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1
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Etikyala U, Reddyrajula R, Vani T, Kuchana V, Dalimba U, Manga V. An in silico approach to identify novel and potential Akt1 (protein kinase B-alpha) inhibitors as anticancer drugs. Mol Divers 2025; 29:1009-1032. [PMID: 38796797 DOI: 10.1007/s11030-024-10887-9] [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: 03/22/2024] [Accepted: 04/27/2024] [Indexed: 05/29/2024]
Abstract
Akt1 (protein kinase B) has become a major focus of attention due to its significant functionality in a variety of cellular processes and the inhibition of Akt1 could lead to a decrease in tumour growth effectively in cancer cells. In the present work, we discovered a set of novel Akt1 inhibitors by using multiple computational techniques, i.e. pharmacophore-based virtual screening, molecular docking, binding free energy calculations, and ADME properties. A five-point pharmacophore hypothesis was implemented and validated with AADRR38. The obtained R2 and Q2 values are in the acceptable region with the values of 0.90 and 0.64, respectively. The generated pharmacophore model was employed for virtual screening to find out the potential Akt1 inhibitors. Further, the selected hits were subjected to molecular docking, binding free energy analysis, and refined using ADME properties. Also, we designed a series of 6-methoxybenzo[b]oxazole analogues by comprising the structural characteristics of the hits acquired from the database. Molecules D1-D10 were found to have strong binding interactions and higher binding free energy values. In addition, Molecular dynamic simulation was performed to understand the conformational changes of protein-ligand complex.
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Affiliation(s)
- Umadevi Etikyala
- Medicinal Chemistry Laboratory, Department of Chemistry, Osmania University, Hyderabad, 500076, India
| | - Rajkumar Reddyrajula
- Central Research Facility, National Institute of Technology Karnataka, Surathkal, Mangalore, 575025, India
| | - T Vani
- Medicinal Chemistry Laboratory, Department of Chemistry, Osmania University, Hyderabad, 500076, India
| | - Vinutha Kuchana
- Medicinal Chemistry Laboratory, Department of Chemistry, Osmania University, Hyderabad, 500076, India
| | - Udayakumar Dalimba
- Organic Chemistry Laboratory, Department of Chemistry, National Institute of Technology Karnataka, Surathkal, Mangalore, 575025, India
| | - Vijjulatha Manga
- Medicinal Chemistry Laboratory, Department of Chemistry, Osmania University, Hyderabad, 500076, India.
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Qiang M, Chen Z, Liu H, Dong J, Gong K, Zhang X, Huo P, Zhu J, Shao Y, Ma J, Zhang B, Liu W, Tang M. Targeting the PI3K/AKT/mTOR pathway in lung cancer: mechanisms and therapeutic targeting. Front Pharmacol 2025; 16:1516583. [PMID: 40041495 PMCID: PMC11877449 DOI: 10.3389/fphar.2025.1516583] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Accepted: 01/27/2025] [Indexed: 03/06/2025] Open
Abstract
Owing to its high mortality rate, lung cancer (LC) remains the most common cancer worldwide, with the highest malignancy diagnosis rate. The phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling (PAM) pathway is a critical intracellular pathway involved in various cellular functions and regulates numerous cellular processes, including growth, survival, proliferation, metabolism, apoptosis, invasion, and angiogenesis. This review aims to highlight preclinical and clinical studies focusing on the PAM signaling pathway in LC and underscore the potential of natural products targeting it. Additionally, this review synthesizes the existing literature and discusses combination therapy and future directions for LC treatment while acknowledging the ongoing challenges in the field. Continuous development of novel therapeutic agents, technologies, and precision medicine offers an increasingly optimistic outlook for the treatment of LC.
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Affiliation(s)
- Min Qiang
- Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, China
- College of Clinical Medicine, Jilin University, Changchun, China
| | - Zhe Chen
- Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, China
| | - Hongyang Liu
- College of Clinical Medicine, Jilin University, Changchun, China
| | - Junxue Dong
- Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany
| | - Kejian Gong
- Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, China
| | - Xinjun Zhang
- Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, China
| | - Peng Huo
- Laboratory of Infection Oncology, Institute of Clinical Molecular Biology, Christian-Albrechts-Universität zu Kiel and University Hospital Schleswig-Holstein, Kiel, Germany
| | - Jingjun Zhu
- Department of Thoracic and Cardiovascular Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Yifeng Shao
- Department of General Surgery, Capital Institute of Pediatrics’ Children’s Hospital, Beijing, China
| | - Jinazun Ma
- Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, China
| | - Bowei Zhang
- Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, China
| | - Wei Liu
- Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, China
| | - Mingbo Tang
- Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, China
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Sementino E, Hassan D, Bellacosa A, Testa JR. AKT and the Hallmarks of Cancer. Cancer Res 2024; 84:4126-4139. [PMID: 39437156 DOI: 10.1158/0008-5472.can-24-1846] [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: 06/01/2024] [Revised: 08/17/2024] [Accepted: 10/15/2024] [Indexed: 10/25/2024]
Abstract
Nearly a quarter century ago, Hanahan and Weinberg conceived six unifying principles explaining how normal cells transform into malignant tumors. Their provisional set of biological capabilities acquired during tumor development-cancer hallmarks-would evolve to 14 tenets as knowledge of cancer genomes, molecular mechanisms, and the tumor microenvironment expanded, most recently adding four emerging enabling characteristics: phenotypic plasticity, epigenetic reprogramming, polymorphic microbiomes, and senescent cells. AKT kinases are critical signaling molecules that regulate cellular physiology upon receptor tyrosine kinases and PI3K activation. The complex branching of the AKT signaling network involves several critical downstream nodes that significantly magnify its functional impact, such that nearly every organ system and cell in the body may be affected by AKT activity. Conversely, tumor-intrinsic dysregulation of AKT can have numerous adverse cellular and pathologic ramifications, particularly in oncogenesis, as multiple tumor suppressors and oncogenic proteins regulate AKT signaling. Herein, we review the mounting evidence implicating the AKT pathway in the aggregate of currently recognized hallmarks of cancer underlying the complexities of human malignant diseases. The challenges, recent successes, and likely areas for exciting future advances in targeting this complex pathway are also discussed.
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Affiliation(s)
- Eleonora Sementino
- Cancer Prevention and Control Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania
| | - Dalal Hassan
- Nuclear Dynamics and Cancer Program, Cancer Epigenetics Institute, Fox Chase Cancer Center, Philadelphia, Pennsylvania
- Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Alfonso Bellacosa
- Nuclear Dynamics and Cancer Program, Cancer Epigenetics Institute, Fox Chase Cancer Center, Philadelphia, Pennsylvania
| | - Joseph R Testa
- Cancer Prevention and Control Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania
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4
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Sheida A, Farshadi M, Mirzaei A, Najjar Khalilabad S, Zarepour F, Taghavi SP, Hosseini Khabr MS, Ravaei F, Rafiei S, Mosadeghi K, Yazdani MS, Fakhraie A, Ghattan A, Zamani Fard MM, Shahyan M, Rafiei M, Rahimian N, Talaei Zavareh SA, Mirzaei H. Potential of Natural Products in the Treatment of Glioma: Focus on Molecular Mechanisms. Cell Biochem Biophys 2024; 82:3157-3208. [PMID: 39150676 DOI: 10.1007/s12013-024-01447-x] [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] [Accepted: 07/17/2024] [Indexed: 08/17/2024]
Abstract
Despite the waning of traditional treatments for glioma due to possible long-term issues, the healing possibilities of substances derived from nature have been reignited in the scientific community. These natural substances, commonly found in fruits and vegetables, are considered potential alternatives to pharmaceuticals, as they have been shown in prior research to impact pathways surrounding cancer progression, metastases, invasion, and resistance. This review will explore the supposed molecular mechanisms of different natural components, such as berberine, curcumin, coffee, resveratrol, epigallocatechin-3-gallate, quercetin, tanshinone, silymarin, coumarin, and lycopene, concerning glioma treatment. While the benefits of a balanced diet containing these compounds are widely recognized, there is considerable scope for investigating the efficacy of these natural products in treating glioma.
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Affiliation(s)
- Amirhossein Sheida
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | | | - Amirhossein Mirzaei
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Shakiba Najjar Khalilabad
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Fatemeh Zarepour
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Seyed Pouya Taghavi
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Maryam Sadat Hosseini Khabr
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Fatemeh Ravaei
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Sara Rafiei
- Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences (IUMS), Tehran, Iran
- Department of Internal Medicine, School of Medicine, Firoozgar Hospital, Iran University of Medical Sciences, Tehran, Iran
| | - Kimia Mosadeghi
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Mohammad Sepehr Yazdani
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Ali Fakhraie
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Alireza Ghattan
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Mohammad Masoud Zamani Fard
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Maryam Shahyan
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Moein Rafiei
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Neda Rahimian
- Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences (IUMS), Tehran, Iran.
- Department of Internal Medicine, School of Medicine, Firoozgar Hospital, Iran University of Medical Sciences, Tehran, Iran.
| | | | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran.
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Hassan D, Menges CW, Testa JR, Bellacosa A. AKT kinases as therapeutic targets. J Exp Clin Cancer Res 2024; 43:313. [PMID: 39614261 PMCID: PMC11606119 DOI: 10.1186/s13046-024-03207-4] [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: 07/24/2024] [Accepted: 10/03/2024] [Indexed: 12/01/2024] Open
Abstract
AKT, or protein kinase B, is a central node of the PI3K signaling pathway that is pivotal for a range of normal cellular physiologies that also underlie several pathological conditions, including inflammatory and autoimmune diseases, overgrowth syndromes, and neoplastic transformation. These pathologies, notably cancer, arise if either the activity of AKT or its positive or negative upstream or downstream regulators or effectors goes unchecked, superimposed on by its intersection with a slew of other pathways. Targeting the PI3K/AKT pathway is, therefore, a prudent countermeasure. AKT inhibitors have been tested in many clinical trials, primarily in combination with other drugs. While some have recently garnered attention for their favorable profile, concern over resistance and off-target effects have continued to hinder their widespread adoption in the clinic, mandating a discussion on alternative modes of targeting. In this review, we discuss isoform-centric targeting that may be more effective and less toxic than traditional pan-AKT inhibitors and its significance for disease prevention and treatment, including immunotherapy. We also touch on the emerging mutant- or allele-selective covalent allosteric AKT inhibitors (CAAIs), as well as indirect, novel AKT-targeting approaches, and end with a briefing on the ongoing quest for more reliable biomarkers predicting sensitivity and response to AKT inhibitors, and their current state of affairs.
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Affiliation(s)
- Dalal Hassan
- Nuclear Dynamics and Cancer Program, Cancer Epigenetics Institute, Institute for Cancer Research, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA
- Thomas Jefferson University, 901 Walnut St, Philadelphia, PA, 19107, USA
| | - Craig W Menges
- Cancer Prevention and Control Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA
| | - Joseph R Testa
- Cancer Prevention and Control Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA
| | - Alfonso Bellacosa
- Nuclear Dynamics and Cancer Program, Cancer Epigenetics Institute, Institute for Cancer Research, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA.
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Xu M, Li X, Yuan C, Zhu T, Wang M, Zhu Y, Duan Y, Yao J, Luo B, Wang Z, Yin S, Zhao Y. Ursolic Acid Inhibits Glycolysis of Ovarian Cancer via KLF5/PI3K/AKT Signaling Pathway. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2024; 52:2211-2231. [PMID: 39614414 DOI: 10.1142/s0192415x2450085x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/01/2024]
Abstract
Glycolysis is one of the key metabolic reprogramming characteristics of ovarian cancer. Ursolic Acid (UA), as a natural compound, exerts a beneficial regulatory effect on tumor metabolism. In this study, we have confirmed through RNA-seq analysis and a series of in vitro and in vivo functional experiments that UA significantly inhibits ovarian cancer cell proliferation, promotes tumor apoptosis, and reduces glycolysis levels. Additionally, it demonstrates synergistic therapeutic effects with cisplatin in both in vitro and in vivo experiments. Furthermore, at the molecular level, we found that UA inhibits glycolysis in ovarian cancer by binding to the transcription factor KLF5 and blocking the transcriptional expression of the downstream PI3K/AKT signaling pathway, thereby exerting its therapeutic effect. In conclusion, our research indicates that UA can inhibit the proliferation, apoptosis, and glycolysis levels of ovarian cancer cells through the KLF5/PI3K/AKT signaling axis. Our findings offer a new perspective on the therapeutic application of the natural compound UA in ovarian cancer and support its potential development as a candidate for chemotherapy.
