowering drugs, the role of Akt in cancer cells, and the effects of cholesterol-lowering drugs on Akt in the prevention of therapy resistance and metastasis.
Collapse
Affiliation(s)
- Navneet Kumar
- Department of Biochemistry, All India Institute of Medical Sciences, Bhopal, India
| | - Chandi C Mandal
- Department of Biochemistry, School of Life Sciences, Central University of Rajasthan, Ajmer, India
| |
Collapse
|
|
14
|
Xie L, Zhu G, Shang J, Chen X, Zhang C, Ji X, Zhang Q, Wei Y. An overview on the biological activity and anti-cancer mechanism of lovastatin. Cell Signal 2021; 87:110122. [PMID: 34438015 DOI: 10.1016/j.cellsig.2021.110122] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2021] [Revised: 08/19/2021] [Accepted: 08/20/2021] [Indexed: 02/07/2023]
Abstract
Lovastatin, a secondary metabolite isolated from fungi, is often used as a representative drug to reduce blood lipid concentration and treat hypercholesterolemia. Its structure is similar to that of HMG-CoA. Lovastatin inhibits the binding of the substrate to HMG-CoA reductase, and strongly competes with HMG-CoA reductase (HMGR), thereby exerting a hypolipidemic effect. Further, its safety has been confirmed in vivo and in vitro. Lovastatin also has anti-inflammatory, anti-cancer, and neuroprotective effects. Therefore, the biological activity of lovastatin, especially its anti-cancer effect, has garnered research attention. Several in vitro studies have confirmed that lovastatin has a significant inhibitory effect on cancer cell viability in a variety of cancers (such as breast, liver, cervical, lung, and colon cancer). At the same time, lovastatin can also increase the sensitivity of some types of cancer cells to chemotherapeutic drugs and strengthen their therapeutic effect. Lovastatin inhibits cell proliferation and regulates cancer cell signaling pathways, thereby inducing apoptosis and cell cycle arrest. This article reviews the structure, biosynthetic pathways, and applications of lovastatin, focusing on the anti-cancer effects and mechanisms of action.
Collapse
Affiliation(s)
- Liguo Xie
- Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming 650500, China.
| | - Guodong Zhu
- Yunnan Minzu University, Library, Kunming 650500, China.
| | - Junjie Shang
- Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming 650500, China.
| | - Xuemei Chen
- Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming 650500, China.
| | - Chunting Zhang
- Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming 650500, China.
| | - Xiuling Ji
- Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming 650500, China.
| | - Qi Zhang
- Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming 650500, China.
| | - Yunlin Wei
- Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming 650500, China.
| |
Collapse
|
|
15
|
Zhang Y, Chen Z, Wen Q, Xiong Z, Cao X, Zheng Z, Zhang Y, Huang Z. An overview on the biosynthesis and metabolic regulation of monacolin K/lovastatin. Food Funct 2021; 11:5738-5748. [PMID: 32555902 DOI: 10.1039/d0fo00691b] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Lovastatin/monacolin K (MK) is used as a lipid lowering drug, due to its effective hypercholesterolemic properties, comparable to synthetic statins. Lovastatin's biosynthetic pathway and gene cluster composition have been studied in depth in Aspergillus terreus. Evidence shows that the MK biosynthetic pathway and gene cluster in Monascus sp. are similar to those of lovastatin in A. terreus. Currently, research efforts have been focusing on the metabolic regulation of MK/lovastatin synthesis, and the evidence shows that a combination of extracellular and intracellular factors is essential for proper MK/lovastatin metabolism. Here, we comprehensively review the research progress on MK/lovastatin biosynthetic pathways, its synthetic precursors and inducing substances and metabolic regulation, with a view to providing reference for future research on fungal metabolism regulation and metabolic engineering for MK/lovastatin production.
Collapse
Affiliation(s)
- Yaru Zhang
- College of Food Science, Fujian Agriculture and Forestry University, Fuzhou 350002, China. and Fujian Provincial Key Laboratory of Quality Science and Processing Technology in Special Starch, Fujian Agriculture and Forestry University, Fuzhou 350002, China
| | - Zhiting Chen
- College of Food Science, Fujian Agriculture and Forestry University, Fuzhou 350002, China. and Fujian Provincial Key Laboratory of Quality Science and Processing Technology in Special Starch, Fujian Agriculture and Forestry University, Fuzhou 350002, China
| | - Qinyou Wen
- College of Food Science, Fujian Agriculture and Forestry University, Fuzhou 350002, China. and Fujian Provincial Key Laboratory of Quality Science and Processing Technology in Special Starch, Fujian Agriculture and Forestry University, Fuzhou 350002, China
| | - Zixiao Xiong
- College of Food Science, Fujian Agriculture and Forestry University, Fuzhou 350002, China. and Fujian Provincial Key Laboratory of Quality Science and Processing Technology in Special Starch, Fujian Agriculture and Forestry University, Fuzhou 350002, China
| | - Xiaohua Cao
- Key Laboratory of Crop Biotechnology (Fujian Agriculture and Forestry University), Fujian Province University, Fuzhou 350002, China
| | - Zhenghuai Zheng
- College of Food Science, Fujian Agriculture and Forestry University, Fuzhou 350002, China.
| | - Yangxin Zhang
- College of Food Science, Fujian Agriculture and Forestry University, Fuzhou 350002, China.
| | - Zhiwei Huang
- College of Food Science, Fujian Agriculture and Forestry University, Fuzhou 350002, China. and Fujian Provincial Key Laboratory of Quality Science and Processing Technology in Special Starch, Fujian Agriculture and Forestry University, Fuzhou 350002, China and China-Ireland International Cooperation Centre for Food Material Science and Structure Design, Fujian Agriculture and Forestry University, Fuzhou 350002, China
| |
Collapse
|
|
16
|
Del Gaudio F, Guerrera IC, Riccio R, Monti MC. Quantitative proteomics discloses monacolin K-induced alterations in triple-negative breast cancer cell proteomes and phosphoproteomes. Mol Omics 2021; 16:19-30. [PMID: 31859329 DOI: 10.1039/c9mo00140a] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
A positive prognosis of triple-negative breast cancer can be considered as one of the major challenges in clinical studies; accordingly, scientific research has the mission to find out novel chemotherapeutics to make it curable. In recent times, a good potential of dietary bioactive natural substances, called nutraceuticals, in suppressing cancer cell proliferation via gene expression regulation has been discovered: this effect and the lack of toxicity make nutraceuticals potentially effective agents against cancers. Monacolin K from red rice, a FDA-approved and well-tolerated compound generally employed to treat hypercholesterolemia, has been proved to have anti-proliferative and apoptotic effects in a wide panel of triple-negative breast cancers. Thus, an unbiased analysis of monacolin K-induced MDA-MB-231 cellular pathway alterations has been carried out by quantitative proteomics exploiting isobaric tags. Despite the positive modulation of some proteins already reported in the literature, an increased concentration of the tissue-type plasminogen activator PLAT has interestingly been found. This is a marker of good prognosis in mammary cancer, suggesting the anti-metastatic properties of this molecule as strongly associated with the alterations in the cytoskeleton organization and the consequent modulation of adhesion, motility and proteolysis. In accordance, some of the found monacolin K-induced phosphoproteome alterations have a tight connection to cell migration mechanisms. In this setting, the over-phosphorylation of Lamin A and of melanophilin induced by monacolin K has been very attractive. Moreover, monacolin K exerts its effect on the over-expression of the tissue inhibitor metalloproteinase-2 (TIMP-2), an endogenous metalloproteinase inhibitor. This protein modulates growth, migration and invasion of tumor cells and inhibits tumor angiogenesis.
Collapse
Affiliation(s)
- Federica Del Gaudio
- Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 132, 84084 Fisciano (SA), Italy.
| | | | | | | |
Collapse
|
|
17
|
El-Ashmawy NE, Al-Ashmawy GM, Amr EA, Khedr EG. Inhibition of lovastatin- and docosahexaenoic acid-initiated autophagy in triple negative breast cancer reverted resistance and enhanced cytotoxicity. Life Sci 2020; 259:118212. [PMID: 32768581 DOI: 10.1016/j.lfs.2020.118212] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2020] [Revised: 07/26/2020] [Accepted: 08/03/2020] [Indexed: 12/17/2022]
Abstract
AIMS Autophagy plays a complex role in breast cancer by suppressing or improving the efficiency of treatment. Triple-negative breast cancer (TNBC) cell line (MDA-MB-231) is associated with aggressive response and developing therapy resistance. MDA-MB-231 cells depend on autophagy for survival. Also, the potential benefits of autophagy inhibition in ameliorating developed chemotherapy resistance towards MDA-MB-231 remains to be elucidated. Despite showing anti-tumorigenic activities, the use of lovastatin and docosahexaenoic acid (DHA) for treating different types of cancers is still limited. We aimed to investigate the protective effect of autophagy inhibition by chloroquine (CQ) in MDA-MB-231 cells resistance treated with lovastatin or DHA. MAIN METHODS MDA-MB-231 cells were treated with 30 μM lovastatin and/or 100 μM DHA for 48 h plus 20 μM CQ. Autophagic flux was assessed in association with the expression of multidrug resistance gene 1 (MDR1), transforming growth factor beta 1 gene (TGF-β1), and autophagy-related 7 gene (ATG7). KEY FINDINGS Both drugs exhibited dose-dependent cytotoxicity, enhanced the autophagic flux represented by increased LC3BII protein concentration and decreased p62 protein concentration, and up-regulated the expression of MDR1, TGF-β1, and ATG7 genes. CQ addition enhanced the cytotoxicity of drugs and inhibited the autophagic flux which is detected by higher levels of LC3BII and p62 correlated with the reverted MDR1, TGF-β1 and ATG7 genes expression. SIGNIFICANCE Autophagy inhibition by CQ showed an ameliorative effect on lovastatin- and DHA-induced resistance and enhanced their cytotoxicity, providing a promising strategy in breast cancer therapy.