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Affiliation(s)
- Meng Xu
- Cancer Institute, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, P. R. China
| | - Xiaoqi Li
- Department of Gynecologic Oncology, Fudan University Shanghai Cancer Centre, Shanghai 200032, P. R. China
| | - Chenyue Yuan
- Cancer Institute, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, P. R. China
| | - Tingting Zhu
- Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200090, P. R. China
| | - Mengfei Wang
- Cancer Institute, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, P. R. China
| | - Ying Zhu
- Central Laboratory, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, P. R. China
| | - Yanqiu Duan
- Central Laboratory, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, P. R. China
| | - Jialiang Yao
- Department of Oncology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, P. R. China
| | - Bin Luo
- Department of Oncology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, P. R. China
| | - Ziliang Wang
- Cancer Institute, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, P. R. China
| | - Sheng Yin
- Department of Obstetrics and Gynecology, Zhongshan Hospital, Fudan University, Shanghai 200032, P. R. China
| | - Yuqing Zhao
- Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200090, P. R. China
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Li SL, Wang PY, Jia YP, Zhang ZX, He HY, Chen PY, Liu X, Liu B, Lu L, Fu WH. BIRC3 induces the phosphoinositide 3-kinase-Akt pathway activation to promote trastuzumab resistance in human epidermal growth factor receptor 2-positive gastric cancer. World J Gastrointest Oncol 2024; 16:4436-4455. [PMID: 39554734 PMCID: PMC11551635 DOI: 10.4251/wjgo.v16.i11.4436] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Revised: 08/13/2024] [Accepted: 09/10/2024] [Indexed: 10/25/2024] Open
Abstract
BACKGROUND Trastuzumab-targeted therapy is currently the standard of care for advanced human epidermal growth factor receptor 2 (HER2)-positive gastric cancer. However, the emergence of resistance to trastuzumab poses significant challenges. AIM To identify the key genes associated with trastuzumab resistance. These results provide a basis for the development of interventions to address drug resistance and improve patient outcomes. METHODS High-throughput sequencing and bioinformatics were used to identify the differentially expressed pivotal gene BIRC3 and delineate its potential function and pathway regulation. Tumor samples were collected from patients with HER2-positive gastric cancer to evaluate the correlation between BIRC3 expression and trastuzumab resistance. We established gastric cancer cell lines with both highly expressed and suppressed levels of BIRC3, followed by comprehensive in vitro and in vivo experiments to confirm the involvement of BIRC3 in trastuzumab resistance and to elucidate its underlying mechanisms. RESULTS In patients with HER2-positive gastric cancer, there is a significant correlation between elevated BIRC3 expression in tumor tissues and higher T stage, tumor node metastasis stage, as well as poor overall survival and progression-free survival. BIRC3 is highly expressed in trastuzumab-resistant gastric cancer cell lines, where it inhibits tumor cell apoptosis and enhances trastuzumab resistance by promoting the phosphorylation and activation of the phosphoinositide 3-kinase-Akt (PI3K-AKT) pathway in HER2-positive gastric cancer cells, both in vivo and in vitro. CONCLUSION This study revealed a robust association between high BIRC3 expression and an unfavorable prognosis in patients with HER2-positive gastric cancer. Thus, the high expression of BIRC3 stimulated PI3K-AKT phosphorylation and activation, stimulating the proliferation of HER2-positive tumor cells and suppressing apoptosis, ultimately leading to trastuzumab resistance.
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Affiliation(s)
- Shu-Liang Li
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin 300052, China
- Department of Gastrointestinal Surgery, The Second People’s Hospital of Liaocheng, Liaocheng 252600, Shandong Province, China
- Department of Gastrointestinal Surgery, The Second Hospital of Liaocheng, Affiliated to Shandong First Medical University, Liaocheng 252600, Shandong Province, China
| | - Pei-Yao Wang
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin 300052, China
| | - Yang-Pu Jia
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin 300052, China
| | - Zhao-Xiong Zhang
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin 300052, China
| | - Hao-Yu He
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin 300052, China
| | - Peng-Yu Chen
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin 300052, China
| | - Xin Liu
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin 300052, China
| | - Bang Liu
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin 300052, China
| | - Li Lu
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin 300052, China
| | - Wei-Hua Fu
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin 300052, China
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Aliyari M, Hashemy SI, Hashemi SF, Reihani A, Kesharwani P, Hosseini H, Sahebkar A. Targeting the Akt signaling pathway: Exploiting curcumin's anticancer potential. Pathol Res Pract 2024; 261:155479. [PMID: 39068859 DOI: 10.1016/j.prp.2024.155479] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2024] [Revised: 07/13/2024] [Accepted: 07/19/2024] [Indexed: 07/30/2024]
Abstract
Cancer is recognized as one of the leading causes of death worldwide. In recent years, advancements in early detection and expanding treatment options have contributed to a decrease in mortality rates. However, the emergence of drug-resistant cancers necessitates the exploration of innovative and more effective drugs. The Akt kinases play a central role in various signaling pathways that regulate crucial cellular processes, including cell growth, proliferation, survival, angiogenesis, and glucose metabolism. Due to frequent disruptions of the Akt signaling pathway in numerous human cancers and its broad biological implications, targeting this pathway has become a key focus in combating tumor aggressiveness and a promising avenue for therapeutic intervention. Curcumin, a compound found in turmeric, has been extensively studied for its potential as an anti-cancer agent. It demonstrates inhibitory effects on cancer initiation, progression, and metastasis by influencing various processes involved in tumor growth and development. These effects are achieved through negative regulation of transcription factors, growth factors, cytokines, protein kinases, and other oncogenic molecules. This review aims to explore curcumin's anticancer activity against different types of cancer mediated via the PI3K/Akt signaling pathway, as well as its practical applications in treatment.
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Affiliation(s)
- Mahdieh Aliyari
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed Isaac Hashemy
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Surgical Oncology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyedeh Fatemeh Hashemi
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amirali Reihani
- Surgical Oncology Research Center, 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; Metabolic Syndrome Research Center, 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.
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9
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AnnaDurai KS, Chandrasekaran N, Velraja S, Hikku GS, Parvathi VD. Essential oil nanoemulsion: An emerging eco-friendly strategy towards mosquito control. Acta Trop 2024; 257:107290. [PMID: 38909722 DOI: 10.1016/j.actatropica.2024.107290] [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: 04/01/2024] [Revised: 06/12/2024] [Accepted: 06/12/2024] [Indexed: 06/25/2024]
Abstract
Mosquito borne diseases are impeding to human health due to their uncontrolled proliferation. Various commercial insecticides currently used become ineffective due to the resistance acquired by mosquitoes. It is necessary and a priority to combat mosquito population. Plant-based products are gaining interest over the past few decades due to their environment friendliness and their effectiveness in controlling mosquitoes along with their lack of toxicity. Essential oil nanoemulsions are found to be highly effective when compared to their bulk counterparts. Due to their nano size, they can effectively interact and yield 100 % mortality with the mosquito larvae and encounter with minimal concentrations. This is the main advantage of the nano-sized particles due to which they find application in various disciplines and have also received the attention of researchers globally. There are various components present in essential oils that have been analysed using GC-MS. These findings reflect the challenge to mosquitoes to gain resistance against each component and therefore it requires time. Commercially used repellants are synthesised using materials like DEET are not advisable for topical application on human skin and essential oil nanoemulsions could be an ideal non toxic candidate that can be used against mosquito adults and larvae. However, there are other synthesis, optimisation parameters, and toxicity towards non-target organisms that have to be taken into account when essential oil nanoemulsions are considered for commercial applications. Here we review the strategies used by the nanoemulsions against the mosquito population. Apart from the positive effects, their minor drawbacks also have to be scrutinised in the future.
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Affiliation(s)
- Kavitha Sri AnnaDurai
- Department of Biomedical Sciences, Faculty of Biomedical Sciences and Technology, Sri Ramachandra Institute of Higher Education and Research (SRIHER), Chennai-600116, Tamil Nadu, India
| | | | - Supriya Velraja
- Department of Clinical Nutrition, Faculty of Allied Health Sciences, Sri Ramachandra Institute of Higher Education and Research (SRIHER), Chennai 600116, Tamil Nadu, India
| | - Gnanadhas Sobhin Hikku
- Center for Global Health Research, Saveetha Medical College and Hospital, Saveetha Institute of Medical and Technical Sciences (SIMATS), Chennai 602105, Tamilnadu, India; Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Education (CARE), Kelambakkam, Chennai 603103, India
| | - Venkatachalam Deepa Parvathi
- Department of Biomedical Sciences, Faculty of Biomedical Sciences and Technology, Sri Ramachandra Institute of Higher Education and Research (SRIHER), Chennai-600116, Tamil Nadu, India.
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10
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Menges CW, Hassan D, Cheung M, Bellacosa A, Testa JR. Alterations of the AKT Pathway in Sporadic Human Tumors, Inherited Susceptibility to Cancer, and Overgrowth Syndromes. Curr Top Microbiol Immunol 2024. [PMID: 39192048 DOI: 10.1007/82_2024_278] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/29/2024]
Abstract
The AKT kinases are critical signaling molecules that regulate cellular physiology upon the activation of tyrosine kinase receptors and phosphatidylinositol 3-kinases (PI3K). AKT kinases govern many cellular processes considered hallmarks of cancer, including cell proliferation and survival, cell size, tumor invasion, metastasis, and angiogenesis. AKT signaling is regulated by multiple tumor suppressors and oncogenic proteins whose loss or activation, respectively, leads to dysregulation of this pathway, thereby contributing to oncogenesis. Herein, we review the enormous body of literature documenting how the AKT pathway becomes hyperactivated in sporadic human tumors and various hereditary cancer syndromes. We also discuss the role of activating mutations of AKT pathway genes in various chimeric overgrowth disorders, including Proteus syndrome, hypoglycemia with hypertrophy, CLOVES and SOLAMEN syndromes, and hemimegalencephaly.
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Affiliation(s)
- Craig W Menges
- Cancer Prevention and Control Program, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA
- Eurofins Lancaster Laboratories Professional Scientific Services, Lancaster, PA, 17601, USA
| | - Dalal Hassan
- Cancer Epigenetics Institute, Nuclear Dynamics and Cancer Program, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA
- Thomas Jefferson University, Philadelphia, PA, 19107, USA
| | - Mitchell Cheung
- Cancer Prevention and Control Program, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA
| | - Alfonso Bellacosa
- Cancer Epigenetics Institute, Nuclear Dynamics and Cancer Program, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA
| | - Joseph R Testa
- Cancer Prevention and Control Program, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA.
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Chen C, Jiang YP, You I, Gray NS, Lin RZ. Down-Regulation of AKT Proteins Slows the Growth of Mutant-KRAS Pancreatic Tumors. Cells 2024; 13:1061. [PMID: 38920688 PMCID: PMC11202146 DOI: 10.3390/cells13121061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Revised: 06/07/2024] [Accepted: 06/10/2024] [Indexed: 06/27/2024] Open
Abstract
Serine/threonine kinase AKT isoforms play a well-established role in cell metabolism and growth. Most pancreatic adenocarcinomas (PDACs) harbor activation mutations of KRAS, which activates the PI3K/AKT signaling pathway. However, AKT inhibitors are not effective in the treatment of pancreatic cancer. To better understand the role of AKT signaling in mutant-KRAS pancreatic tumors, this study utilized proteolysis-targeting chimeras (PROTACs) and CRISPR-Cas9-genome editing to investigate AKT proteins. The PROTAC down-regulation of AKT proteins markedly slowed the growth of three pancreatic tumor cell lines harboring mutant KRAS. In contrast, the inhibition of AKT kinase activity alone had very little effect on the growth of these cell lines. The concurrent genetic deletion of all AKT isoforms (AKT1, AKT2, and AKT3) in the KPC (KrasG12D; Trp53R172H; Pdx1-Cre) pancreatic cancer cell line also dramatically slowed its growth in vitro and when orthotopically implanted in syngeneic mice. Surprisingly, insulin-like growth factor-1 (IGF-1), but not epidermal growth factor (EGF), restored KPC cell growth in serum-deprived conditions, and the IGF-1 growth stimulation effect was AKT-dependent. The RNA-seq analysis of AKT1/2/3-deficient KPC cells suggested that reduced cholesterol synthesis may be responsible for the decreased response to IGF-1 stimulation. These results indicate that the presence of all three AKT isoforms supports pancreatic tumor cell growth, and the pharmacological degradation of AKT proteins may be more effective than AKT catalytic inhibitors for treating pancreatic cancer.
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Affiliation(s)
- Chuankai Chen
- Department of Physiology & Biophysics, Stony Brook University, Stony Brook, NY 11794, USA; (C.C.); (Y.-P.J.)
- Graduate Program in Genetics, Stony Brook University, Stony Brook, NY 11790, USA
| | - Ya-Ping Jiang
- Department of Physiology & Biophysics, Stony Brook University, Stony Brook, NY 11794, USA; (C.C.); (Y.-P.J.)
| | - Inchul You
- Department of Chemical and Systems Biology, ChEM-H, and Stanford Cancer Institute, Stanford School of Medicine, Stanford University, Stanford, CA 94305, USA; (I.Y.); (N.S.G.)
| | - Nathanael S. Gray
- Department of Chemical and Systems Biology, ChEM-H, and Stanford Cancer Institute, Stanford School of Medicine, Stanford University, Stanford, CA 94305, USA; (I.Y.); (N.S.G.)
| | - Richard Z. Lin
- Department of Physiology & Biophysics, Stony Brook University, Stony Brook, NY 11794, USA; (C.C.); (Y.-P.J.)
- Northport VA Medical Center, Northport, NY 11768, USA
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12
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Chen C, Jiang YP, You I, Gray NS, Lin RZ. Down-regulation of AKT proteins slows the growth of mutant-KRAS pancreatic tumors. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.05.03.592345. [PMID: 38746217 PMCID: PMC11092743 DOI: 10.1101/2024.05.03.592345] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/16/2024]
Abstract
Serine/threonine kinase AKT isoforms play a well-established role in cell metabolism and growth. Most pancreatic adenocarcinoma (PDAC) harbors activation mutations of KRAS, which activates the PI3K/AKT signaling pathway. However, AKT inhibitors are not effective in the treatment of pancreatic cancer. To better understand the role of AKT signaling in mutant-KRAS pancreatic tumors, this study utilizes proteolysis-targeting chimeras (PROTACs) and CRISPR-Cas9-genome editing to investigate AKT proteins. PROTAC down-regulation of AKT proteins markedly slowed the growth of three pancreatic tumor cell lines harboring mutant KRAS. In contrast, inhibition of AKT kinase activity alone had very little effect on the growth of these cell lines. Concurrent genetic deletion of all AKT isoforms (AKT1, AKT2, and AKT3) in the KPC (KrasG12D; Trp53R172H; Pdx1-Cre) pancreatic cancer cell line also dramatically slowed its growth in vitro and when orthotopically implanted in syngeneic mice. Surprisingly, insulin-like growth factor-1 (IGF-1), but not epidermal growth factor (EGF), restored KPC cell growth in serum-deprived conditions and the IGF-1 growth stimulation effect was AKT dependent. RNA-seq analysis of AKT1/2/3-deficient KPC cells suggested that reduced cholesterol synthesis may be responsible for the decreased response to IGF-1 stimulation. These results indicate that the presence of all three AKT isoforms supports pancreatic tumor cell growth and pharmacological degradation of AKT proteins may be more effective than AKT catalytic inhibitors for treating pancreatic cancer.
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Affiliation(s)
- Chuankai Chen
- Department of Physiology & Biophysics, Stony Brook University, Stony Brook, New York, USA
- Graduate Program in Genetics, Stony Brook University, New York, USA
| | - Ya-Ping Jiang
- Department of Physiology & Biophysics, Stony Brook University, Stony Brook, New York, USA
| | - Inchul You
- Department of Chemical and Systems Biology, ChEM-H, and Stanford Cancer Institute, Stanford School of Medicine, Stanford University, Stanford, California 94305, USA
| | - Nathanael S. Gray
- Department of Chemical and Systems Biology, ChEM-H, and Stanford Cancer Institute, Stanford School of Medicine, Stanford University, Stanford, California 94305, USA
| | - Richard Z. Lin
- Department of Physiology & Biophysics, Stony Brook University, Stony Brook, New York, USA
- Northport VA Medical Center, Northport, New York, USA
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Geißert R, Lammert A, Wirth S, Hönig R, Lohfink D, Unger M, Pek D, Schlüter K, Scheftschik T, Smit DJ, Jücker M, Menke A, Giehl K. K-Ras(V12) differentially affects the three Akt isoforms in lung and pancreatic carcinoma cells and upregulates E-cadherin and NCAM via Akt3. Cell Commun Signal 2024; 22:85. [PMID: 38291468 PMCID: PMC10826106 DOI: 10.1186/s12964-024-01484-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Accepted: 01/08/2024] [Indexed: 02/01/2024] Open
Abstract
K-Ras is the most frequently mutated Ras variant in pancreatic, colon and non-small cell lung adenocarcinoma. Activating mutations in K-Ras result in increased amounts of active Ras-GTP and subsequently a hyperactivation of effector proteins and downstream signaling pathways. Here, we demonstrate that oncogenic K-Ras(V12) regulates tumor cell migration by activating the phosphatidylinositol 3-kinases (PI3-K)/Akt pathway and induces the expression of E-cadherin and neural cell adhesion molecule (NCAM) by upregulation of Akt3. In vitro interaction and co-precipitation assays identified PI3-Kα as a bona fide effector of active K-Ras4B but not of H-Ras or N-Ras, resulting in enhanced Akt phosphorylation. Moreover, K-Ras(V12)-induced PI3-K/Akt activation enhanced migration in all analyzed cell lines. Interestingly, Western blot analyses with Akt isoform-specific antibodies as well as qPCR studies revealed, that the amount and the activity of Akt3 was markedly increased whereas the amount of Akt1 and Akt2 was downregulated in EGFP-K-Ras(V12)-expressing cell clones. To investigate the functional role of each Akt isoform and a possible crosstalk of the isoforms in more detail, each isoform was stably depleted in PANC-1 pancreatic and H23 lung carcinoma cells. Akt3, the least expressed Akt isoform in most cell lines, is especially upregulated and active in Akt2-depleted cells. Since expression of EGFP-K-Ras(V12) reduced E-cadherin-mediated cell-cell adhesion by induction of polysialylated NCAM, Akt3 was analyzed as regulator of E-cadherin and NCAM. Western blot analyses revealed pronounced reduction of E-cadherin and NCAM in the Akt3-kd cells, whereas Akt1 and Akt2 depletion upregulated E-cadherin, especially in H23 lung carcinoma cells. In summary, we identified oncogenic K-Ras4B as a key regulator of PI3-Kα-Akt signaling and Akt3 as a crucial regulator of K-Ras4B-induced modulation of E-cadherin and NCAM expression and localization.
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Affiliation(s)
- Rebekka Geißert
- Signal Transduction of Cellular Motility, Internal Medicine IV, Science Unit for Basic and Clinical Medicine, Justus Liebig University Giessen, Aulweg 128, D-35392, Giessen, Germany
| | - Angela Lammert
- Signal Transduction of Cellular Motility, Internal Medicine IV, Science Unit for Basic and Clinical Medicine, Justus Liebig University Giessen, Aulweg 128, D-35392, Giessen, Germany
| | - Stefanie Wirth
- Signal Transduction of Cellular Motility, Internal Medicine IV, Science Unit for Basic and Clinical Medicine, Justus Liebig University Giessen, Aulweg 128, D-35392, Giessen, Germany
| | - Rabea Hönig
- Signal Transduction of Cellular Motility, Internal Medicine IV, Science Unit for Basic and Clinical Medicine, Justus Liebig University Giessen, Aulweg 128, D-35392, Giessen, Germany
| | - Dirk Lohfink
- Molecular Oncology of Solid Tumors, Internal Medicine IV, Justus Liebig University Giessen, Aulweg 128, D-35392, Giessen, Germany
| | - Monika Unger
- Institute of Pharmacology and Toxicology, University of Ulm, D-89069, Ulm, Germany
| | - Denis Pek
- Institute of Pharmacology and Toxicology, University of Ulm, D-89069, Ulm, Germany
| | - Konstantin Schlüter
- Signal Transduction of Cellular Motility, Internal Medicine IV, Science Unit for Basic and Clinical Medicine, Justus Liebig University Giessen, Aulweg 128, D-35392, Giessen, Germany
| | - Theresa Scheftschik
- Molecular Oncology of Solid Tumors, Internal Medicine IV, Justus Liebig University Giessen, Aulweg 128, D-35392, Giessen, Germany
| | - Daniel J Smit
- Institute of Biochemistry and Signal Transduction, University Medical Center Hamburg-Eppendorf, D-20246, Hamburg, Germany
| | - Manfred Jücker
- Institute of Biochemistry and Signal Transduction, University Medical Center Hamburg-Eppendorf, D-20246, Hamburg, Germany
| | - Andre Menke
- Molecular Oncology of Solid Tumors, Internal Medicine IV, Justus Liebig University Giessen, Aulweg 128, D-35392, Giessen, Germany
| | - Klaudia Giehl
- Signal Transduction of Cellular Motility, Internal Medicine IV, Science Unit for Basic and Clinical Medicine, Justus Liebig University Giessen, Aulweg 128, D-35392, Giessen, Germany.
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Khezri MR, Mohammadipanah S, Ghasemnejad-Berenji M. The pharmacological effects of Berberine and its therapeutic potential in different diseases: Role of the phosphatidylinositol 3-kinase/AKT signaling pathway. Phytother Res 2024; 38:349-367. [PMID: 37922566 DOI: 10.1002/ptr.8040] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Revised: 09/15/2023] [Accepted: 09/30/2023] [Indexed: 11/07/2023]
Abstract
The phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway plays a central role in cell growth and survival and is disturbed in various pathologies. The PI3K is a kinase that generates phosphatidylinositol-3,4,5-trisphosphate (PI (3-5) P3), as a second messenger responsible for the translocation of AKT to the plasma membrane and its activation. However, due to the crucial role of the PI3K/AKT pathway in regulation of cell survival processes, it has been introduced as a main therapeutic target for natural compounds during the progression of different pathologies. Berberine, a plant-derived isoquinone alkaloid, is known because of its anti-inflammatory, antioxidant, antidiabetic, and antitumor properties. The effect of this natural compound on cell survival processes has been shown to be mediated by modulation of the intracellular pathways. However, the effects of this natural compound on the PI3K/AKT pathway in various pathologies have not been reviewed so far. Therefore, this paper aims to review the PI3K/AKT-mediated effects of Berberine in different types of cancer, diabetes, cardiovascular, and central nervous system diseases.
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Affiliation(s)
- Mohammad Rafi Khezri
- Student Research Committee, Urmia University of Medical Sciences, Urmia, Iran
- School of Pharmacy, Urmia University of Medical Sciences, Urmia, Iran
| | | | - Morteza Ghasemnejad-Berenji
- Department of Pharmacology and Toxicology, School of Pharmacy, Urmia University of Medical Sciences, Urmia, Iran
- Research Center for Experimental and Applied Pharmaceutical Sciences, Urmia University of Medical Sciences, Urmia, Iran
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Aliakbarian M, Ferns GA, Shabestari MM, Ahmadzadeh AM, Abdollahzade A, Rahimi H, Khodashahi R, Arjmand MH. Elucidating the Role of Pro-renin Receptors in Pancreatic Ductal Adenocarcinoma Progression: A Novel Therapeutic Target in Cancer Therapy. Curr Cancer Drug Targets 2024; 24:881-889. [PMID: 38279719 DOI: 10.2174/0115680096279288231205105904] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2023] [Revised: 10/14/2023] [Accepted: 10/20/2023] [Indexed: 01/28/2024]
Abstract
Pancreatic cancer is a highly aggressive malignancy with a very poor prognosis. The 5- year survival in these patients is very low, and most patients develop drug resistance to current therapies, so additional studies are needed to identify the potential role of new drug targets for the treatment of pancreatic cancer. Recent investigations have been performed regarding the roles of pro-renin receptors (PRR) in the initiation and development of cancers. PRR is a component of the local renin-angiotensin system (RAS). Local tissue RAS has been known in diverse organ systems, including the pancreas. Various investigations have implicated that PRRs are associated with the upregulation of various signaling pathways, like the renin-angiotensin system pathway, PI3K/Akt/mTOR, and the Wnt-signaling pathways, to contribute to pathological conditions, including cancer. In this review, we presented an overview of the role of PRR in the progression of pancreatic adenocarcinoma.
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Affiliation(s)
- Mohsen Aliakbarian
- Transplant Research Center, Clinical Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Surgical Oncology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Gordon A Ferns
- Department of Biochemistry, Division of Medical, Brighton & Sussex Medical School, Brighton, UK
| | | | - Amir Mahmoud Ahmadzadeh
- Transplant Research Center, Clinical Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Radiology, Ghaem Hospital, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Aref Abdollahzade
- Transplant Research Center, Clinical Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hoda Rahimi
- Transplant Research Center, Clinical Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Rozita Khodashahi
- Transplant Research Center, Clinical Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Clinical Research Development Unit, Imam Reza Hospital, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad-Hassan Arjmand
- Transplant Research Center, Clinical Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran
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16
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Handra-Luca A. AKT and mTOR expression in human pancreatic ductal adenocarcinoma. Relevance for tumor biology. Pathol Res Pract 2023; 251:154878. [PMID: 37890271 DOI: 10.1016/j.prp.2023.154878] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Accepted: 10/06/2023] [Indexed: 10/29/2023]
Abstract
BACKGROUND AND STUDY AIMS Several signaling pathways interfere with pancreatic ductal adenocarcinoma (PDAC) carcinogenesis processes, among which the AKT-pathway. The relevance of proteins in this pathway for the malignant phenotype or prognosis of PDAC is incompletely understood. We aimed to study AKT-pathway proteins in PDAC. METHODS We examined immunohistochemical expression of two main AKT pathway proteins, AKT and mTOR, in 99 PDAC. Protein expression patterns were analysed with regard to tumor features, to MAPK and TGFbeta pathway protein expression and, to cell proliferation. RESULTS Tumor AKT was more frequent in PDAC with an abundant stromal inflammatory infiltrate (p = 0.03). When considering intra-pancreatic PDACs, mTOR correlated to T2 as compared to T1-TNM stage tumors. When considering the entire series, mTOR correlated to intra-pancreatic tumors (T1- and T2-TNM stage) as compared to T3-TNM PDAC (Fisher p < 0.01 for both comparisons). mTOR expression was more frequent in PDAC with an abundant intratumor stromal component and tumors with a high Ki67-positive tumor cell component (Fisher p = 0.05 and p < 0.01, respectively). mTOR, related to SMAD4 (Fisher p < 0.01) as well as to nuclear ERK (Fisher p = 0.02). CONCLUSION The results of this study indicate an intricated role, mainly for mTOR in PDAC cell proliferation and tumor components development. The relationships we have found between AKT and mTOR and, MAPK and SMAD-pathway proteins suggest interactions at several levels of the protein framework resulting in varied impact on cell proliferation and tumor behavior/development.