Collapse
Affiliation(s)
- Nahla E El-Ashmawy
- Department of Biochemistry, Faculty of Pharmacy, Tanta University, Egypt, Postal code: 31527.
| | - Ghada M Al-Ashmawy
- Department of Biochemistry, Faculty of Pharmacy, Tanta University, Egypt, Postal code: 31527.
| | - Eman A Amr
- Department of Biochemistry, Faculty of Pharmacy, Tanta University, Egypt, Postal code: 31527.
| | - Eman G Khedr
- Department of Biochemistry, Faculty of Pharmacy, Tanta University, Egypt, Postal code: 31527.
| |
Collapse
|
|
18
|
A Prospective, Randomized, Placebo-Controlled Study of a Combination of Simvastatin and Chemotherapy in Metastatic Breast Cancer. JOURNAL OF ONCOLOGY 2020; 2020:4174395. [PMID: 32849871 PMCID: PMC7436279 DOI: 10.1155/2020/4174395] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Revised: 06/03/2020] [Accepted: 06/21/2020] [Indexed: 01/22/2023]
Abstract
Preclinical studies support the anticancer activity of statins; however, the existing clinical evidence is inconsistent and not definitive. Our study aimed at evaluating a postulated cancer chemo-sensitizing effect of statin (simvastatin) in a cohort of metastatic breast cancer (MBC) patients. We designed a prospective, single-centered, randomized, double blinded, placebo-controlled trial that encompassed MBC patients with an ECOG Performance Status Scale ≤2 and scheduled to be treated with a chemotherapy regimen consisting of carboplatin and vinorelbine every 3 weeks at Al-Baironi Hospital, Damascus, Syria. Patients were enrolled between August 2011 and July 2012 and randomly allocated to receive a 15-day course of either simvastatin (40 mg) or placebo seven days prior to the first day of each chemotherapy cycle and then continued for eight days in each individual cycle. Primary endpoints were objective response rate (ORR) and toxicity, and the secondary endpoint was overall survival (OS). Eighty-two patients met the inclusion criteria and consented. ORR (35% vs. 32.5%) and predominant toxicity and grade ≥3 neutropenia (occurred in 30% vs. 40% of the patients) were not significantly different between simvastatin and placebo groups, respectively. Over a median follow-up of 44 months (range, 10-60), median OS was 15 months in the simvastatin group and 17 the in placebo group (hazard ratio (HR) = 1.16, 95% CI (0.70-1.91), P=0.57). Elevated baseline values of high-sensitivity C-reactive protein (hsCRP >10 mg/l), lactate dehydrogenase (LDH >480 U/L), and chemotherapy being ≥2nd line were significantly associated with shorter OS for the total cohort in both Univariate and multivariate analyses. Our data prove a safe profile of simvastatin at 40 mg per day combined with carboplatin and vinorelbine in MBC patients but without any beneficial increase of tumor sensitivity to chemotherapy. Moreover, we demonstrated a strong clinical advantage of baseline values of hsCRP and LDH as useful prognostic tools in MBC patients. This trial is registered with ISRCTN12964275.
Collapse
|
|
19
|
Gachpazan M, Kashani H, Khazaei M, Hassanian SM, Rezayi M, Asgharzadeh F, Ghayour-Mobarhan M, Ferns GA, Avan A. The Impact of Statin Therapy on the Survival of Patients with Gastrointestinal Cancer. Curr Drug Targets 2020; 20:738-747. [PMID: 30539694 DOI: 10.2174/1389450120666181211165449] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Revised: 10/25/2018] [Accepted: 12/05/2018] [Indexed: 12/13/2022]
Abstract
Statins are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors that may play an important role in the evolution of cancers, due to their effects on cancer cell metabolism. Statins affect several potential pathways, including cell proliferation, angiogenesis, apoptosis and metastasis. The number of trials assessing the putative clinical benefits of statins in cancer is increasing. Currently, there are several trials listed on the global trial identifier website clinicaltrials.gov. Given the compelling evidence from these trials in a variety of clinical settings, there have been calls for a clinical trial of statins in the adjuvant gastrointestinal cancer setting. However, randomized controlled trials on specific cancer types in relation to statin use, as well as studies on populations without a clinical indication for using statins, have elucidated some potential underlying biological mechanisms, and the investigation of different statins is probably warranted. It would be useful for these trials to incorporate the assessment of tumour biomarkers predictive of statin response in their design. This review summarizes the recent preclinical and clinical studies that assess the application of statins in the treatment of gastrointestinal cancers with particular emphasize on their association with cancer risk.
Collapse
Affiliation(s)
- Meysam Gachpazan
- Metabolic syndrome Research center, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Modern Sciences and Technologies; Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hoda Kashani
- Department of Modern Sciences and Technologies; Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Majid Khazaei
- Metabolic syndrome Research center, Mashhad University of Medical Sciences, Mashhad, Iran.,Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed Mahdi Hassanian
- Metabolic syndrome Research center, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Medical Biochemistry; Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Majid Rezayi
- Metabolic syndrome Research center, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Modern Sciences and Technologies; Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Fereshteh Asgharzadeh
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Majid Ghayour-Mobarhan
- Metabolic syndrome Research center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Gordon A Ferns
- Brighton & Sussex Medical School, Division of Medical Education, Falmer, Brighton, Sussex BN1 9PH, United Kingdom
| | - Amir Avan
- Metabolic syndrome Research center, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Modern Sciences and Technologies; Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Cancer Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| |
Collapse
|
|
20
|
Costa B, Amorim I, Gärtner F, Vale N. Understanding Breast cancer: from conventional therapies to repurposed drugs. Eur J Pharm Sci 2020; 151:105401. [PMID: 32504806 DOI: 10.1016/j.ejps.2020.105401] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Revised: 04/22/2020] [Accepted: 05/27/2020] [Indexed: 12/18/2022]
Abstract
Breast cancer is the most common cancer among women and is considered a developed country disease. Moreover, is a heterogenous disease, existing different types and stages of breast cancer development, therefore, better understanding of cancer biology, helps to improve the development of therapies. The conventional treatments accessible after diagnosis, have the main goal of controlling the disease, by improving survival. In more advance stages the aim is to prolong life and symptom palliation care. Surgery, radiation therapy and chemotherapy are the main options available, which must be adapted to each person individually. However, patients are developing resistance to the conventional therapies. This resistance is due to alterations in important regulatory pathways such as PI3K/AKt/mTOR, this pathway contributes to trastuzumab resistance, a reference drug to treat breast cancer. Therefore, is proposed the repurposing of drugs, instead of developing drugs de novo, for example, to seek new medical treatments within the drugs available, to be used in breast cancer treatment. Providing safe and tolerable treatments to patients, and new insights to efficacy and efficiency of breast cancer treatments. The economic and social burden of cancer is enormous so it must be taken measures to relieve this burden and to ensure continued access to therapies to all patients. In this review we focus on how conventional therapies against breast cancer are leading to resistance, by reviewing those mechanisms and discussing the efficacy of repurposed drugs to fight breast cancer.
Collapse
Affiliation(s)
- Bárbara Costa
- Laboratory of Pharmacology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, Rua Jorge Viterbo 228, 4050-313 Porto, Portugal
| | - Irina Amorim
- Department of Molecular Pathology and Immunology, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Rua Jorge Viterbo 228, Porto, Portugal; Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Rua Júlio Amaral de Carvalho 45, 4200-135 Porto, Portugal; i3S, Instituto de Investigação e Inovação em Saúde, University of Porto, Rua Alfredo Allen, 4200-135 Porto, Portugal
| | - Fátima Gärtner
- Department of Molecular Pathology and Immunology, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Rua Jorge Viterbo 228, Porto, Portugal; Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Rua Júlio Amaral de Carvalho 45, 4200-135 Porto, Portugal; i3S, Instituto de Investigação e Inovação em Saúde, University of Porto, Rua Alfredo Allen, 4200-135 Porto, Portugal
| | - Nuno Vale
- Laboratory of Pharmacology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, Rua Jorge Viterbo 228, 4050-313 Porto, Portugal; Department of Molecular Pathology and Immunology, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Rua Jorge Viterbo 228, Porto, Portugal; Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Rua Júlio Amaral de Carvalho 45, 4200-135 Porto, Portugal; i3S, Instituto de Investigação e Inovação em Saúde, University of Porto, Rua Alfredo Allen, 4200-135 Porto, Portugal.
| |
Collapse
|
|
21
|
Jin W. Novel Insights into PARK7 (DJ-1), a Potential Anti-Cancer Therapeutic Target, and Implications for Cancer Progression. J Clin Med 2020; 9:jcm9051256. [PMID: 32357493 PMCID: PMC7288009 DOI: 10.3390/jcm9051256] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Revised: 04/23/2020] [Accepted: 04/24/2020] [Indexed: 12/28/2022] Open
Abstract
The expression of PARK7 is upregulated in various types of cancer, suggesting its potential role as a critical regulator of the pathogenesis of cancer and in the treatment of cancer and neurodegenerative diseases, including Parkinson’s disease, Alzheimer’s disease, and Huntington disease. PARK7 activates various intracellular signaling pathways that have been implicated in the induction of tumor progression, which subsequently enhances tumor initiation, continued proliferation, metastasis, recurrence, and resistance to chemotherapy. Additionally, secreted PARK7 has been identified as a high-risk factor for the pathogenesis and survival of various cancers. This review summarizes the current understanding of the correlation between the expression of PARK7 and tumor progression.