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Affiliation(s)
- A Handra-Luca
- UFR SMBH Bobigny, University Sorbonne Paris Nord, France; APHP HUPSSD, Bobigny, France.
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Elhariri A, Alhaj A, Ahn D, Sonbol MB, Bekaii-Saab T, Wu C, Rutenberg MS, Stauffer J, Starr J, Majeed U, Jones J, Borad M, Babiker H. Targeting KRAS in pancreatic adenocarcinoma: Progress in demystifying the holy grail. World J Clin Oncol 2023; 14:285-296. [PMID: 37700806 PMCID: PMC10494558 DOI: 10.5306/wjco.v14.i8.285] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Revised: 07/05/2023] [Accepted: 07/27/2023] [Indexed: 08/22/2023] Open
Abstract
Pancreatic cancer (PC) remains one of the most challenging diseases, with a very poor 5-year overall survival of around 11.5%. Kirsten rat sarcoma virus (KRAS) mutation is seen in 90%-95% of PC patients and plays an important role in cancer cell proliferation, differentiation, metabolism, and survival, making it an essential mutation for targeted therapy. Despite extensive efforts in studying this oncogene, there has been little success in finding a drug to target this pathway, labelling it for decades as "undruggable". In this article we summarize some of the efforts made to target the KRAS pathway in PC, discuss the challenges, and shed light on promising clinical trials.
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Affiliation(s)
- Ahmed Elhariri
- Division of Hematology-Oncology, Department of Medicine, Mayo Clinic Florida, Mayo Clinic Cancer Center, Jacksonville, FL 32224, United States
| | - Ahmed Alhaj
- Division of Hematology-Oncology, Department of Medicine, Mayo Clinic Florida, Mayo Clinic Cancer Center, Jacksonville, FL 32224, United States
| | - Daniel Ahn
- Division of Hematology-Oncology, Department of Medicine, Mayo Clinic Arizona, Mayo Clinic Cancer Center, Phoenix, AZ 85054, United States
| | - Mohamad Bassam Sonbol
- Division of Hematology-Oncology, Department of Medicine, Mayo Clinic Arizona, Mayo Clinic Cancer Center, Phoenix, AZ 85054, United States
| | - Tanios Bekaii-Saab
- Division of Hematology-Oncology, Department of Medicine, Mayo Clinic Arizona, Mayo Clinic Cancer Center, Phoenix, AZ 85054, United States
| | - Christina Wu
- Division of Hematology-Oncology, Department of Medicine, Mayo Clinic Arizona, Mayo Clinic Cancer Center, Phoenix, AZ 85054, United States
| | - Michael Scott Rutenberg
- Department of Radiation-Oncology, Mayo Clinic Florida, Mayo Clinic Cancer Center, Jacksonville, FL 32224, United States
| | - John Stauffer
- Department of Surgical Oncology, Hepatopancreatobiliary Surgery, Mayo Clinic Florida, Jacksonville, FL 32224, United States
| | - Jason Starr
- Division of Hematology-Oncology, Department of Medicine, Mayo Clinic Florida, Mayo Clinic Cancer Center, Jacksonville, FL 32224, United States
| | - Umair Majeed
- Division of Hematology-Oncology, Department of Medicine, Mayo Clinic Florida, Mayo Clinic Cancer Center, Jacksonville, FL 32224, United States
| | - Jeremy Jones
- Division of Hematology-Oncology, Department of Medicine, Mayo Clinic Florida, Mayo Clinic Cancer Center, Jacksonville, FL 32224, United States
| | - Mitesh Borad
- Division of Hematology-Oncology, Department of Medicine, Mayo Clinic Arizona, Mayo Clinic Cancer Center, Phoenix, AZ 85054, United States
| | - Hani Babiker
- Division of Hematology-Oncology, Department of Medicine, Mayo Clinic Florida, Mayo Clinic Cancer Center, Jacksonville, FL 32224, United States
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Li L, Guo Y, Lu Y, Xu Y, Lu Y, Zhu X, Dong X, Che J. An updated patent review of AKT inhibitors (2020 - present). Expert Opin Ther Pat 2023; 33:549-564. [PMID: 37864349 DOI: 10.1080/13543776.2023.2273895] [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: 04/20/2023] [Accepted: 10/18/2023] [Indexed: 10/22/2023]
Abstract
INTRODUCTION Protein kinase B (Akt), an essential protein in the PI3K/Akt/mTOR signaling pathway, plays a crucial role in tumor progression. Over the past two years, different types of Akt modulators have continued to emerge in the patent literature. AREAS COVERED This review focuses on the patent literature covering small molecule inhibitors, peptides, PROTACs, and antisense nucleic acids targetingAkt from 2020 to present. Also, we discuss the outcomes of several clinical trials, combination strategies for different mechanisms, and the application of Akt regulators in other non-oncology indications.Our search for relevant information was conducted using various databases, including the European Patent Office, SciFinder, andPubMed, from 01.2020 to 04.2023. EXPERT OPINION In recent years, some combination therapeutic strategies involvingAkt inhibitors have shown promising clinical outcomes. Future research can be directed toward developing new applications of Akt inhibitors, which may have implications for other diseases beyond cancer. New attempts suggest that targeting allosteric sites may be a potential solution to the problem of isoform selectivity.Furthermore, directly knocking out Akt protein by using the degraderssuggests a promising direction for future development.
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Affiliation(s)
- Linjie Li
- Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, P.R. China
| | - Yu Guo
- Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, P.R. China
| | - Yang Lu
- Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, P.R. China
| | - Yaping Xu
- Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, P.R. China
| | - Yan Lu
- Department of Pharmacy, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, P. R. China
| | - Xiuping Zhu
- Department of Pharmacy, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, P. R. China
| | - Xiaowu Dong
- Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, P.R. China
- Department of Pharmacy, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, P. R. China
- Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou, P.R. China
- Cancer Center, Zhejiang University, Hangzhou, P. R. China
| | - Jinxin Che
- Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, P.R. China
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Caserta S, Genovese C, Cicero N, Gangemi S, Allegra A. The Anti-Cancer Effect of Cinnamon Aqueous Extract: A Focus on Hematological Malignancies. Life (Basel) 2023; 13:life13051176. [PMID: 37240821 DOI: 10.3390/life13051176] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Revised: 05/10/2023] [Accepted: 05/10/2023] [Indexed: 05/28/2023] Open
Abstract
Cinnamon is an evergreen and tropical plant of the family Lauraceae, growing particularly in Sri Lanka, whose aqueous extract has been tested in different studies to evaluate its possible use as an anti-cancer compound. Both in vitro and in vivo experiments seem to confirm that it acts on various cellular pathways, contributing to down-regulating the activity of molecules that stimulate the proliferation and survival of cells such as the transcription factors NF-KB and AP-1, COX-2, dihydrofolate reductase and pro-angiogenic substances such as VEGF, while up-regulating the function of immune cells against tumors, such as cytotoxic CD8+ T cells. In hematological malignancies, aqueous cinnamon extract has been studied in order to understand if it is possible to count on its help, alone or in combination with traditional drugs such as doxorubicin, to treat patients. The aim of our work is to investigate results from in vitro and in vivo studies about the possible anti-cancer effect of aqueous cinnamon extract in hematological malignancies and the different pathways involved in its action. The possibility of using cinnamon extract in clinical practice is discussed; even if its use could appear very interesting, more studies are necessary to clear the real potentiality of this substance in cancer.
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Affiliation(s)
- Santino Caserta
- Division of Hematology, Department of Human Pathology in Adulthood and Childhood "Gaetano Barresi", University of Messina, Via Consolare Valeria, 98125 Messina, Italy
| | - Claudia Genovese
- National Research Council, Institute for Agricultural and Forest Systems in the Mediterranean, Via Empedocle 58, 95128 Catania, Italy
| | - Nicola Cicero
- Department of Biomedical, Dental, Morphological and Functional Imaging Sciences, University of Messina, Via Consolare Valeria, 98125 Messina, Italy
| | - Sebastiano Gangemi
- Allergy and Clinical Immunology Unit, Department of Clinical and Experimental Medicine, University of Messina, Via Consolare Valeria, 98125 Messina, Italy
| | - Alessandro Allegra
- Division of Hematology, Department of Human Pathology in Adulthood and Childhood "Gaetano Barresi", University of Messina, Via Consolare Valeria, 98125 Messina, Italy
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20
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Mukherjee P, Bagchi A, Banerjee A, Roy H, Bhattacharya A, Biswas A, Chatterji U. PDE4 inhibitor eliminates breast cancer stem cells via noncanonical activation of mTOR. J Cell Biochem 2022; 123:1980-1996. [PMID: 36063486 DOI: 10.1002/jcb.30325] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Revised: 05/25/2022] [Accepted: 08/17/2022] [Indexed: 12/24/2022]
Abstract
Ineffective cancer treatment is implicated in metastasis, recurrence, resistance to chemotherapy and radiotherapy, and evasion of immune surveillance. All these failures occur due to the persistence of cancer stem cells (CSCs) even after rigorous therapy, thereby rendering them as essential targets for cancer management. Contrary to the quiescent nature of CSCs, a gene profiler array disclosed that phosphatidylinositol-3-kinase (PI3K), which is known to be crucial for cell proliferation, differentiation, and survival, was significantly upregulated in CSCs. Since PI3K is modulated by cyclic adenosine 3',5' monophosphate (cAMP), analyses of cAMP regulation revealed that breast CSCs expressed increased levels of phosphodiesterase 4 (PDE4) in contrast to normal stem cells. In accordance, the effects of rolipram, a PDE4 inhibitor, were evaluated on PI3K regulators and signaling. The efficacy of rolipram was compared with paclitaxel, an anticancer drug that is ineffective in obliterating breast CSCs. Analyses of downstream signaling components revealed a switch between cell survival and death, in response to rolipram, specifically of the CSCs. Rolipram-mediated downregulation of PDE4A levels in breast CSCs led to an increase in cAMP levels and protein kinase A (PKA) expression. Subsequently, PKA-mediated upregulation of phosphatase and tensin homolog antagonized the PI3K/AKT/mTOR pathway and led to cell cycle arrest. Interestingly, direct yet noncanonical activation of mTOR by PKA, circumventing the influence of PI3K and AKT, temporally shifted the fate of CSCs toward apoptosis. Rolipram in combination with paclitaxel indicated synergistic consequences, which effectively obliterated CSCs within a tumor, thereby suggesting combinatorial therapy as a sustainable and effective strategy to abrogate breast CSCs for better patient prognosis.
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Affiliation(s)
- Pritha Mukherjee
- Cancer Research Laboratory, Department of Zoology, University of Calcutta, Kolkata, India
| | - Arka Bagchi
- Molecular Cell Biology Laboratory, Department of Zoology, University of Kalyani, Kalyani, India
| | - Ananya Banerjee
- Cancer Research Laboratory, Department of Zoology, University of Calcutta, Kolkata, India
| | - Himansu Roy
- Department of Surgery, Calcutta Medical College, Kolkata, India
| | | | - Arunima Biswas
- Molecular Cell Biology Laboratory, Department of Zoology, University of Kalyani, Kalyani, India
| | - Urmi Chatterji
- Cancer Research Laboratory, Department of Zoology, University of Calcutta, Kolkata, India.,Centre for Research in Nanoscience and Nanotechnology, University of Calcutta, Kolkata, India
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Siddika T, Balasuriya N, Frederick MI, Rozik P, Heinemann IU, O’Donoghue P. Delivery of Active AKT1 to Human Cells. Cells 2022; 11:cells11233834. [PMID: 36497091 PMCID: PMC9738475 DOI: 10.3390/cells11233834] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Revised: 11/22/2022] [Accepted: 11/28/2022] [Indexed: 12/03/2022] Open
Abstract
Protein kinase B (AKT1) is a serine/threonine kinase and central transducer of cell survival pathways. Typical approaches to study AKT1 biology in cells rely on growth factor or insulin stimulation that activates AKT1 via phosphorylation at two key regulatory sites (Thr308, Ser473), yet cell stimulation also activates many other kinases. To produce cells with specific AKT1 activity, we developed a novel system to deliver active AKT1 to human cells. We recently established a method to produce AKT1 phospho-variants from Escherichia coli with programmed phosphorylation. Here, we fused AKT1 with an N-terminal cell penetrating peptide tag derived from the human immunodeficiency virus trans-activator of transcription (TAT) protein. The TAT-tag did not alter AKT1 kinase activity and was necessary and sufficient to rapidly deliver AKT1 protein variants that persisted in human cells for 24 h without the need to use transfection reagents. TAT-pAKT1T308 induced selective phosphorylation of the known AKT1 substrate GSK-3α, but not GSK-3β, and downstream stimulation of the AKT1 pathway as evidenced by phosphorylation of ribosomal protein S6 at Ser240/244. The data demonstrate efficient delivery of AKT1 with programmed phosphorylation to human cells, thus establishing a cell-based model system to investigate signaling that is dependent on AKT1 activity.
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Affiliation(s)
- Tarana Siddika
- Department of Biochemistry, The University of Western Ontario, London, ON N6A 5C1, Canada
| | - Nileeka Balasuriya
- Department of Biochemistry, The University of Western Ontario, London, ON N6A 5C1, Canada
| | - Mallory I. Frederick
- Department of Biochemistry, The University of Western Ontario, London, ON N6A 5C1, Canada
| | - Peter Rozik
- Department of Biochemistry, The University of Western Ontario, London, ON N6A 5C1, Canada
| | - Ilka U. Heinemann
- Department of Biochemistry, The University of Western Ontario, London, ON N6A 5C1, Canada
- Correspondence: (I.U.H.); (P.O.)
| | - Patrick O’Donoghue
- Department of Biochemistry, The University of Western Ontario, London, ON N6A 5C1, Canada
- Department of Chemistry, The University of Western Ontario, London, ON N6A 5C1, Canada
- Correspondence: (I.U.H.); (P.O.)
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22
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Yang PW, Xu PL, Cheng CS, Jiao JY, Wu Y, Dong S, Xie J, Zhu XY. Integrating network pharmacology and experimental models to investigate the efficacy of QYHJ on pancreatic cancer. JOURNAL OF ETHNOPHARMACOLOGY 2022; 297:115516. [PMID: 35817247 DOI: 10.1016/j.jep.2022.115516] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/19/2022] [Revised: 06/19/2022] [Accepted: 06/26/2022] [Indexed: 06/15/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE The Qingyihuaji decoction (QYHJ) is composed of seven herbs: Scutellaria barbata D.Don (Banzhilian, HSB), Gynostemma pentaphyllum (Thunb.) Makino (Jiaogulan, GP), Oldenlandia diffusa (Willd.) Roxb. (Baihuasheshecao, HDH), Ganoderma lucidum (Leyss. ex Fr.) Karst. (Lingzhi, GL), Myristica fragrans Houtt. (Doukou, AK), and Amorphophallus kiusianus (Makino) Makino (Sheliugu, RA), and Coix lacryma-jobi var. ma-yuen (Rom.Caill.) Stapf (Yiyiren, CL). QYHJ has been reported to exhibit clinical efficacy in the treatment of pancreatic adenocarcinoma (PAAD). However, the molecular mechanism remains unclear. AIM OF THE STUDY This study explores the therapeutic mechanism of QYHJ in the treatment of PAAD using network pharmacology to identify related targets and pathways in vivo and in vitro. MATERIALS AND METHODS The bioactive compounds of QYHJ were retrieved and screened using the ADME network pharmacology approach, followed by compound-target prediction and overlapping genes between PAAD oncogenes and QYHJ target genes. The compound-target-pathway network was established using The KEGG pathway, GO analysis, and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) analysis to identify potential action pathways. The effects of QYHJ on PAAD were evaluated in vivo and in vitro, and the predicted targets and potential pathways related to QYHJ in PAAD treatment were evaluated using qRT-PCR and immunoblotting. RESULTS A total of 68 bioactive compounds of QYHJ fulfilled the ADME screening criterion, and their respective 242 target genes were retrieved. The compound-target-disease network identified 11 possible target genes. The KEGG pathway analysis showed significant enrichment of pathways in cancers, involving regulating cancer-related pathways of inflammation, oxidative stress, and apoptosis. Furthermore, QYHJ inhibited PAAD growth in vivo; suppressed cell proliferation, invasion, and migration of PAAD; and induced cellular apoptosis in vitro. The qRT-PCR results showed that QYHJ suppressed the mRNA expression of ICAM1, VCAM1, and Bcl2, and increased that of HMOX1 and NQO1. Immunoblotting revealed changes in the PI3K/AKT/mTOR, Keap1/Nrf2/HO-1/NQO1, and Bcl2/Bax pathways upon QYHJ treatment. CONCLUSIONS QYHJ can suppress PAAD growth and progression through various mechanisms, including anti-inflammation and apoptosis-induction.
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Affiliation(s)
- Pei-Wen Yang
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, 200032, Shanghai, China
| | - Pan-Ling Xu
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Chinese Integrative Medicine Oncology, The First Affiliated Hospital of Anhui Medical University, 230022, Hefei, Anhui, China
| | - Chien-Shan Cheng
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, 200032, Shanghai, China; Department of Traditional Chinese Medicine, Shanghai Jiao Tong University School of Medicine Affiliated Ruijin Hospital, 200025, Shanghai, China
| | - Ju-Ying Jiao
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, 200032, Shanghai, China
| | - Yuan Wu
- Department of Traditional Chinese Medicine, Shanghai Jiao Tong University School of Medicine Affiliated Ruijin Hospital, 200025, Shanghai, China
| | - Shu Dong
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, 200032, Shanghai, China
| | - Jing Xie
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, 200032, Shanghai, China.
| | - Xiao-Yan Zhu
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, 200032, Shanghai, China.
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23
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Fang H, Li H, Zhang H, Wang S, Xu S, Chang L, Yang Y, Cui R. Short-chain L-3-hydroxyacyl-CoA dehydrogenase: A novel vital oncogene or tumor suppressor gene in cancers. Front Pharmacol 2022; 13:1019312. [PMID: 36313354 PMCID: PMC9614034 DOI: 10.3389/fphar.2022.1019312] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Accepted: 09/23/2022] [Indexed: 08/22/2023] Open
Abstract
The reprogramming of cellular metabolism is frequently linked to tumorigenesis. Glucose, fatty acids, and amino acids are the specific substrates involved in how an organism maintains metabolic equilibrium. The HADH gene codes for the short-chain L-3-hydroxyacyl-CoA dehydrogenase (HADH), a crucial enzyme in fatty acid oxidation that catalyzes the third phase of fatty acid oxidation in mitochondria. Increasing data suggest that HADH is differentially expressed in various types of malignancies and is linked to cancer development and progression. The significance of HADH expression in tumors and its potential mechanisms of action in the onset and progression of certain cancers are summarized in this article. The possible roles of HADH as a target and/or biomarker for the detection and treatment of various malignancies is also described here.
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Affiliation(s)
- He Fang
- Department of Hepatobiliary and Pancreatic Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Hanyang Li
- Department of Thyroid Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Hang Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Shu Wang
- Department of Radiotherapy, The Second Hospital of Jilin University, Changchun, China
| | - Shuang Xu
- Department of Anesthesiology, The Second Hospital of Jilin University, Changchun, China
| | - Li Chang
- Department of Pathology, The Second Hospital of Jilin University, Changchun, China
| | - Yongsheng Yang
- Department of Hepatobiliary and Pancreatic Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Ranji Cui
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetic, The Second Hospital of Jilin University, Changchun, China
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24
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Radwan IT, Elwahy AH, Darweesh AF, Sharaky M, Bagato N, Khater HF, Salem ME. Design, synthesis, docking study, and anticancer evaluation of novel bis-thiazole derivatives linked to benzofuran or benzothiazole moieties as PI3k inhibitors and apoptosis inducers. J Mol Struct 2022. [DOI: 10.1016/j.molstruc.2022.133454] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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25
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Mortazavi M, Moosavi F, Martini M, Giovannetti E, Firuzi O. Prospects of targeting PI3K/AKT/mTOR pathway in pancreatic cancer. Crit Rev Oncol Hematol 2022; 176:103749. [PMID: 35728737 DOI: 10.1016/j.critrevonc.2022.103749] [Citation(s) in RCA: 67] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Revised: 06/11/2022] [Accepted: 06/16/2022] [Indexed: 02/07/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) has one of the worst prognoses among all malignancies. PI3K/AKT/mTOR signaling pathway, a main downstream effector of KRAS is involved in the regulation of key hallmarks of cancer. We here report that whole-genome analyses demonstrate the frequent involvement of aberrant activations of PI3K/AKT/mTOR pathway components in PDAC patients and critically evaluate preclinical and clinical evidence on the application of PI3K/AKT/mTOR pathway targeting agents. Combinations of these agents with chemotherapeutics or other targeted therapies, including the modulators of cyclin-dependent kinases, receptor tyrosine kinases and RAF/MEK/ERK pathway are also examined. Although human genetic studies and preclinical pharmacological investigations have provided strong evidence on the role of PI3K/AKT/mTOR pathway in PDAC, clinical studies in general have not been as promising. Patient stratification seems to be the key missing point and with the advent of biomarker-guided clinical trials, targeting PI3K/AKT/mTOR pathway could provide valuable assets for treatment of pancreatic cancer patients.
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Affiliation(s)
- Motahareh Mortazavi
- Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Fatemeh Moosavi
- Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Miriam Martini
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Turin, Italy
| | - Elisa Giovannetti
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center (VUmc), Amsterdam, the Netherlands; Cancer Pharmacology Lab, Fondazine Pisana per la Scienza, Pisa, Italy
| | - Omidreza Firuzi
- Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
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The PI3K/AKT signaling pathway in cancer: Molecular mechanisms and possible therapeutic interventions. Exp Mol Pathol 2022; 127:104787. [DOI: 10.1016/j.yexmp.2022.104787] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Revised: 04/15/2022] [Accepted: 05/21/2022] [Indexed: 01/02/2023]
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Li J, Xu Z. NR3C2 suppresses the proliferation, migration, invasion and angiogenesis of colon cancer cells by inhibiting the AKT/ERK signaling pathway. Mol Med Rep 2022; 25:133. [PMID: 35191517 PMCID: PMC8908346 DOI: 10.3892/mmr.2022.12649] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Accepted: 09/23/2021] [Indexed: 11/05/2022] Open
Abstract
Nuclear receptor subfamily 3, group C, member 2 (NR3C2) serves an antitumorigenic role in several types of cancer; however, its role and mechanisms of action in colon cancer remains to be elucidated. The aim of the present study was to explore the effects of NR3C2 on the proliferation, migration, invasion and angiogenesis of colon cancer cells. The expression levels of NR3C2 in human colon epithelial NCM460 cells (spontaneously immortalized cell line) and colon cancer cell lines was detected using reverse transcription-quantitative PCR and western blotting. Cell Counting Kit-8 (CCK-8) and colony formation assays were used to assess cell viability and wound healing and Transwell assays were used to detect cell invasion and migration. ELISA was used to detect the expression levels of VEGF and tube formation assays were used to assess angiogenesis. The expression levels of angiogenesis-related proteins and AKT/ERK signaling pathway-related proteins were detected by western blotting. NR3C2 expression was downregulated in colon cancer cells and overexpression of NR3C2 inhibited proliferation, colony formation, migration and invasion of colon cancer cells. Overexpression of NR3C2 inhibited angiogenesis and activity of the AKT/ERK signaling pathway in colon cancer cells. Thus, it was demonstrated that NR3C2 inhibited the proliferation, colony formation, migration, invasion and angiogenesis of colon cancer cells through the AKT/ERK signaling pathway. These results may highlight novel targets for the treatment of colon cancer.
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Affiliation(s)
- Jia Li
- Nanchang University Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330031, P.R. China
| | - Zhao Xu
- Key Laboratory of Reproductive Physiology and Pathology of Jiangxi Province, Nanchang University, Nanchang, Jiangxi 330031, P.R. China
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28
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Selvarajoo N, Stanslas J, Islam MK, Sagineedu SR, Lian HK, Lim JCW. Pharmacological Modulation of Apoptosis and Autophagy in Pancreatic Cancer Treatment. Mini Rev Med Chem 2022; 22:2581-2595. [PMID: 35331093 DOI: 10.2174/1389557522666220324123605] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 01/02/2022] [Accepted: 01/21/2022] [Indexed: 11/22/2022]
Abstract
BACKGROUND Pancreatic cancer is a fatal malignant neoplasm with infrequent signs and symptoms until a progressive stage. In 2020, GLOBOCAN reported that pancreatic cancer accounts for 4.7% of all cancer deaths. Despite the availability of standard chemotherapy regimens for treatment, the survival benefits are not guaranteed because tumor cells become chemoresistant even due to the development of chemoresistance in tumor cells even with a short treatment course, where apoptosis and autophagy play critical roles. OBJECTIVE This review compiled essential information on the regulatory mechanisms and roles of apoptosis and autophagy in pancreatic cancer, as well as drug-like molecules that target different pathways in pancreatic cancer eradication, with an aim to provide ideas to the scientific communities in discovering novel and specific drugs to treat pancreatic cancer, specifically PDAC. METHOD Electronic databases that were searched for research articles for this review were Scopus, Science Direct, PubMed, Springer Link, and Google Scholar. The published studies were identified and retrieved using selected keywords. DISCUSSION/CONCLUSION Many small-molecule anticancer agents have been developed to regulate autophagy and apoptosis associated with pancreatic cancer treatment, where most of them target apoptosis directly through EGFR/Ras/Raf/MAPK and PI3K/Akt/mTOR pathways. The cancer drugs that regulate autophagy in treating cancer can be categorized into three groups: i) direct autophagy inducers (e.g., rapamycin), ii) indirect autophagy inducers (e.g., resveratrol), and iii) autophagy inhibitors. Resveratrol persuades both apoptosis and autophagy with a cytoprotective effect, while autophagy inhibitors (e.g., 3-methyladenine, chloroquine) can turn off the protective autophagic effect for therapeutic benefits. Several studies showed that autophagy inhibition resulted in a synergistic effect with chemotherapy (e.g., a combination of metformin with gemcitabine/ 5FU). Such drugs possess a unique clinical value in treating pancreatic cancer as well as other autophagy-dependent carcinomas.