Collapse
Affiliation(s)
- Wook Jin
- Laboratory of Molecular Disease and Cell Regulation, Department of Biochemistry, School of Medicine, Gachon University, Incheon 406-840, Korea
| |
Collapse
|
|
22
|
Xiong Z, Cao X, Wen Q, Chen Z, Cheng Z, Huang X, Zhang Y, Long C, Zhang Y, Huang Z. An overview of the bioactivity of monacolin K / lovastatin. Food Chem Toxicol 2019; 131:110585. [DOI: 10.1016/j.fct.2019.110585] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Revised: 06/01/2019] [Accepted: 06/13/2019] [Indexed: 12/20/2022]
|
|
23
|
Chen Z, Li Z, Li H, Jiang Y. Metabolomics: a promising diagnostic and therapeutic implement for breast cancer. Onco Targets Ther 2019; 12:6797-6811. [PMID: 31686838 PMCID: PMC6709037 DOI: 10.2147/ott.s215628] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Accepted: 07/22/2019] [Indexed: 12/24/2022] Open
Abstract
Breast cancer (BC) is the most commonly diagnosed cancer among women and the leading cause of cancer death. Despite the advent of numerous diagnosis and treatment methods in recent years, this heterogeneous disease still presents great challenges in early diagnosis, curative treatments and prognosis monitoring. Thus, finding promising early diagnostic biomarkers and therapeutic targets and approaches is meaningful. Metabolomics, which focuses on the analysis of metabolites that change during metabolism, can reveal even a subtle abnormal change in an individual. In recent decades, the exploration of cancer-related metabolomics has increased. Metabolites can be promising biomarkers for the screening, response evaluation and prognosis of BC. In this review, we summarized the workflow of metabolomics, described metabolite signatures based on molecular subtype as well as reclassification and then discussed the application of metabolomics in the early diagnosis, monitoring and prognosis of BC to offer new insights for clinicians in breast cancer diagnosis and treatment.
Collapse
Affiliation(s)
- Zhanghan Chen
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, People's Republic of China
| | - Zehuan Li
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, People's Republic of China
| | - Haoran Li
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, People's Republic of China
| | - Ying Jiang
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, People's Republic of China
| |
Collapse
|
|
24
|
Zhang J, Li Q, Wu Y, Wang D, Xu L, Zhang Y, Wang S, Wang T, Liu F, Zaky MY, Hou S, Liu S, Zou K, Lei H, Zou L, Zhang Y, Liu H. Cholesterol content in cell membrane maintains surface levels of ErbB2 and confers a therapeutic vulnerability in ErbB2-positive breast cancer. Cell Commun Signal 2019; 17:15. [PMID: 30786890 PMCID: PMC6383291 DOI: 10.1186/s12964-019-0328-4] [Citation(s) in RCA: 81] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2018] [Accepted: 02/13/2019] [Indexed: 11/30/2022] Open
Abstract
Background ErbB2 overexpression identifies a subset of breast cancer as ErbB2-positive and is frequently associated with poor clinical outcomes. As a membrane-embedded receptor tyrosine kinase, cell surface levels of ErbB2 are regulated dynamically by membrane physical properties. The present study aims to investigate the influence of membrane cholesterol contents on ErbB2 status and cellular responses to its tyrosine kinase inhibitors. Methods The cholesterol abundance was examined in ErbB2-positive breast cancer cells using filipin staining. Cellular ErbB2 localizations were investigated by immunofluorescence with altered membrane cholesterol contents. The inhibitory effects of the cholesterol-lowering drug lovastatin were assessed using cell proliferation, apoptosis, immunoblotting and immunofluorescence assays. The synergistic effects of lovastatin with the ErbB2 inhibitor lapatinib were evaluated using an ErbB2-positive breast cancer xenograft mouse model. Results Membrane cholesterol contents positively correlated with cell surface distribution of ErbB2 through increasing the rigidity and decreasing the fluidity of cell membranes. Reduction in cholesterol abundance assisted the internalization and degradation of ErbB2. The cholesterol-lowering drug lovastatin significantly potentiated the inhibitory effects of ErbB2 kinase inhibitors, accompanied with enhanced ErbB2 endocytosis. Lovastatin also synergized with lapatinib to strongly suppress the in vivo growth of ErbB2-positive breast cancer xenografts. Conclusion The cell surface distribution of ErbB2 was closely regulated by membrane physical properties governed by cholesterol contents. The cholesterol-lowering medications can hence be exploited for potential combinatorial therapies with ErbB2 kinase inhibitors in the clinical treatment of ErbB2-positive breast cancer.
Collapse
Affiliation(s)
- Jinrui Zhang
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
| | - Qiong Li
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.,The Second Affiliated Hospital, Dalian Medical University, Dalian, China
| | - Yueguang Wu
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
| | - Duchuang Wang
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
| | - Lu Xu
- The Second Affiliated Hospital, Dalian Medical University, Dalian, China
| | - Yang Zhang
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
| | - Shanshan Wang
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
| | - Taishu Wang
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
| | - Fang Liu
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
| | - Mohamed Y Zaky
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.,Molecular Physiology Division, Department of Zoology, Faculty of Science, Beni-Suef University, Beni Suef, Egypt
| | - Shuai Hou
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
| | - Shuyan Liu
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
| | - Kun Zou
- Department of Radiotherapy Oncology, the First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Haixin Lei
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
| | - Lijuan Zou
- The Second Affiliated Hospital, Dalian Medical University, Dalian, China
| | - Yingqiu Zhang
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
| | - Han Liu
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China. .,Cancer Biotherapy & Translational Medicine Center of Liaoning Province, Dalian Medical University, Dalian, China.
| |
Collapse
|
|
25
|
Lu X, Zhang X, Zhang Y, Zhang K, Zhan C, Shi X, Li Y, Zhao J, Bai Y, Wang Y, Nie H, Li Y. Metabolic profiling analysis upon acylcarnitines in tissues of hepatocellular carcinoma revealed the inhibited carnitine shuttle system caused by the downregulated carnitine palmitoyltransferase 2. Mol Carcinog 2019; 58:749-759. [PMID: 30604893 DOI: 10.1002/mc.22967] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2018] [Revised: 12/22/2018] [Accepted: 12/26/2018] [Indexed: 02/06/2023]
Abstract
The carnitine shuttle system (CSS) plays a crucial role in the transportation of fatty acyls during fatty acid β-oxidation for energy supplementation, especially in cases of high energy demand, such as in cancer. In this study, to systematically characterize alterations of the CSS in hepatocellular carcinoma (HCC), acylcarnitine metabolic profiling was carried out on 80 pairs of HCC tissues and adjacent noncancerous tissues (ANTs) by using ultra-performance liquid chromatography coupled to mass spectrometry. Twenty-four acylcarnitines classified into five categories were identified and characterized between HCCs and ANTs. Notably, increased saturated long-chain acylcarnitines (LCACs) and decreased short- and medium-chain acylcarnitines (S/MCACs) were simultaneously observed in HCC samples. Subsequent correlation network and heatmap analysis indicated low correlations between LCACs and S/MCACs. The mRNA and protein expressions of carnitine palmitoyltransferase 2 (CPT2) was significantly downregulated in HCC samples, whereas CPT1A expression was not significantly changed. Correspondingly, the relative levels of S/MCACs were reduced and those of LCACs were increased in BEL-7402/CPT2-knockdown cells compared to negative controls. Both results suggested that decreased shuttling efficiency in HCC might be associated with downregulation of CPT2. In addition, decreases in the mRNA expression of acetyl-CoA acyltransferase 2 were also observed in HCC tissues and BEL-7402/CPT2-knockdown cells, suggesting potential low β-oxidation efficiency, which was consistent with the increased expression of stearoyl-CoA desaturase 1 in both samples. The systematic strategy applied in our study illustrated decreased shuttling efficiency of the carnitine shuttle system in HCC and can provide biologists with an in-depth understanding of β-oxidation in HCC.
Collapse
Affiliation(s)
- Xin Lu
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, China
| | - Xiaohan Zhang
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, China
| | - Yongjian Zhang
- The Affiliated Tumor Hospital, Harbin Medical University, Harbin, China
| | - Kun Zhang
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, China
| | - Chao Zhan
- The Affiliated Tumor Hospital, Harbin Medical University, Harbin, China
| | - Xiuyun Shi
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, China
| | - Yiqun Li
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, China
| | - Jianxiang Zhao
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, China
| | - Yunfan Bai
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, China
| | - Yu Wang
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, China
| | - Huan Nie
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, China
| | - Yu Li
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, China
| |
Collapse
|
|
26
|
Palko-Łabuz A, Środa-Pomianek K, Wesołowska O, Kostrzewa-Susłow E, Uryga A, Michalak K. MDR reversal and pro-apoptotic effects of statins and statins combined with flavonoids in colon cancer cells. Biomed Pharmacother 2018; 109:1511-1522. [PMID: 30551403 DOI: 10.1016/j.biopha.2018.10.169] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2018] [Revised: 10/22/2018] [Accepted: 10/30/2018] [Indexed: 12/19/2022] Open
Abstract
The resistance of cancer cells to a variety of structurally non-related cytotoxic drugs is known as multidrug resistance phenomenon (MDR). In cellular membranes an activity of MDR transporters such as P-glycoprotein (ABCB1) is affected by their lipid environment. Many various compounds have been examined for their ability to restore drug-sensitivity of resistant cancer cells. Statins, inhibitors of the key enzyme of mevalonate pathway HMG-CoA (3-hydroxy-3-methyl-glutaryl-coenzyme A) reductase are drugs commonly prescribed in order to reduce serum level of cholesterol and to diminish the risk of cardiovascular disease. Statins as drugs that influence lipid composition of cell membrane and in that way they also exert influence on lipid bilayer properties appear to be good candidates as MDR modulators. In this work it was shown that statins - mevastatin and simvastatin exert antiproliferative, pro-apoptotic and reversing drug resistance effect in human colon adenocarcinoma cell line LoVo and its drug-resistant subline LoVo/Dx. A hypothesis was also checked whether flavones, which as it is well known are able to influence the biosynthesis of cholesterol, may change the anticancer activity of statins. Our investigations have revealed that combined use of statins and studied flavonoids results in enhanced cell growth inhibition and apoptosis and lower cancer cell proliferation as compared to the application only statins alone. Moreover, in drug resistant LoVo/Dx cells a stronger decrease of resistance to doxorubicine was observed in the presence of statins in combination with flavones as compared to the effect observed for statins only.