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Affiliation(s)
- Nityaa Selvarajoo
- Pharmacotherapeutics Unit, Department of Medicine, Faculty of Medicine and Health Sciences, University Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia
| | - Johnson Stanslas
- Pharmacotherapeutics Unit, Department of Medicine, Faculty of Medicine and Health Sciences, University Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia
| | - Mohammad Kaisarul Islam
- Pharmacotherapeutics Unit, Department of Medicine, Faculty of Medicine and Health Sciences, University Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia
| | - Sreenivasa Rao Sagineedu
- Department of Pharmaceutical Chemistry, School of Pharmacy, International Medical University, 57000 Kuala Lumpur, Malaysia
| | - Ho Kok Lian
- Department of Pathology, Faculty of Medicine and Health Sciences, University Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia
| | - Jonathan Chee Woei Lim
- Pharmacotherapeutics Unit, Department of Medicine, Faculty of Medicine and Health Sciences, University Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia
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Singh K, Shishodia G, Koul HK. Pancreatic cancer: genetics, disease progression, therapeutic resistance and treatment strategies. JOURNAL OF CANCER METASTASIS AND TREATMENT 2021; 7:60. [PMID: 38107772 PMCID: PMC10722911 DOI: 10.20517/2394-4722.2021.96] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/19/2023]
Abstract
Pancreatic cancer is a deadly disease and the third-highest cause of cancer-related deaths in the United States. It has a very low five-year survival rate (< 5%) in the United States as well as in the world (about 9%). The current gemcitabine-based therapy soon becomes ineffective because treatment resistance and surgical resection also provides only selective benefit. Signature mutations in pancreatic cancer confer chemoresistance by deregulating the cell cycle and promoting anti-apoptotic mechanisms. The stroma-rich tumor microenvironment impairs drug delivery and promotes tumor-specific immune escape. All these factors render the current treatment incompetent and prompt an urgent need for new, improved therapy. In this review, we have discussed the genetics of pancreatic cancer and its role in tumor evolution and treatment resistance. We have also evaluated new treatment strategies for pancreatic cancer, like targeted therapy and immunotherapy.
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Affiliation(s)
- Karnika Singh
- Department of Radiation Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
| | - Gauri Shishodia
- Department of Otolaryngology/Head & Neck Cancer Surgery, LSU Health Sciences Center, Shreveport, LA 71103, USA
| | - Hari K. Koul
- Department of Biochemistry & Molecular Biology, Urology and Stanley S Scott Cancer Center School of Medicine LSU Health Sciences Center, New Orleans, LA 70112, USA
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30
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Sankarasubramanian S, Pfohl U, Regenbrecht CRA, Reinhard C, Wedeken L. Context Matters-Why We Need to Change From a One Size Fits all Approach to Made-to-Measure Therapies for Individual Patients With Pancreatic Cancer. Front Cell Dev Biol 2021; 9:760705. [PMID: 34805167 PMCID: PMC8599957 DOI: 10.3389/fcell.2021.760705] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Accepted: 10/18/2021] [Indexed: 12/12/2022] Open
Abstract
Pancreatic cancer is one of the deadliest cancers and remains a major unsolved health problem. While pancreatic ductal adenocarcinoma (PDAC) is associated with driver mutations in only four major genes (KRAS, TP53, SMAD4, and CDKN2A), every tumor differs in its molecular landscape, histology, and prognosis. It is crucial to understand and consider these differences to be able to tailor treatment regimens specific to the vulnerabilities of the individual tumor to enhance patient outcome. This review focuses on the heterogeneity of pancreatic tumor cells and how in addition to genetic alterations, the subsequent dysregulation of multiple signaling cascades at various levels, epigenetic and metabolic factors contribute to the oncogenesis of PDAC and compensate for each other in driving cancer progression if one is tackled by a therapeutic approach. This implicates that besides the need for new combinatorial therapies for PDAC, a personalized approach for treating this highly complex cancer is required. A strategy that combines both a target-based and phenotypic approach to identify an effective treatment, like Reverse Clinical Engineering® using patient-derived organoids, is discussed as a promising way forward in the field of personalized medicine to tackle this deadly disease.
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Affiliation(s)
| | - Ulrike Pfohl
- CELLphenomics GmbH, Berlin, Germany
- ASC Oncology GmbH, Berlin, Germany
- Institute for Molecular Bio Science, Goethe University Frankfurt Am Main, Frankfurt, Germany
| | - Christian R. A. Regenbrecht
- CELLphenomics GmbH, Berlin, Germany
- ASC Oncology GmbH, Berlin, Germany
- Institute for Pathology, Universitätsklinikum Göttingen, Göttingen, Germany
| | | | - Lena Wedeken
- CELLphenomics GmbH, Berlin, Germany
- ASC Oncology GmbH, Berlin, Germany
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31
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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.
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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
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32
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Targeting PI3K Pathway in Pancreatic Ductal Adenocarcinoma: Rationale and Progress. Cancers (Basel) 2021; 13:cancers13174434. [PMID: 34503244 PMCID: PMC8430624 DOI: 10.3390/cancers13174434] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 08/24/2021] [Accepted: 08/30/2021] [Indexed: 12/12/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains among the deadliest solid tumors that remain treatment-refractory and show a dismal prognosis. More than 90% of PDAC tumors harbor mutations in the K-Ras that exert a strong pro-tumorigenic effect by activating several downstream effector pathways, including phosphatidylinositol-3-kinase (PI3K)-Akt. The role of frequently activated PI3K/Akt pathway in promoting PDAC aggressiveness is well established. Therapeutic approaches targeting PI3K and downstream signaling components in different cellular compartments, including tumor, stromal and immune cells, have directly impacted the tumor burden in this cancer type. Our previous work has demonstrated that targeting the PI3K/Akt/mTOR pathway reduced tumor growth and improved survival in the genetic mouse model of PDAC. Here, we discuss the significance of targeting PI3K signaling and the biological impact of PI3K inhibition in modulating the tumor-stromal immune crosstalk within the microenvironment of pancreatic cancer. Furthermore, this review updates on the current challenges involving the therapeutic implications of targeting this pathway in PDAC.
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33
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Kisling SG, Natarajan G, Pothuraju R, Shah A, Batra SK, Kaur S. Implications of prognosis-associated genes in pancreatic tumor metastasis: lessons from global studies in bioinformatics. Cancer Metastasis Rev 2021; 40:721-738. [PMID: 34591244 PMCID: PMC8556170 DOI: 10.1007/s10555-021-09991-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Accepted: 08/31/2021] [Indexed: 12/13/2022]
Abstract
Pancreatic cancer (PC) is a highly lethal malignancy with a 5-year survival rate of 10%. The occurrence of metastasis, among other hallmarks, is the main contributor to its poor prognosis. Consequently, the elucidation of metastatic genes involved in the aggressive nature of the disease and its poor prognosis will result in the development of new treatment modalities for improved management of PC. There is a deep interest in understanding underlying disease pathology, identifying key prognostic genes, and genes associated with metastasis. Computational approaches, which have become increasingly relevant over the last decade, are commonly used to explore such interests. This review aims to address global studies that have employed global approaches to identify prognostic and metastatic genes, while highlighting their methods and limitations. A panel of 48 prognostic genes were identified across these studies, but only five, including ANLN, ARNTL2, PLAU, TOP2A, and VCAN, were validated in multiple studies and associated with metastasis. Their association with metastasis has been further explored here, and the implications of these genes in the metastatic cascade have been interpreted.
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Affiliation(s)
- Sophia G Kisling
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Gopalakrishnan Natarajan
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Ramesh Pothuraju
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Ashu Shah
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA.
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA.
- Fred and Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.
| | - Sukhwinder Kaur
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA.
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Marcano VC, Cardenas-Garcia S, Diel DG, Antoniassi da Silva LH, Gogal RM, Miller PJ, Brown CC, Butt SL, Goraichuk IV, Dimitrov KM, Taylor TL, Williams-Coplin D, Olivier TL, Stanton JB, Afonso CL. A Novel Recombinant Newcastle Disease Vaccine Improves Post- In Ovo Vaccination Survival with Sustained Protection against Virulent Challenge. Vaccines (Basel) 2021; 9:vaccines9090953. [PMID: 34579191 PMCID: PMC8472951 DOI: 10.3390/vaccines9090953] [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: 06/30/2021] [Revised: 08/10/2021] [Accepted: 08/19/2021] [Indexed: 01/23/2023] Open
Abstract
In ovo vaccination has been employed by the poultry industry for over 20 years to control numerous avian diseases. Unfortunately, in ovo live vaccines against Newcastle disease have significant limitations, including high embryo mortality and the inability to induce full protection during the first two weeks of life. In this study, a recombinant live attenuated Newcastle disease virus vaccine containing the antisense sequence of chicken interleukin 4 (IL-4), rZJ1*L-IL4R, was used. The rZJ1*L-IL4R vaccine was administered in ovo to naïve specific pathogen free embryonated chicken eggs (ECEs) and evaluated against a homologous challenge. Controls included a live attenuated recombinant genotype VII vaccine based on the virus ZJ1 (rZJ1*L) backbone, the LaSota vaccine and diluent alone. In the first of two experiments, ECEs were vaccinated at 18 days of embryonation (DOE) with either 104.5 or 103.5 50% embryo infectious dose (EID50/egg) and chickens were challenged at 21 days post-hatch (DPH). In the second experiment, 103.5 EID50/egg of each vaccine was administered at 19 DOE, and chickens were challenged at 14 DPH. Chickens vaccinated with 103.5 EID50/egg of rZJ1*L-IL4R had hatch rates comparable to the group that received diluent alone, whereas other groups had significantly lower hatch rates. All vaccinated chickens survived challenge without displaying clinical disease, had protective hemagglutination inhibition titers, and shed comparable levels of challenge virus. The recombinant rZJ1*L-IL4R vaccine yielded lower post-vaccination mortality rates compared with the other in ovo NDV live vaccine candidates as well as provided strong protection post-challenge.
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Affiliation(s)
- Valerie C. Marcano
- Exotic and Emerging Avian Viral Diseases Research Unit, Southeast Poultry Research Laboratory, US National Poultry Research Center, Agricultural Research Service, USDA, 934 College Station Rd., Athens, GA 30605, USA; (V.C.M.); (S.C.-G.); (D.G.D.); (L.H.A.d.S.); (P.J.M.); (S.L.B.); (I.V.G.); (K.M.D.); (T.L.T.); (D.W.-C.); (T.L.O.)
- Department of Veterinary Pathology, College of Veterinary Medicine, The University of Georgia, Athens, GA 30602, USA; (C.C.B.); (J.B.S.)
| | - Stivalis Cardenas-Garcia
- Exotic and Emerging Avian Viral Diseases Research Unit, Southeast Poultry Research Laboratory, US National Poultry Research Center, Agricultural Research Service, USDA, 934 College Station Rd., Athens, GA 30605, USA; (V.C.M.); (S.C.-G.); (D.G.D.); (L.H.A.d.S.); (P.J.M.); (S.L.B.); (I.V.G.); (K.M.D.); (T.L.T.); (D.W.-C.); (T.L.O.)
- Department of Veterinary Pathology, College of Veterinary Medicine, The University of Georgia, Athens, GA 30602, USA; (C.C.B.); (J.B.S.)
| | - Diego G. Diel
- Exotic and Emerging Avian Viral Diseases Research Unit, Southeast Poultry Research Laboratory, US National Poultry Research Center, Agricultural Research Service, USDA, 934 College Station Rd., Athens, GA 30605, USA; (V.C.M.); (S.C.-G.); (D.G.D.); (L.H.A.d.S.); (P.J.M.); (S.L.B.); (I.V.G.); (K.M.D.); (T.L.T.); (D.W.-C.); (T.L.O.)
| | - Luciana H. Antoniassi da Silva
- Exotic and Emerging Avian Viral Diseases Research Unit, Southeast Poultry Research Laboratory, US National Poultry Research Center, Agricultural Research Service, USDA, 934 College Station Rd., Athens, GA 30605, USA; (V.C.M.); (S.C.-G.); (D.G.D.); (L.H.A.d.S.); (P.J.M.); (S.L.B.); (I.V.G.); (K.M.D.); (T.L.T.); (D.W.-C.); (T.L.O.)
| | - Robert M. Gogal
- Department of Veterinary Biosciences & Diagnostic Imaging, College of Veterinary Medicine, The University of Georgia, Athens, GA 30602, USA;
| | - Patti J. Miller
- Exotic and Emerging Avian Viral Diseases Research Unit, Southeast Poultry Research Laboratory, US National Poultry Research Center, Agricultural Research Service, USDA, 934 College Station Rd., Athens, GA 30605, USA; (V.C.M.); (S.C.-G.); (D.G.D.); (L.H.A.d.S.); (P.J.M.); (S.L.B.); (I.V.G.); (K.M.D.); (T.L.T.); (D.W.-C.); (T.L.O.)
| | - Corrie C. Brown
- Department of Veterinary Pathology, College of Veterinary Medicine, The University of Georgia, Athens, GA 30602, USA; (C.C.B.); (J.B.S.)
| | - Salman Latif Butt
- Exotic and Emerging Avian Viral Diseases Research Unit, Southeast Poultry Research Laboratory, US National Poultry Research Center, Agricultural Research Service, USDA, 934 College Station Rd., Athens, GA 30605, USA; (V.C.M.); (S.C.-G.); (D.G.D.); (L.H.A.d.S.); (P.J.M.); (S.L.B.); (I.V.G.); (K.M.D.); (T.L.T.); (D.W.-C.); (T.L.O.)
- Department of Veterinary Pathology, College of Veterinary Medicine, The University of Georgia, Athens, GA 30602, USA; (C.C.B.); (J.B.S.)
- Department of Pathology, UAF Sub Campus TTS, University of Agriculture Faisalabad, Punjab 38000, Pakistan
| | - Iryna V. Goraichuk
- Exotic and Emerging Avian Viral Diseases Research Unit, Southeast Poultry Research Laboratory, US National Poultry Research Center, Agricultural Research Service, USDA, 934 College Station Rd., Athens, GA 30605, USA; (V.C.M.); (S.C.-G.); (D.G.D.); (L.H.A.d.S.); (P.J.M.); (S.L.B.); (I.V.G.); (K.M.D.); (T.L.T.); (D.W.-C.); (T.L.O.)
- National Scientific Center Institute of Experimental and Clinical Veterinary Medicine, 83 Pushkinska St., 61023 Kharkiv, Ukraine
| | - Kiril M. Dimitrov
- Exotic and Emerging Avian Viral Diseases Research Unit, Southeast Poultry Research Laboratory, US National Poultry Research Center, Agricultural Research Service, USDA, 934 College Station Rd., Athens, GA 30605, USA; (V.C.M.); (S.C.-G.); (D.G.D.); (L.H.A.d.S.); (P.J.M.); (S.L.B.); (I.V.G.); (K.M.D.); (T.L.T.); (D.W.-C.); (T.L.O.)
| | - Tonya L. Taylor
- Exotic and Emerging Avian Viral Diseases Research Unit, Southeast Poultry Research Laboratory, US National Poultry Research Center, Agricultural Research Service, USDA, 934 College Station Rd., Athens, GA 30605, USA; (V.C.M.); (S.C.-G.); (D.G.D.); (L.H.A.d.S.); (P.J.M.); (S.L.B.); (I.V.G.); (K.M.D.); (T.L.T.); (D.W.-C.); (T.L.O.)
| | - Dawn Williams-Coplin
- Exotic and Emerging Avian Viral Diseases Research Unit, Southeast Poultry Research Laboratory, US National Poultry Research Center, Agricultural Research Service, USDA, 934 College Station Rd., Athens, GA 30605, USA; (V.C.M.); (S.C.-G.); (D.G.D.); (L.H.A.d.S.); (P.J.M.); (S.L.B.); (I.V.G.); (K.M.D.); (T.L.T.); (D.W.-C.); (T.L.O.)
| | - Timothy L. Olivier
- Exotic and Emerging Avian Viral Diseases Research Unit, Southeast Poultry Research Laboratory, US National Poultry Research Center, Agricultural Research Service, USDA, 934 College Station Rd., Athens, GA 30605, USA; (V.C.M.); (S.C.-G.); (D.G.D.); (L.H.A.d.S.); (P.J.M.); (S.L.B.); (I.V.G.); (K.M.D.); (T.L.T.); (D.W.-C.); (T.L.O.)
| | - James B. Stanton
- Department of Veterinary Pathology, College of Veterinary Medicine, The University of Georgia, Athens, GA 30602, USA; (C.C.B.); (J.B.S.)
| | - Claudio L. Afonso
- Exotic and Emerging Avian Viral Diseases Research Unit, Southeast Poultry Research Laboratory, US National Poultry Research Center, Agricultural Research Service, USDA, 934 College Station Rd., Athens, GA 30605, USA; (V.C.M.); (S.C.-G.); (D.G.D.); (L.H.A.d.S.); (P.J.M.); (S.L.B.); (I.V.G.); (K.M.D.); (T.L.T.); (D.W.-C.); (T.L.O.)
- Correspondence:
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Kang BW, Chau I. Molecular target: pan-AKT in gastric cancer. ESMO Open 2021; 5:e000728. [PMID: 32948630 PMCID: PMC7511610 DOI: 10.1136/esmoopen-2020-000728] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 06/16/2020] [Accepted: 07/17/2020] [Indexed: 02/07/2023] Open
Abstract
The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signalling pathway is involved in multiple cellular processes, including cell survival, proliferation, differentiation, metabolism and cytoskeletal reorganisation. The downstream effectors of this PI3K pathway are also essential for maintaining physiologic homeostasis, commonly dysregulated in most solid tumours. AKT is the key regulator in PI3K/AKT/mTOR signalling, interacting with multiple intracellular molecules. AKT activation subsequently leads to a number of potential downstream effects, and its aberrant activation results in the pathogenesis of cancer. Accordingly, as an attractive therapeutic target for cancer treatment, several AKT inhibitors are currently under development and in multiple stages of clinical trials for various types of malignancy, including gastric cancer (GC). Therefore, the authors review the significance of AKT and recent studies on AKT inhibitors in GC, focusing on the scientific background with the potential to improve treatment outcomes.
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Affiliation(s)
- Byung Woog Kang
- Department of Oncology/Hematology, Kyungpook National University Hospital, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Ian Chau
- Department of Medicine, Royal Marsden Hospital, London and Surrey, UK.
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Rascio F, Spadaccino F, Rocchetti MT, Castellano G, Stallone G, Netti GS, Ranieri E. The Pathogenic Role of PI3K/AKT Pathway in Cancer Onset and Drug Resistance: An Updated Review. Cancers (Basel) 2021; 13:3949. [PMID: 34439105 PMCID: PMC8394096 DOI: 10.3390/cancers13163949] [Citation(s) in RCA: 206] [Impact Index Per Article: 51.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 07/30/2021] [Indexed: 12/12/2022] Open
Abstract
The PI3K/AKT pathway is one of the most frequently over-activated intracellular pathways in several human cancers. This pathway, acting on different downstream target proteins, contributes to the carcinogenesis, proliferation, invasion, and metastasis of tumour cells. A multi-level impairment, involving mutation and genetic alteration, aberrant regulation of miRNAs sequences, and abnormal phosphorylation of cascade factors, has been found in multiple cancer types. The deregulation of this pathway counteracts common therapeutic strategies and contributes to multidrug resistance. In this review, we underline the involvement of this pathway in patho-physiological cell survival mechanisms, emphasizing its key role in the development of drug resistance. We also provide an overview of the potential inhibition strategies currently available.
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Affiliation(s)
- Federica Rascio
- Nephrology Dialysis and Transplantation Unit, Advanced Research Center on Kidney Aging (A.R.K.A.), Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy; (G.C.); (G.S.)
| | - Federica Spadaccino
- Clinical Pathology Unit, Advanced Research Center on Kidney Aging (A.R.K.A.), Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy; (F.S.); (G.S.N.); (E.R.)
| | - Maria Teresa Rocchetti
- Cell Biology Unit, Department of Clinical and Experimental Medicine, University of Foggia, 71122 Foggia, Italy;
| | - Giuseppe Castellano
- Nephrology Dialysis and Transplantation Unit, Advanced Research Center on Kidney Aging (A.R.K.A.), Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy; (G.C.); (G.S.)
| | - Giovanni Stallone
- Nephrology Dialysis and Transplantation Unit, Advanced Research Center on Kidney Aging (A.R.K.A.), Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy; (G.C.); (G.S.)
| | - Giuseppe Stefano Netti
- Clinical Pathology Unit, Advanced Research Center on Kidney Aging (A.R.K.A.), Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy; (F.S.); (G.S.N.); (E.R.)
| | - Elena Ranieri
- Clinical Pathology Unit, Advanced Research Center on Kidney Aging (A.R.K.A.), Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy; (F.S.); (G.S.N.); (E.R.)
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Phosphorylation of RCC1 on Serine 11 Facilitates G1/S Transition in HPV E7-Expressing Cells. Biomolecules 2021; 11:biom11070995. [PMID: 34356619 PMCID: PMC8301946 DOI: 10.3390/biom11070995] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Revised: 07/01/2021] [Accepted: 07/01/2021] [Indexed: 11/25/2022] Open
Abstract
Persistent infection of high-risk human papillomavirus (HR-HPV) plays a causal role in cervical cancer. Regulator of chromosome condensation 1 (RCC1) is a critical cell cycle regulator, which undergoes a few post-translational modifications including phosphorylation. Here, we showed that serine 11 (S11) of RCC1 was phosphorylated in HPV E7-expressing cells. However, S11 phosphorylation was not up-regulated by CDK1 in E7-expressing cells; instead, the PI3K/AKT/mTOR pathway promoted S11 phosphorylation. Knockdown of AKT or inhibition of the PI3K/AKT/mTOR pathway down-regulated phosphorylation of RCC1 S11. Furthermore, S11 phosphorylation occurred throughout the cell cycle, and reached its peak during the mitosis phase. Our previous data proved that RCC1 was necessary for the G1/S cell cycle progression, and in the present study we showed that the RCC1 mutant, in which S11 was mutated to alanine (S11A) to mimic non-phosphorylation status, lost the ability to facilitate G1/S transition in E7-expressing cells. Moreover, RCC1 S11 was phosphorylated by the PI3K/AKT/mTOR pathway in HPV-positive cervical cancer SiHa and HeLa cells. We conclude that S11 of RCC1 is phosphorylated by the PI3K/AKT/mTOR pathway and phosphorylation of RCC1 S11 facilitates the abrogation of G1 checkpoint in HPV E7-expressing cells. In short, our study explores a new role of RCC1 S11 phosphorylation in cell cycle regulation.
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Junaid M, Akter Y, Afrose SS, Tania M, Khan MA. Biological Role of AKT and Regulation of AKT Signaling Pathway by Thymoquinone: Perspectives in Cancer Therapeutics. Mini Rev Med Chem 2021; 21:288-301. [PMID: 33019927 DOI: 10.2174/1389557520666201005143818] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2020] [Revised: 09/02/2020] [Accepted: 09/08/2020] [Indexed: 11/22/2022]
Abstract
BACKGROUND AKT/PKB is an important enzyme with numerous biological functions, and its overexpression is related to carcinogenesis. AKT stimulates different signaling pathways that are downstream of activated tyrosine kinases and phosphatidylinositol 3-kinase, hence functions as an important target for anti-cancer drugs. OBJECTIVE In this review article, we have interpreted the role of AKT signaling pathway in cancer and the natural inhibitory effect of Thymoquinone (TQ) in AKT and its possible mechanisms. METHOD We have collected the updated information and data on AKT, its role in cancer and the inhibitory effect of TQ in AKT signaling pathway from Google Scholar, PubMed, Web of Science, Elsevier, Scopus, and many more. RESULTS Many drugs are already developed, which can target AKT, but very few among them have passed clinical trials. TQ is a natural compound, mainly found in black cumin, which has been found to have potential anti-cancer activities. TQ targets numerous signaling pathways, including AKT, in different cancers. In fact, many studies revealed that AKT is one of the major targets of TQ. The preclinical success of TQ suggests its clinical studies on cancer. CONCLUSION This review article summarizes the role of AKT in carcinogenesis, its potent inhibitors in clinical trials, and how TQ acts as an inhibitor of AKT and TQ's future as a cancer therapeutic drug.
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Affiliation(s)
- Md Junaid
- Molecular Modeling Drug-design and Discovery Laboratory, Pharmacology Research Division, Bangladesh Council of Scientific and Industrial Research, Chattogram, Bangladesh
| | - Yeasmin Akter
- Department of Biotechnology and Genetic Engineering, Noakhali Science & Technology University, Noakhali, Bangladesh
| | | | - Mousumi Tania
- Division of Molecular Cancer, Red Green Research Center, Dhaka, Bangladesh
| | - Md Asaduzzaman Khan
- The research center for preclinical medicine, Southwest Medical University, Luzhou, China
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Trafalis DT, Sagredou S, Dalezis P, Voura M, Fountoulaki S, Nikoleousakos N, Almpanakis K, Deligiorgi MV, Sarli V. Anticancer Activity of Triazolo-Thiadiazole Derivatives and Inhibition of AKT1 and AKT2 Activation. Pharmaceutics 2021; 13:pharmaceutics13040493. [PMID: 33916378 PMCID: PMC8066331 DOI: 10.3390/pharmaceutics13040493] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 03/28/2021] [Accepted: 03/29/2021] [Indexed: 12/18/2022] Open
Abstract
The fusion of 1,2,4-triazole and 1,3,4-thiadiazole rings results in a class of heterocycles compounds with an extensive range of pharmacological properties. A series of 1,2,4-triazolo[3,4-b]-1,2,4-thiadiazoles was synthesized and tested for its enzyme inhibition potential and anticancer activity. The results show that 1,2,4-triazolo[3,4-b]-1,2,4-thiadiazoles display potent anticancer properties in vitro against a panel of cancer cells and in vivo efficacy in HT-29 human colon tumor xenograft in CB17 severe combined immunodeficient (SCID) mice. Preliminary mechanistic studies revealed that KA25 and KA39 exhibit time- and concentration-dependent inhibition of Akt Ser-473 phosphorylation. Molecular modeling experiments indicated that 1,2,4-triazolo[3,4-b]-1,2,4-thiadiazoles bind well to the ATP binding site in Akt1 and Akt2. The low acute toxicity combined with in vitro and in vivo anticancer activity render triazolo[3,4-b]thiadiazoles KA25, KA26, and KA39 promising cancer therapeutic agents.