Collapse
Affiliation(s)
- Anna Palko-Łabuz
- Department of Biophysics, Wroclaw Medical University, Chalubinskiego 10, 50-368, Wroclaw, Poland.
| | - Kamila Środa-Pomianek
- Department of Biophysics, Wroclaw Medical University, Chalubinskiego 10, 50-368, Wroclaw, Poland
| | - Olga Wesołowska
- Department of Biophysics, Wroclaw Medical University, Chalubinskiego 10, 50-368, Wroclaw, Poland
| | - Edyta Kostrzewa-Susłow
- Department of Chemistry, Wroclaw University of Environmental and Life Sciences, Norwida 25, 50-375, Wroclaw, Poland
| | - Anna Uryga
- Department of Biophysics, Wroclaw Medical University, Chalubinskiego 10, 50-368, Wroclaw, Poland
| | - Krystyna Michalak
- Department of Biophysics, Wroclaw Medical University, Chalubinskiego 10, 50-368, Wroclaw, Poland
| |
Collapse
|
|
27
|
Lim B, Woodward WA, Wang X, Reuben JM, Ueno NT. Inflammatory breast cancer biology: the tumour microenvironment is key. Nat Rev Cancer 2018; 18:485-499. [PMID: 29703913 DOI: 10.1038/s41568-018-0010-y] [Citation(s) in RCA: 217] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Inflammatory breast cancer (IBC) is a rare and aggressive disease that accounts for ~2-4% of all breast cancers. However, despite its low incidence rate, IBC is responsible for 7-10% of breast cancer-related mortality in Western countries. Thus, the discovery of robust biological targets and the development of more effective therapeutics in IBC are crucial. Despite major international efforts to understand IBC biology, genomic studies have not led to the discovery of distinct biological mechanisms in IBC that can be translated into novel therapeutic strategies. In this Review, we discuss these molecular profiling efforts and highlight other important aspects of IBC biology. We present the intrinsic characteristics of IBC, including stemness, metastatic potential and hormone receptor positivity; the extrinsic features of the IBC tumour microenvironment (TME), including various constituent cell types; and lastly, the communication between these intrinsic and extrinsic components. We summarize the latest perspectives on the key biological features of IBC, with particular emphasis on the TME as an important contributor to the aggressive nature of IBC. On the basis of the current understanding of IBC, we hope to develop the next generation of translational studies, which will lead to much-needed survival improvements in patients with this deadly disease.
Collapse
Affiliation(s)
- Bora Lim
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
- Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| | - Wendy A Woodward
- Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Xiaoping Wang
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - James M Reuben
- Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Naoto T Ueno
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
- Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| |
Collapse
|
|
28
|
Technological advances and proteomic applications in drug discovery and target deconvolution: identification of the pleiotropic effects of statins. Drug Discov Today 2017; 22:848-869. [PMID: 28284830 DOI: 10.1016/j.drudis.2017.03.001] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2016] [Revised: 02/09/2017] [Accepted: 03/01/2017] [Indexed: 01/05/2023]
Abstract
Proteomic-based techniques provide a powerful tool for identifying the full spectrum of protein targets of a drug, elucidating its mechanism(s) of action, and identifying biomarkers of its efficacy and safety. Herein, we outline the technological advancements in the field, and illustrate the contribution of proteomics to the definition of the pharmacological profile of statins, which represent the cornerstone of the prevention and treatment of cardiovascular diseases (CVDs). Statins act by inhibiting 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase, thus reducing cholesterol biosynthesis and consequently enhancing the clearance of low-density lipoproteins from the blood; however, HMG-CoA reductase inhibition can result in a multitude of additional effects beyond lipid lowering, known as 'pleiotropic effects'. The case of statins highlights the unique contribution of proteomics to the target profiling of a drug molecule.
Collapse
|
|
29
|
Liu PC, Lu G, Deng Y, Wang CD, Su XW, Zhou JY, Chan TM, Hu X, Poon WS. Inhibition of NF-κB Pathway and Modulation of MAPK Signaling Pathways in Glioblastoma and Implications for Lovastatin and Tumor Necrosis Factor-Related Apoptosis Inducing Ligand (TRAIL) Combination Therapy. PLoS One 2017; 12:e0171157. [PMID: 28135339 PMCID: PMC5279772 DOI: 10.1371/journal.pone.0171157] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2016] [Accepted: 01/16/2017] [Indexed: 11/18/2022] Open
Abstract
Glioblastoma is a common malignant brain tumor and it is refractory to therapy because it usually contains a mixture of cell types. The tumor necrosis factor-related apoptosis inducing ligand (TRAIL) has been shown to induce apoptosis in a range of tumor cell types. Previously, we found that two human glioblastoma cell lines are resistant to TRAIL, while lovastatin sensitizes these glioblastoma cells to TRAIL-induced cell death. In this study, we investigated the mechanisms underlying the TRAIL-induced apoptosis in human glioblastoma cell lines by lovastatin. Furthermore, we have confirmed the anti-tumor effect of combination therapy with lovastatin and TRAIL in the subcutaneous brain tumor model. We showed that lovastatin significantly up-regulated the expression of death receptor 5 (DR5) in glioblastoma cell lines as well as in tumor-bearing mice with peri-tumoral administration of lovastatin. Further study in glioblastoma cell lines suggested that lovastatin treatment could inhibit NF-κB and Erk/MAPK pathways but activates JNK pathway. These results suggest that lovastatin sensitizes TRAIL-induced apoptosis by up-regulation of DR5 level via NF-κB inactivation, but also directly induces apoptosis by dysregulation of MAPK pathway. Our in vivo study showed that local peri-tumoral co-injection of lovastatin and TRAIL substantially reduced tumor growth compared with single injection of lovastatin or TRAIL in subcutaneous nude mice model. This study suggests that combined treatment of lovastatin and TRAIL is a promising therapeutic strategy to TRAIL-resistant glioblastoma.
Collapse
Affiliation(s)
- Pi Chu Liu
- Division of Neurosurgery, Department of Surgery, The Chinese University of Hong Kong, Hong Kong, China
| | - Gang Lu
- Division of Neurosurgery, Department of Surgery, The Chinese University of Hong Kong, Hong Kong, China
| | - Yi Deng
- Shenzhen Key Laboratory of Cell Microenvironment, Department of Biology, South University of Science and Technology of China, Shenzhen, Guangdong, China
| | - Cheng Dong Wang
- Division of Neurosurgery, Department of Surgery, The Chinese University of Hong Kong, Hong Kong, China
| | - Xian Wei Su
- Division of Neurosurgery, Department of Surgery, The Chinese University of Hong Kong, Hong Kong, China
| | - Jing Ye Zhou
- Division of Neurosurgery, Department of Surgery, The Chinese University of Hong Kong, Hong Kong, China
| | - Tat Ming Chan
- Division of Neurosurgery, Department of Surgery, The Chinese University of Hong Kong, Hong Kong, China
| | - Xiang Hu
- Shenzhen Beike Cell Engineering Research Institute, Shenzhen, China
| | - Wai Sang Poon
- Division of Neurosurgery, Department of Surgery, The Chinese University of Hong Kong, Hong Kong, China
- * E-mail:
| |
Collapse
|
|
30
|
Wang T, Seah S, Loh X, Chan CW, Hartman M, Goh BC, Lee SC. Simvastatin-induced breast cancer cell death and deactivation of PI3K/Akt and MAPK/ERK signalling are reversed by metabolic products of the mevalonate pathway. Oncotarget 2016; 7:2532-44. [PMID: 26565813 PMCID: PMC4823053 DOI: 10.18632/oncotarget.6304] [Citation(s) in RCA: 95] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2015] [Accepted: 10/14/2015] [Indexed: 02/07/2023] Open
Abstract
Statins purportedly exert anti-tumoral effects on breast cancer. However, the biologic mechanisms for these actions are not fully elucidated. The aims of this study were 1) to explore the effects of simvastatin on apoptosis, proliferation as well as PI3K/Akt/mTOR and MAPK/ERK pathway in a window-of-opportunity breast cancer trial; 2) to further confirm findings from the clinical trial by functional studies; 3) to explore the regulatory role of mevalonate pathway on the anti-tumoral effects of simvastatin. In clinical samples, simvastatin led to increase in cleaved caspase-3 (p = 0.002) and decreased trend for Ki67 (p = 0.245). Simvastatin markedly suppressed PI3K/Akt/mTOR signalling by activating PTEN (p = 0.005) and by dephosphorylating Akt (p = 0.002) and S6RP (p = 0.033); it also inhibited MAPK/ERK pathway by dephosphorylating c-Raf (p = 0.018) and ERK1/2 (p = 0.002). In ER-positive (MCF-7, T47D) and ER-negative (MDA-MB-231, BT-549) breast cancer cells, simvastatin treatment consistently induced apoptosis and inhibited proliferation by deregulating caspase cascades and cell cycle proteins in a dose dependent manner. Concordantly, simvastatin strongly suppressed PI3K/Akt/mTOR pathway by enhancing PTEN expression and by further sequentially dephosphorylating downstream cascades including Akt, mTOR, p70S6K, S6RP and 4E-BP1. Furthermore, simvastatin significantly inhibited MAPK/ERK pathway by dephosphorylating sequential cascades such as c-Raf, MEK1/2 and ERK1/2. These simvastatin anti-tumoral effects were reversed by metabolic products of the mevalonate pathway, including mevalonate, farnesyl pyrophosphate and geranylgeranyl pyrophosphate. These findings shed light on the biological and potential anti-tumoral effects of simvastatin in breast cancer.
Collapse
Affiliation(s)
- Tingting Wang
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
| | - Serena Seah
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
| | - Xinyi Loh
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
| | - Ching-Wan Chan
- Department of Surgery, National University Cancer Institute, National University Health System, Singapore, Singapore
| | - Mikael Hartman
- Department of Surgery, National University Cancer Institute, National University Health System, Singapore, Singapore
| | - Boon-Cher Goh
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.,Department of Haematology and Oncology, National University Cancer Institute, National University Health System, Singapore, Singapore
| | - Soo-Chin Lee
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.,Department of Haematology and Oncology, National University Cancer Institute, National University Health System, Singapore, Singapore
| |
Collapse
|
|
31
|
Murakami R, Chen C, Lyu SY, Lin CE, Tzeng PC, Wang TF, Chang JC, Shieh YH, Chen IF, Huang SK, Lin HW. Lovastatin lowers the risk of breast cancer: a population-based study using logistic regression with a random effects model. SPRINGERPLUS 2016; 5:1932. [PMID: 27872797 PMCID: PMC5101241 DOI: 10.1186/s40064-016-3606-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/24/2016] [Accepted: 10/27/2016] [Indexed: 12/11/2022]
Abstract
BACKGROUND Laboratory studies have demonstrated statin-induced apoptosis of cancer cells, including breast cancer cells, and evidence is accumulating on the mechanism of statin-induced apoptosis. However, despite numerous epidemiological studies, no consensus has been reached regarding the relationship between statin use and breast cancer risk. METHODS This retrospective case-control study enrolled 4332 breast cancer patients and 21,660 age-matched controls registered in the National Health Insurance program of Taiwan, which covers approximately 99% of the population. The study cases were women for whom a diagnosis of breast cancer (ICD-9-CM code 174.X) had been recorded in LHID2005 between January 1, 2004 and December 31, 2010. A logistic regression model was adjusted for potential confounding factors, including the level of urbanization, and the Charlson Comorbidity Index was applied to assess potential comorbidities. We also considered possible bias caused by random urbanization, because nutrition and lifestyle factors are related to breast cancer incidence. RESULTS Our results showed that lovastatin was associated with a lower risk of breast cancer (adjusted OR 0.596; 95% CI 0.497-0.714; p < 0.001), and atorvastatin exhibited a protective tendency against breast cancer (adjusted OR 0.887; 95% CI 0.776-1.013; p < 0.077). CONCLUSIONS Although no consensus has been established regarding the relationship between statin use and breast cancer risk, our study indicated that lovastatin is a potential chemopreventive agent against breast cancer. Further detailed research is warranted.
Collapse
Affiliation(s)
- Rimi Murakami
- Department of Family Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
| | - Chiehfeng Chen
- Division of Plastic Surgery, Department of Surgery, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.,Department of Public Health, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Evidence-Based Medicine Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.,Cochrane Taiwan, Taipei Medical University, Taipei, Taiwan
| | - Shu-Yu Lyu
- School of Public Health, Taipei Medical University, Taipei, Taiwan.,Department of Leisure Industry and Health Promotion, National Taipei University of Nursing and Health Sciences, Taipei, Taiwan
| | - Ching-En Lin
- Department of Family Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
| | - Pei-Chuan Tzeng
- Evidence-Based Medicine Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
| | - Tzu-Feng Wang
- Department of Family Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
| | - Juei-Chin Chang
- Department of Family Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
| | - Ying-Hua Shieh
- Department of Family Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
| | - I-Fan Chen
- Graduate Institute of Management of Technology, National Chiao Tung University, Hsinchu, Taiwan
| | - Shihping Kevin Huang
- Institute of Management of Technology, National Chiao Tung University, Hsinchu, Taiwan
| | - Hui-Wen Lin
- Evidence-Based Medicine Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.,Department of Mathematics, Soochow University, 70 Linhsi Road, Shihlin, Taipei, Taiwan
| |
Collapse
|
|
32
|
Abstract
Considerable debate exists regarding the potential antineoplastic effect of dietary long-chain n-3 PUFA contained in fatty fishes. Since the majority of published data has proven that their intake does not induce toxic or carcinogenic effects in humans, their possible preventive use against cancer has been suggested. On the other hand, it is unlikely that they could be effective in cancer patients as a single therapy. Nevertheless, a considerable effort has been put forth in recent years to evaluate the hypothesis that n-3 PUFA might improve the antineoplastic efficiency of currently used anticancer agents. The rationale for this therapeutic combinatory strategy is trying to increase cancer sensitivity to conventional therapies. This could allow the use of lower drug/radiation doses and, thereby, a reduction in the detrimental health effects associated with these treatments. We will here critically examine the studies that have investigated this possibility, by focusing particularly on the biological and molecular mechanisms underlying the antineoplastic effect of these combined treatments. A possible use of n-3 PUFA in combination with the innovative single-targeted anti-cancer therapies, that often are not completely devoid of dangerous side-effects, is also suggested.
Collapse
|
|
33
|
Woschek M, Kneip N, Jurida K, Marzi I, Relja B. Simvastatin Reduces Cancerogenic Potential of Renal Cancer Cells via Geranylgeranyl Pyrophosphate and Mevalonate Pathway. Nutr Cancer 2016; 68:420-7. [PMID: 27042994 DOI: 10.1080/01635581.2016.1152383] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Simvastatin is a cholesterol-lowering drug, inhibiting 3-hydroxy-3-methylglutaryl-coenzyme CoA (HMG-CoA) reductase. Previous studies have indicated the anticancerous effects of simvastatin. Here, we evaluated the anticancerous potential of simvastatin in renal cell carcinoma (RCC) cell lines. RCC occurs with an incidence of 2-3% of all cancer entities with high chemoresistance rate. Therefore, the understanding of underlying mechanisms for RCC activity and the development of alternative therapies are essential. Human RCC cell lines Caki-1 and KTC-26 were treated with simvastatin (16 or 33 µM) for 48 or 72 h. The effects of the downstream substrates mevalonate (MA), farnesyl pyrophosphate (FPP), and geranylgeranyl pyrophosphate (GGPP) were evaluated using add-back experiments. Cell growth was assessed using MTT assay. Apoptosis and cell cycle were analyzed by flow cytometry. Apoptosis-involved proteins were evaluated by Western blot. Simvastatin caused dose- and time-dependent inhibition of RCC cell growth by cell cycle arrest and apoptosis induction. Substitution of MA or GGPP abolished these effects to a large extent. These findings suggest that the antiproliferative effects of simvastatin are not only mediated through cholesterol deprivation but also by prenylation-associated mechanisms, thereby providing new insights into tumor-suppressive ability of simvastatin and into novel additive treatment options in the management of RCC.
Collapse
Affiliation(s)
- Mathias Woschek
- a Department of Trauma , Hand and Reconstructive Surgery, University Hospital Frankfurt, Goethe University , Frankfurt am Main , Germany
| | - Niels Kneip
- a Department of Trauma , Hand and Reconstructive Surgery, University Hospital Frankfurt, Goethe University , Frankfurt am Main , Germany
| | - Katrin Jurida
- a Department of Trauma , Hand and Reconstructive Surgery, University Hospital Frankfurt, Goethe University , Frankfurt am Main , Germany
| | - Ingo Marzi
- a Department of Trauma , Hand and Reconstructive Surgery, University Hospital Frankfurt, Goethe University , Frankfurt am Main , Germany
| | - Borna Relja
- a Department of Trauma , Hand and Reconstructive Surgery, University Hospital Frankfurt, Goethe University , Frankfurt am Main , Germany
| |
Collapse
|
|
34
|
Mahmoud AM, Aboul-Soud MAM, Han J, Al-Sheikh YA, Al-Abd AM, El-Shemy HA. Transcriptional profiling of breast cancer cells in response to mevinolin: Evidence of cell cycle arrest, DNA degradation and apoptosis. Int J Oncol 2016; 48:1886-94. [PMID: 26983896 PMCID: PMC4809649 DOI: 10.3892/ijo.2016.3418] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2015] [Accepted: 03/03/2016] [Indexed: 12/23/2022] Open
Abstract
The merging of high-throughput gene expression techniques, such as microarray, in the screening of natural products as anticancer agents, is considered the optimal solution for gaining a better understanding of the intervention mechanism. Red yeast rice (RYR), a Chinese dietary product, contains a mixture of hypocholesterolemia agents such as statins. Typically, statins have this effect via the inhibition of HMG-CoA reductase, the key enzyme in the biosynthesis of cholesterol. Recently, statins have been shown to exhibit various beneficial antineoplastic properties through the disruption of tumor angiogenesis and metastatic processes. Mevinolin (MVN) is a member of statins and is abundantly present in RYR. Early experimental trials suggested that the mixed apoptotic/necrotic cell death pathway is activated in response to MVN exposure. In the current study, the cytotoxic profile of MVN was evaluated against MCF-7, a breast cancer-derived cell line. The obtained results indicated that MVN-induced cytotoxicity is multi-factorial involving several regulatory pathways in the cytotoxic effects of MVN on breast cancer cell lines. In addition, MVN-induced transcript abundance profiles inferred from microarrays showed significant changes in some key cell processes. The changes were predicted to induce cell cycle arrest and reactive oxygen species generation but inhibit DNA repair and cell proliferation. This MVN-mediated multi-factorial stress triggered specific programmed cell death (apoptosis) and DNA degradation responses in breast cancer cells. Taken together, the observed MVN-induced effects underscore the potential of this ubiquitous natural compound as a selective anticancer activity, with broad safety margins and low cost compared to benchmarked traditional synthetic chemotherapeutic agents. Additionally, the data support further pre-clinical and clinical evaluations of MVN as a novel strategy to combat breast cancer and overcome drug resistance.
Collapse
Affiliation(s)
- Ali M Mahmoud
- Department of Biochemistry, Faculty of Agriculture, Cairo University, Giza 12613, Egypt
| | - Mourad A M Aboul-Soud
- Department of Biochemistry, Faculty of Agriculture, Cairo University, Giza 12613, Egypt
| | - Junkyu Han
- Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki 305‑8572, Japan
| | - Yazeed A Al-Sheikh
- Chair of Medical and Molecular Genetics Research, Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, Riyadh 11433, Kingdom of Saudi Arabia
| | - Ahmed M Al-Abd
- Department of Pharmacology, Medical Division, National Research Centre, Cairo 21622, Egypt
| | - Hany A El-Shemy
- Department of Biochemistry, Faculty of Agriculture, Cairo University, Giza 12613, Egypt
| |
Collapse
|
|
35
|
Yang T, Yao H, He G, Song L, Liu N, Wang Y, Yang Y, Keller ET, Deng X. Effects of Lovastatin on MDA-MB-231 Breast Cancer Cells: An Antibody Microarray Analysis. J Cancer 2016; 7:192-9. [PMID: 26819643 PMCID: PMC4716852 DOI: 10.7150/jca.13414] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2015] [Accepted: 10/27/2015] [Indexed: 12/21/2022] Open
Abstract
Despite the tremendous improvement in cancer therapeutics, treatment of late-stage breast cancer remains a challenge for both basic scientists and clinicians. Lovastatin, a natural product derived from Aspergillus terreus or Monascus ruber, has been widely used as cholesterol-lowing drug in the clinic. It also has anti-cancer properties through poorly defined molecular mechanisms. In the present study, we employed a novel antibody microarray technology to investigate the molecular mechanisms through which lovastatin inhibits breast cancer. We found that lovastatin up-regulated 17 proteins and down-regulated 20 proteins in MDA-MB-231 breast cancer cells. These included proteins that modulate apoptosis, cell proliferation, differentiation, signal transduction, epithelial-to-mesenchymal transition and tumor metastasis. Modulation of these pathways may mediate, in part, the inhibitory activity of lovastatin on breast cancer.
Collapse
Affiliation(s)
- Tao Yang
- 1. National Engineering Laboratory for Rice and Byproduct Deep Processing, Central South University of Forestry and Technology, Changsha, Hunan 410004, China
| | - Hui Yao
- 2. Medical College, Hunan Normal University, Changsha, Hunan 410013, China
| | - Guangchun He
- 2. Medical College, Hunan Normal University, Changsha, Hunan 410013, China
| | - Liujiang Song
- 2. Medical College, Hunan Normal University, Changsha, Hunan 410013, China
| | - Ning Liu
- 2. Medical College, Hunan Normal University, Changsha, Hunan 410013, China
| | - Yan Wang
- 1. National Engineering Laboratory for Rice and Byproduct Deep Processing, Central South University of Forestry and Technology, Changsha, Hunan 410004, China
| | - Yingke Yang
- 3. College of Biology, Hunan University, Changsha, Hunan 410082, China
| | - Evan T Keller
- 4. Department of Urology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Xiyun Deng
- 2. Medical College, Hunan Normal University, Changsha, Hunan 410013, China
| |
Collapse
|
|
36
|
Wolfe AR, Debeb BG, Lacerda L, Larson R, Bambhroliya A, Huang X, Bertucci F, Finetti P, Birnbaum D, Van Laere S, Diagaradjan P, Ruffell B, Trenton NJ, Chu K, Hittelman W, Diehl M, Levental I, Ueno NT, Woodward WA. Simvastatin prevents triple-negative breast cancer metastasis in pre-clinical models through regulation of FOXO3a. Breast Cancer Res Treat 2015; 154:495-508. [PMID: 26590814 PMCID: PMC5901982 DOI: 10.1007/s10549-015-3645-3] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2015] [Accepted: 11/13/2015] [Indexed: 12/12/2022]
Abstract
We previously reported using statins was correlated with improved metastasis-free survival in aggressive breast cancer. The purpose of this study was to examine the effect of statins on metastatic colonization by triple-negative breast cancer (TNBC) cells. TNBC cell lines were treated with simvastatin and then studied for cell cycle progression and proliferation in vitro, and metastasis formation in vivo, following injection of statin-treated cells. Reverse-phase protein assay (RPPA) analysis was performed on statin-treated and control breast cancer cells. RNA interference targeting FOXO3a was used to measure the impact of simvastatin on FOXO3a-expressing cells. The prognostic value of FOXO3a mRNA expression was examined in eight public breast cancer gene expression datasets including 1479 patients. Simvastatin increased G1/S-phase arrest of the cell cycle and inhibited both proliferation and migration of TNBC cells in vitro. In vitro pre-treatment and in vivo treatment with simvastatin reduced metastases. Phosphorylated FOXO3a was downregulated after simvastatin treatment in (RPPA) analysis. Ectopic expression of FOXO3a enhanced mammosphere formation and migratory capacity in vitro. Knockdown of FOXO3a attenuated the effect of simvastatin on mammosphere formation and migration. Analysis of public gene expression data demonstrates FOXO3a mRNA downregulation was independently associated with shorter metastasis-free survival in all breast cancers, as well as in TNBC breast cancers. Simvastatin inhibits in vitro endpoints associated with metastasis through a FOXO3a mechanism and reduced metastasis formation in vivo. FOXO3a expression is prognostic for metastasis formation in patient data. Further investigation of simvastatin as a cancer therapy is warranted.
Collapse
Affiliation(s)
- Adam R Wolfe
- MD Anderson Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd. Unit 1202, Houston, TX, 77030, USA
| | - Bisrat G Debeb
- MD Anderson Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd. Unit 1202, Houston, TX, 77030, USA
| | - Lara Lacerda
- MD Anderson Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd. Unit 1202, Houston, TX, 77030, USA
| | - Richard Larson
- MD Anderson Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd. Unit 1202, Houston, TX, 77030, USA
| | - Arvind Bambhroliya
- MD Anderson Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd. Unit 1202, Houston, TX, 77030, USA
| | - Xuelin Huang
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Francois Bertucci
- Department of Molecular Oncology, Institut Paoli-Calmettes, Marseille, France
| | - Pascal Finetti
- Department of Molecular Oncology, Institut Paoli-Calmettes, Marseille, France
| | - Daniel Birnbaum
- Department of Molecular Oncology, Institut Paoli-Calmettes, Marseille, France
| | | | - Parmeswaran Diagaradjan
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd. Unit 1202, Houston, TX, 77030, USA
| | - Brian Ruffell
- Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA
| | - Nicholaus J Trenton
- Departments of Chemistry and Bioengineering, Rice University, Houston, TX, USA
| | - Khoi Chu
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Walter Hittelman
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Michael Diehl
- Departments of Chemistry and Bioengineering, Rice University, Houston, TX, USA
| | - Ilya Levental
- Department of Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Naoto T Ueno
- MD Anderson Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Wendy A Woodward
- MD Anderson Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd. Unit 1202, Houston, TX, 77030, USA.
| |
Collapse
|
|
37
|
Xiao H, Chen W, Tang GX, Smeekens JM, Wu R. Systematic Investigation of Cellular Response and Pleiotropic Effects in Atorvastatin-Treated Liver Cells by MS-Based Proteomics. J Proteome Res 2015; 14:1600-11. [DOI: 10.1021/pr501277g] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- Haopeng Xiao
- School
of Chemistry and Biochemistry
and the Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia 30332, United States
| | - Weixuan Chen
- School
of Chemistry and Biochemistry
and the Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia 30332, United States
| | - George X. Tang
- School
of Chemistry and Biochemistry
and the Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia 30332, United States
| | - Johanna M. Smeekens
- School
of Chemistry and Biochemistry
and the Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia 30332, United States
| | - Ronghu Wu
- School
of Chemistry and Biochemistry
and the Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia 30332, United States
| |
Collapse
|
|
38
|
Chen CC, Wu ML, Ho CT, Huang TC. Blockade of the Ras/Raf/ERK and Ras/PI3K/Akt Pathways by Monacolin K Reduces the Expression of GLO1 and Induces Apoptosis in U937 Cells. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2015; 63:1186-1195. [PMID: 25569448 DOI: 10.1021/jf505275s] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
Abstract
Monacolin K, a hydrolytic product of icaritin, is the major active component in the traditional fermented Monascus purpureus. Monacolin K inhibits the proliferation of acute myeloid leukemia (AML), but underlying mechanisms remain to be identified. The present study demonstrates that monacolin K inhibits the proliferation of human AML cell line U937 in a dose-dependent manner. Importantly, morphological, DNA fragmentation, and image cytometry analyses indicated that monacolin K induced U937 cell apoptosis. Monacolin K could inactivate Ras translocation from cytosol to cell membrane. Monacolin K could also reduce the Ras-dependent phosphorylation of ERK and Akt, and the subsequent translocation of nuclear factor kappa B (NF-κB) from cytosol to nucleus in U937 cells. The underlying mechanisms of apoptotic activity of monacolin K were associated with inhibition of the Ras/Raf/ERK and Ras/PI3K/Akt signals and down-regulation of HMG-CoA reductase and glyoxalase 1. On the basis of results obtained using specific inhibitors U0126, LY294002, and JSH-23, the Ras/Raf/ERK/NF-κB/GLO1 and Ras/Akt/NF-κB/GLO1 pathways were proposed for the apoptotic effect of monacolin K in U937 cells.
Collapse
Affiliation(s)
- Chun-Chia Chen
- Department of Food Science, National Pingtung University of Science and Technology , Pingtung 91201, Taiwan
| | - Mei-Li Wu
- Department of Food Science, National Pingtung University of Science and Technology , Pingtung 91201, Taiwan
| | - Chi-Tang Ho
- Department of Food Science, Rutgers University , New Brunswick, New Jersey 08901, United States
| | - Tzou-Chi Huang
- Department of Food Science, National Pingtung University of Science and Technology , Pingtung 91201, Taiwan
| |
Collapse
|
|
39
|
Chen CB, Chen J, Wang J, Zhu YY, Shi JH. Combined spectroscopic and molecular docking approach to probing binding interactions between lovastatin and calf thymus DNA. LUMINESCENCE 2015; 30:1004-10. [DOI: 10.1002/bio.2851] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2014] [Revised: 12/03/2014] [Accepted: 12/29/2014] [Indexed: 01/21/2023]
Affiliation(s)
- C.-B. Chen
- College of Pharmaceutical Science; Zhejiang University of Technology; Hangzhou 310032 China
| | - J. Chen
- College of Pharmaceutical Science; Zhejiang University of Technology; Hangzhou 310032 China
| | - J. Wang
- College of Pharmaceutical Science; Zhejiang University of Technology; Hangzhou 310032 China
| | - Y.-Y. Zhu
- College of Pharmaceutical Science; Zhejiang University of Technology; Hangzhou 310032 China
| | - J.-H. Shi
- College of Pharmaceutical Science; Zhejiang University of Technology; Hangzhou 310032 China
- State Key Laboratory Breeding Base of Green Chemistry Synthesis Technology; Zhejiang University of Technology; Hangzhou 310032 China
| |
Collapse
|
|
40
|
Ahern TP, Lash TL, Damkier P, Christiansen PM, Cronin-Fenton DP. Statins and breast cancer prognosis: evidence and opportunities. Lancet Oncol 2015; 15:e461-8. [PMID: 25186049 DOI: 10.1016/s1470-2045(14)70119-6] [Citation(s) in RCA: 138] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Much preclinical and epidemiological evidence supports the anticancer effects of statins. Epidemiological evidence does not suggest an association between statin use and reduced incidence of breast cancer, but does support a protective effect of statins--especially simvastatin--on breast cancer recurrence. Here, we argue that the existing evidence base is sufficient to justify a clinical trial of breast cancer adjuvant therapy with statins and we advocate for such a trial to be initiated without delay. If a protective effect of statins on breast cancer recurrence is supported by trial evidence, then the indications for a safe, well tolerated, and inexpensive treatment can be expanded to improve outcomes for breast cancer survivors. We discuss several trial design opportunities--including candidate predictive biomarkers of statin safety and efficacy--and offer solutions to the key challenges involved in the enrolment, follow-up, and analysis of such a trial.
Collapse
Affiliation(s)
- Thomas P Ahern
- Departments of Surgery and Biochemistry, University of Vermont College of Medicine, Burlington, VT, USA.
| | - Timothy L Lash
- Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA
| | - Per Damkier
- Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark
| | - Peer M Christiansen
- Unit of Breast and Endocrine Surgery, Aarhus University Hospital, Aarhus, Denmark; Danish Breast Cancer Cooperative Group, Copenhagen, Denmark
| | | |
Collapse
|
|
41
|
Cao MD, Lamichhane S, Lundgren S, Bofin A, Fjøsne H, Giskeødegård GF, Bathen TF. Metabolic characterization of triple negative breast cancer. BMC Cancer 2014; 14:941. [PMID: 25495193 PMCID: PMC4295321 DOI: 10.1186/1471-2407-14-941] [Citation(s) in RCA: 111] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2014] [Accepted: 11/25/2014] [Indexed: 01/11/2023] Open
Abstract
Background The aims of this study were to characterize the metabolite profiles of triple negative breast cancer (TNBC) and to investigate the metabolite profiles associated with human epidermal growth factor receptor-2/neu (HER-2) overexpression using ex vivo high resolution magic angle spinning magnetic resonance spectroscopy (HR MAS MRS). Metabolic alterations caused by the different estrogen receptor (ER), progesterone receptor (PgR) and HER-2 receptor statuses were also examined. To investigate the metabolic differences between two distinct receptor groups, TNBC tumors were compared to tumors with ERpos/PgRpos/HER-2pos status which for the sake of simplicity is called triple positive breast cancer (TPBC). Methods The study included 75 breast cancer patients without known distant metastases. HR MAS MRS was performed for identification and quantification of the metabolite content in the tumors. Multivariate partial least squares discriminant analysis (PLS-DA) modeling and relative metabolite quantification were used to analyze the MR data. Results Choline levels were found to be higher in TNBC compared to TPBC tumors, possibly related to cell proliferation and oncogenic signaling. In addition, TNBC tumors contain a lower level of Glutamine and a higher level of Glutamate compared to TPBC tumors, which indicate an increase in glutaminolysis metabolism. The development of glutamine dependent cell growth or “Glutamine addiction” has been suggested as a new therapeutic target in cancer. Our results show that the metabolite profiles associated with HER-2 overexpression may affect the metabolic characterization of TNBC. High Glycine levels were found in HER-2pos tumors, which support Glycine as potential marker for tumor aggressiveness. Conclusions Metabolic alterations caused by the individual and combined receptors involved in breast cancer progression can provide a better understanding of the biochemical changes underlying the different breast cancer subtypes. Studies are needed to validate the potential of metabolic markers as targets for personalized treatment of breast cancer subtypes.
Collapse
Affiliation(s)
- Maria D Cao
- Department of Circulation and Medical Imaging, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
| | | | | | | | | | | | | |
Collapse
|
|
42
|
Kanugula AK, Dhople VM, Völker U, Ummanni R, Kotamraju S. Fluvastatin mediated breast cancer cell death: a proteomic approach to identify differentially regulated proteins in MDA-MB-231 cells. PLoS One 2014; 9:e108890. [PMID: 25268751 PMCID: PMC4182601 DOI: 10.1371/journal.pone.0108890] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2014] [Accepted: 09/04/2014] [Indexed: 01/12/2023] Open
Abstract
Statins are increasingly being recognized as anti-cancer agents against various cancers including breast cancer. To understand the molecular pathways targeted by fluvastatin and its differential sensitivity against metastatic breast cancer cells, we analyzed protein alterations in MDA-MB-231 cells treated with fluvastatin using 2-DE in combination with LC-MS/MS. Results revealed dys-regulation of 39 protein spots corresponding to 35 different proteins. To determine the relevance of altered protein profiles with breast cancer cell death, we mapped these proteins to major pathways involved in the regulation of cell-to-cell signaling and interaction, cell cycle, Rho GDI and proteasomal pathways using IPA analysis. Highly interconnected sub networks showed that vimentin and ERK1/2 proteins play a central role in controlling the expression of altered proteins. Fluvastatin treatment caused proteolysis of vimentin, a marker of epithelial to mesenchymal transition. This effect of fluvastatin was reversed in the presence of mevalonate, a downstream product of HMG-CoA and caspase-3 inhibitor. Interestingly, fluvastatin neither caused an appreciable cell death nor did modulate vimentin expression in normal mammary epithelial cells. In conclusion, fluvastatin alters levels of cytoskeletal proteins, primarily targeting vimentin through increased caspase-3- mediated proteolysis, thereby suggesting a role for vimentin in statin-induced breast cancer cell death.
Collapse
Affiliation(s)
| | - Vishnu M. Dhople
- Interfacultary Institute of Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany
| | - Uwe Völker
- Interfacultary Institute of Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany
| | - Ramesh Ummanni
- Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad, India
- * E-mail: (SK); (RU)
| | - Srigiridhar Kotamraju
- Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad, India
- * E-mail: (SK); (RU)
| |
Collapse
|
|
43
|
Pisanti S, Picardi P, Ciaglia E, D'Alessandro A, Bifulco M. Novel prospects of statins as therapeutic agents in cancer. Pharmacol Res 2014; 88:84-98. [PMID: 25009097 DOI: 10.1016/j.phrs.2014.06.013] [Citation(s) in RCA: 89] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2014] [Revised: 06/25/2014] [Accepted: 06/25/2014] [Indexed: 02/07/2023]
Abstract
Statins are well known competitive inhibitors of hydroxymethylglutaryl-CoA reductase enzyme (HMG-CoA reductase), thus traditionally used as cholesterol-lowering agents. In recent years, more and more effects of statins have been revealed. Nowadays alterations of lipid metabolism have been increasingly recognized as a hallmark of cancer cells. Consequently, much attention has been directed toward the potential of statins as therapeutic agents in the oncological field. Accumulated in vitro and in vivo clinical evidence point out the role of statins in a variety of human malignancies, in regulating tumor cell growth and anti-tumor immune response. Herein, we summarize and discuss, in light of the most recent observations, the anti-tumor effects of statins, underpinning the detailed mode of action and looking for their true significance in cancer prevention and treatment, to determine if and in which case statin repositioning could be really justified for neoplastic diseases.
Collapse
Affiliation(s)
- Simona Pisanti
- Department of Medicine and Surgery, University of Salerno, Italy; Department of Pharmacy, University of Salerno, Italy.
| | - Paola Picardi
- Department of Medicine and Surgery, University of Salerno, Italy; Department of Pharmacy, University of Salerno, Italy
| | - Elena Ciaglia
- Department of Medicine and Surgery, University of Salerno, Italy; Department of Pharmacy, University of Salerno, Italy
| | - Alba D'Alessandro
- Department of Medicine and Surgery, University of Salerno, Italy; Department of Pharmacy, University of Salerno, Italy
| | - Maurizio Bifulco
- Department of Medicine and Surgery, University of Salerno, Italy; Department of Pharmacy, University of Salerno, Italy.
| |
Collapse
|
|
44
|
Zhang A, Yan G, Han Y, Wang X. Metabolomics Approaches and Applications in Prostate Cancer Research. Appl Biochem Biotechnol 2014; 174:6-12. [DOI: 10.1007/s12010-014-0955-6] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2013] [Accepted: 05/09/2014] [Indexed: 01/04/2023]
|
|
45
|
Pampalakis G, Obasuyi O, Papadodima O, Chatziioannou A, Zoumpourlis V, Sotiropoulou G. The KLK5 protease suppresses breast cancer by repressing the mevalonate pathway. Oncotarget 2014; 5:2390-403. [PMID: 24158494 PMCID: PMC4058013 DOI: 10.18632/oncotarget.1235] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2013] [Accepted: 09/01/2013] [Indexed: 12/21/2022] Open
Abstract
Kallikrein-related peptidase 5 (KLK5) displays aberrant expression in cancer. However, any functional association is missing. Here, we show that reconstitution of KLK5 expression in non-expressing MDA-MB-231 breast cancer cells suppresses malignancy in vitro and in vivo dose-dependently. Reactivation of KLK5 suppressed key EMT genes. Unexpectedly, we identified altered expression of genes encoding enzymes of the mevalonate pathway typical of those observed upon cholesterol starvation. Consistently, we found that SREBF1, the master regulator of the mevalonate pathway was induced. KLK5 re-expression leads to reduced cellular cholesterol and fatty acid synthesis and enhanced uptake of LDL-cholesterol. Suppression of the mevalonate pathway in KLK5 transfectants was further shown by reduced synthesis of isoprenoids. Indeed, we found diminished levels of active RhoA, a signaling oncoprotein that requires prenylation for activation. We propose that reduced RhoA activation plays a dominant role in suppression of malignancy by KLK5, since geranylgeranyl pyrophosphate restored active RhoA in KLK5-reverted cells resulting in increased malignancy. For the first time, we suggest that a protease may suppress breast cancer by modulating the mevalonate pathway.
Collapse
Affiliation(s)
| | - Osahon Obasuyi
- Department of Pharmacy, University of Patras, Rion-Patras 26500
| | | | | | | | | |
Collapse
|
|
46
|
Characterization of lovastatin–docosahexaenoate anticancer properties against breast cancer cells. Bioorg Med Chem 2014; 22:1899-908. [DOI: 10.1016/j.bmc.2014.01.051] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2013] [Revised: 01/14/2014] [Accepted: 01/27/2014] [Indexed: 12/21/2022]
|
|
47
|
Metabolomics in noninvasive breast cancer. Clin Chim Acta 2013; 424:3-7. [PMID: 23669185 DOI: 10.1016/j.cca.2013.05.003] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2013] [Revised: 05/03/2013] [Accepted: 05/05/2013] [Indexed: 12/30/2022]
Abstract
Breast cancer remains the most leading cause of death among women worldwide. Common methods for diagnosis and surveillance include mammography, histopathology and blood tests. The major drawback of mammography is the high rate of false reports, aside from the risk from repeated exposure to harmful ionizing radiations; histopathology is time consuming and often prone to subjective interpretations; blood-based tests are attractive, but lack the sensitivity and specificity. Obviously, more sensitive biomarkers for early detection and molecular targets for better treating breast cancer are urgently needed. Fortunately, molecular level 'omics' diagnosis is becoming increasingly popular; metabolomics, diagnosis based on 'metabolic fingerprinting' may provide clinically useful biomarkers applied toward identifying metabolic alterations and has introduced new insights into the pathology of breast cancer. By applying advanced analytical and statistical tools, metabolomics involves the comprehensive profiling of the full complement of low molecular weight compounds in a biological system and could classify the basis of tumor biology of breast cancer, to identify new prognostic and predictive markers and discover new targets for future therapeutic interventions. This advanced bioanalytic methods may now open new avenues for diagnostics in cancer via discovery of biomarkers. In this review we take a closer look at the metabolomics used within the field of breast cancer diagnosis. Further, we highlight the most interesting metabolomics publications and discuss these in detail; additional studies are mentioned as a reference for the interested reader. A general trend is an increased focus on biological interpretation rather than merely the ability to classify samples.
Collapse
|
|
48
|
Plant sterols as anticancer nutrients: evidence for their role in breast cancer. Nutrients 2013; 5:359-87. [PMID: 23434903 PMCID: PMC3635199 DOI: 10.3390/nu5020359] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2012] [Revised: 11/30/2012] [Accepted: 01/24/2013] [Indexed: 12/12/2022] Open
Abstract
While many factors are involved in the etiology of cancer, it has been clearly established that diet significantly impacts one’s risk for this disease. More recently, specific food components have been identified which are uniquely beneficial in mitigating the risk of specific cancer subtypes. Plant sterols are well known for their effects on blood cholesterol levels, however research into their potential role in mitigating cancer risk remains in its infancy. As outlined in this review, the cholesterol modulating actions of plant sterols may overlap with their anti-cancer actions. Breast cancer is the most common malignancy affecting women and there remains a need for effective adjuvant therapies for this disease, for which plant sterols may play a distinctive role.
Collapse
|
|
49
|
Shi Y, Felley-Bosco E, Marti TM, Stahel RA. Differential effects of lovastatin on cisplatin responses in normal human mesothelial cells versus cancer cells: implication for therapy. PLoS One 2012; 7:e45354. [PMID: 23028957 PMCID: PMC3444484 DOI: 10.1371/journal.pone.0045354] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2012] [Accepted: 08/20/2012] [Indexed: 11/18/2022] Open
Abstract
The cancer killing efficacy of standard chemotherapeutic agents such as cisplatin (CDDP) is limited by their side effects to normal tissues. Therefore, research efforts optimizing the safety and efficacy of those agents are clinically relevant. We did screen for agents that specifically protect normal human mesothelial cells against CDDP without reducing the cancer cell killing efficacy. Lovastatin was identified from the screen. Lovastatin at a pharmacologically relevant concentration strongly arrested the proliferation of normal cells, whereas cancer cells were less affected. CDDP-induced DNA damage response was not activated and normal cells showed enhanced tolerance to CDDP when normal cells were treated with the combination of CDDP and lovastatin. We demonstrate that interfering with protein geranylgeranylation is involved in the lovastatin-mediated CDDP protective effect in normal cells. In contrast to normal cells, in cancer cells lovastatin did not change the CDDP-induced response, and cancer cells were not protected by lovastatin. Furthermore, lovastatin at the pharmacological relevant concentration per se induced DNA damage, oxidative stress and autophagy in cancer cells but not in normal mesothelial cells. Therefore, our data suggest that lovastatin has a potential to improve the therapeutic index of cisplatin-based therapy.
Collapse
Affiliation(s)
- Yandong Shi
- Laboratory of Molecular Oncology, University Hospital of Zürich, University of Zürich, Zürich, Switzerland.
| | | | | | | |
Collapse
|
|
50
|
Said HM, Polat B, Stein S, Guckenberger M, Hagemann C, Staab A, Katzer A, Anacker J, Flentje M, Vordermark D. Inhibition of N-Myc down regulated gene 1 in in vitro cultured human glioblastoma cells. World J Clin Oncol 2012; 3:104-10. [PMID: 22787578 PMCID: PMC3394081 DOI: 10.5306/wjco.v3.i7.104] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2011] [Revised: 12/10/2011] [Accepted: 06/30/2012] [Indexed: 02/06/2023] Open
Abstract
AIM: To study short dsRNA oligonucleotides (siRNA) as a potent tool for artificially modulating gene expression of N-Myc down regulated gene 1 (NDRG1) gene induced under different physiological conditions (Normoxia and hypoxia) modulating NDRG1 transcription, mRNA stability and translation.
METHODS: A cell line established from a patient with glioblastoma multiforme. Plasmid DNA for transfections was prepared with the Endofree Plasmid Maxi kit. From plates containing 5 × 107 cells, nuclear extracts were prepared according to previous protocols. The pSUPER-NDRG1 vectors were designed, two sequences were selected from the human NDRG1 cDNA (5’-GCATTATTGGCATGGGAAC-3’ and 5’-ATGCAGAGTAACGTGGAAG-3’. reverse transcription polymerase chain reaction was performed using primers designed using published information on β-actin and hypoxia-inducible factor (HIF)-1α mRNA sequences in GenBank. NDRG1 mRNA and protein level expression results under different conditions of hypoxia or reoxygenation were compared to aerobic control conditions using the Mann-Whitney U test. Reoxygenation values were also compared to the NDRG1 levels after 24 h of hypoxia (P < 0.05 was considered significant).
RESULTS: siRNA- and iodoacetate (IAA)-mediated downregulation of NDRG1 mRNA and protein expression in vitro in human glioblastoma cell lines showed a nearly complete inhibition of NDRG1 expression when compared to the results obtained due to the inhibitory role of glycolysis inhibitor IAA. Hypoxia responsive elements bound by nuclear HIF-1 in human glioblastoma cells in vitro under different oxygenation conditions and the clearly enhanced binding of nuclear extracts from glioblastoma cell samples exposed to extreme hypoxic conditions confirmed the HIF-1 Western blotting results.
CONCLUSION: NDRG1 represents an additional diagnostic marker for brain tumor detection, due to the role of hypoxia in regulating this gene, and it can represent a potential target for tumor treatment in human glioblastoma. The siRNA method can represent an elegant alternative to modulate the expression of the hypoxia induced NDRG1 gene and can help to monitor the development of the cancer disease treatment outcome through monitoring the expression of this gene in the patients undergoing the different therapeutic treatment alternatives available nowadays.
Collapse
Affiliation(s)
- Harun M Said
- Department of Radiation Oncology, University of Wuerzburg, 97080 Würzburg, Germany.
| | | | | | | | | | | | | | | | | | | |
Collapse
|