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Affiliation(s)
- Dimitrios T. Trafalis
- Laboratory of Pharmacology, Faculty of Medicine, National and Kapodistrian University of Athens, 115 27 Athens, Greece; (S.S.); (P.D.); (N.N.); (M.V.D.)
- Correspondence: (D.T.T.); (V.S.)
| | - Sofia Sagredou
- Laboratory of Pharmacology, Faculty of Medicine, National and Kapodistrian University of Athens, 115 27 Athens, Greece; (S.S.); (P.D.); (N.N.); (M.V.D.)
| | - Panayiotis Dalezis
- Laboratory of Pharmacology, Faculty of Medicine, National and Kapodistrian University of Athens, 115 27 Athens, Greece; (S.S.); (P.D.); (N.N.); (M.V.D.)
| | - Maria Voura
- Department of Chemistry, Aristotle University of Thessaloniki, University Campus, 541 24 Thessaloniki, Greece; (M.V.); (S.F.); (K.A.)
| | - Stella Fountoulaki
- Department of Chemistry, Aristotle University of Thessaloniki, University Campus, 541 24 Thessaloniki, Greece; (M.V.); (S.F.); (K.A.)
| | - Nikolaos Nikoleousakos
- Laboratory of Pharmacology, Faculty of Medicine, National and Kapodistrian University of Athens, 115 27 Athens, Greece; (S.S.); (P.D.); (N.N.); (M.V.D.)
| | - Konstantinos Almpanakis
- Department of Chemistry, Aristotle University of Thessaloniki, University Campus, 541 24 Thessaloniki, Greece; (M.V.); (S.F.); (K.A.)
| | - Maria V. Deligiorgi
- Laboratory of Pharmacology, Faculty of Medicine, National and Kapodistrian University of Athens, 115 27 Athens, Greece; (S.S.); (P.D.); (N.N.); (M.V.D.)
| | - Vasiliki Sarli
- Department of Chemistry, Aristotle University of Thessaloniki, University Campus, 541 24 Thessaloniki, Greece; (M.V.); (S.F.); (K.A.)
- Correspondence: (D.T.T.); (V.S.)
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Sarkar T, Raghavan VV, Chen F, Riley A, Zhou S, Xu W. Exploring the effectiveness of the TSR-based protein 3-D structural comparison method for protein clustering, and structural motif identification and discovery of protein kinases, hydrolases, and SARS-CoV-2's protein via the application of amino acid grouping. Comput Biol Chem 2021; 92:107479. [PMID: 33951604 DOI: 10.1016/j.compbiolchem.2021.107479] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Revised: 03/14/2021] [Accepted: 03/23/2021] [Indexed: 12/26/2022]
Abstract
Development of protein 3-D structural comparison methods is essential for understanding protein functions. Some amino acids share structural similarities while others vary considerably. These structures determine the chemical and physical properties of amino acids. Grouping amino acids with similar structures potentially improves the ability to identify structurally conserved regions and increases the global structural similarity between proteins. We systematically studied the effects of amino acid grouping on the numbers of Specific/specific, Common/common, and statistically different keys to achieve a better understanding of protein structure relations. Common keys represent substructures found in all types of proteins and Specific keys represent substructures exclusively belonging to a certain type of proteins in a data set. Our results show that applying amino acid grouping to the Triangular Spatial Relationship (TSR)-based method, while computing structural similarity among proteins, improves the accuracy of protein clustering in certain cases. In addition, applying amino acid grouping facilitates the process of identification or discovery of conserved structural motifs. The results from the principal component analysis (PCA) demonstrate that applying amino acid grouping captures slightly more structural variation than when amino acid grouping is not used, indicating that amino acid grouping reduces structure diversity as predicted. The TSR-based method uniquely identifies and discovers binding sites for drugs or interacting proteins. The binding sites of nsp16 of SARS-CoV-2, SARS-CoV and MERS-CoV that we have defined will aid future antiviral drug design for improving therapeutic outcome. This approach for incorporating the amino acid grouping feature into our structural comparison method is promising and provides a deeper insight into understanding of structural relations of proteins.
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Affiliation(s)
- Titli Sarkar
- The Center for Advanced Computer Studies, University of Louisiana at Lafayette, Lafayette, LA 70504, USA
| | - Vijay V Raghavan
- The Center for Advanced Computer Studies, University of Louisiana at Lafayette, Lafayette, LA 70504, USA
| | - Feng Chen
- High Performance Computing, 329 Frey Computing Services Center, Louisiana State University, Baton Rouge, LA 70803, USA
| | - Andrew Riley
- The Center for Advanced Computer Studies, University of Louisiana at Lafayette, Lafayette, LA 70504, USA
| | - Sophia Zhou
- Department of Chemistry, University of Louisiana at Lafayette, P.O. Box 44370, Lafayette, LA 70504, USA
| | - Wu Xu
- Department of Chemistry, University of Louisiana at Lafayette, P.O. Box 44370, Lafayette, LA 70504, USA.
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Genomic Analyses for Predictors of Response to Chemoradiation in Stage III Non-Small Cell Lung Cancer. Adv Radiat Oncol 2021; 6:100615. [PMID: 33665490 PMCID: PMC7897765 DOI: 10.1016/j.adro.2020.10.027] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Revised: 10/22/2020] [Accepted: 10/29/2020] [Indexed: 12/13/2022] Open
Abstract
Background Radiation with platinum-based chemotherapy is the standard of care for unresectable stage III non-small cell lung cancer (NSCLC). Despite aggressive treatment, progression-free survival and overall survival remain poor. It is unclear whether any tumor genetic mutations are associated with response to chemoradiation therapy. Methods We retrospectively reviewed clinical outcomes of patients with stage III NSCLC treated with definitive radiation who had undergone tumor molecular profiling through a next-generation DNA sequencing platform. Cox proportional hazards model was used to investigate associations between clinical outcomes and genetic mutations detected by next-generation sequencing. Results 110 patients were identified with stage III NSCLC and underwent definitive radiation between 2013 and 2017 and tumor molecular profiling. Concurrent or sequential chemotherapy was given in 104 patients (95%). Unbiased genomic analyses revealed a significant association between AKT2 mutations and decreased local-regional tumor control and overall survival (hazard ratios [HR] 12.5 and 13.7, P = .003 and P = .003, respectively). Analyses restricted to loss-of-function mutations identified KMT2C and KMT2D deleterious mutations as negative prognostic factors for overall survival (HR 13.4 and 7.0, P < .001 and P < .001, respectively). Deleterious mutations in a panel of 38 DNA damage response and repair pathway genes were associated with improved local-regional control (HR 0.32, P = .049). Conclusions This study coupled multiplexed targeted sequencing with clinical outcome and identified mutations in AKT2, KMT2C, and KMT2D as negative predictors of local-regional control and survival, and deleterious mutations in damage response and repair pathway genes were associated with improved local-regional disease control after chemoradiation therapy. These findings will require validation in a larger cohort of patients with prospectively collected and detailed clinical information.
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An Immunohistochemical Study of the PTEN/AKT Pathway Involvement in Canine and Feline Mammary Tumors. Animals (Basel) 2021; 11:ani11020365. [PMID: 33535663 PMCID: PMC7912927 DOI: 10.3390/ani11020365] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Revised: 01/27/2021] [Accepted: 01/28/2021] [Indexed: 01/09/2023] Open
Abstract
Simple Summary The PTEN/AKT pathway is involved in several human and animal tumors’ pathogenesis. This study investigates the PTEN/AKT pathway’s biological and prognostic values in canine and feline mammary tumors. PTEN, phospho-AKT (p-AKT) and Rictor expression was determined by immunohistochemistry in canine mammary adenomas and carcinomas and feline mammary carcinomas. In mammary tumors of both species p-Akt was inversely correlated with PTEN expression and positively with Rictor expression; p-Akt and Rictor expression correlated with poorer prognosis. This data could provide a rationale for further studies of this pathway in veterinary oncology due to prognostic and therapeutic implications. Abstract Phosphatase and tensin homolog deleted on chromosome10 (PTEN), phospho-v-Akt murine thymoma viral oncogene homolog (AKT), and the Rapamycin-Insensitive Companion of mTOR (Rictor) expression was investigated by immunohistochemistry in 10 canine mammary adenomas (CMAs), 40 canine mammary carcinomas (CMCs), and 30 feline mammary carcinomas (FMCs). All the CMAs, 25 of 40 CMCs (63%) and 7 of 30 FMCs (23%), were PTEN-positive. In dogs, no CMAs and 15 of 25 CMCs (37%) expressed phospho-AKT (p-AKT), while 24 of 30 FMCs (82%) were p-AKT-positive. One of 10 CMAs (10%), 24 of 40 CMCs (60%) and 20 of 30 FMCs (67%) were Rictor-positive. In the dog, PTEN expression correlated with less aggressive tumors, absence of lymphatic invasion, and longer survival. P-AKT expression correlated with more aggressive subtype, lymphatic invasion, and poorer survival and Rictor expression with lymphatic invasion. In cats, PTEN correlated with less aggressive carcinomas, absence of lymphatic invasion, and better survival. P-AKT and Rictor expression correlated with poorer survival. PTEN expression was inversely correlated with p-AKT and Rictor in both species, while p-AKT positively correlated with Rictor expression. A strong PTEN/AKT pathway involvement in behavior worsening of CMT and FMTs is demonstrated, providing a rationale for further studies of this pathway in veterinary oncology.
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Minini M, Senni A, Unfer V, Bizzarri M. The Key Role of IP 6K: A Novel Target for Anticancer Treatments? Molecules 2020; 25:molecules25194401. [PMID: 32992691 PMCID: PMC7583815 DOI: 10.3390/molecules25194401] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2020] [Revised: 09/20/2020] [Accepted: 09/21/2020] [Indexed: 12/29/2022] Open
Abstract
Inositol and its phosphate metabolites play a pivotal role in several biochemical pathways and gene expression regulation: inositol pyrophosphates (PP-IPs) have been increasingly appreciated as key signaling modulators. Fluctuations in their intracellular levels hugely impact the transfer of phosphates and the phosphorylation status of several target proteins. Pharmacological modulation of the proteins associated with PP-IP activities has proved to be beneficial in various pathological settings. IP7 has been extensively studied and found to play a key role in pathways associated with PP-IP activities. Three inositol hexakisphosphate kinase (IP6K) isoforms regulate IP7 synthesis in mammals. Genomic deletion or enzymic inhibition of IP6K1 has been shown to reduce cell invasiveness and migration capacity, protecting against chemical-induced carcinogenesis. IP6K1 could therefore be a useful target in anticancer treatment. Here, we summarize the current understanding that established IP6K1 and the other IP6K isoforms as possible targets for cancer therapy. However, it will be necessary to determine whether pharmacological inhibition of IP6K is safe enough to begin clinical study. The development of safe and selective inhibitors of IP6K isoforms is required to minimize undesirable effects.
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Affiliation(s)
- Mirko Minini
- Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy;
- Department of Surgery ‘P. Valdoni’, Sapienza University of Rome, 00161 Rome, Italy
- Systems Biology Group Lab, Sapienza University of Rome, 00185 Rome, Italy;
- Correspondence: (M.M.); (M.B.)
| | - Alice Senni
- Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy;
- Department of Surgery ‘P. Valdoni’, Sapienza University of Rome, 00161 Rome, Italy
| | - Vittorio Unfer
- Systems Biology Group Lab, Sapienza University of Rome, 00185 Rome, Italy;
| | - Mariano Bizzarri
- Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy;
- Systems Biology Group Lab, Sapienza University of Rome, 00185 Rome, Italy;
- Correspondence: (M.M.); (M.B.)
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Parsons R. Discovery of the PTEN Tumor Suppressor and Its Connection to the PI3K and AKT Oncogenes. Cold Spring Harb Perspect Med 2020; 10:a036129. [PMID: 31932465 PMCID: PMC7397838 DOI: 10.1101/cshperspect.a036129] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
PTEN (phosphatase and tensin homolog on chromosome 10) was discovered over 20 years ago in 1997 and linked to the phosphatidylinositol 3-kinase (PI3K) and AKT oncogenes the following year. The discovery of PTEN emerged from the linked concepts of oncogenes and tumor suppressor genes that cause and prevent cancer and the fields of tumor viruses and human cancer genetics from which these two concepts arose. While much has been learned since, the initial discovery and characterization, including the discovery that PTEN is a regulator of PI3K and AKT, provide the foundation on which we continue to build our knowledge. To provide the context in which these cancer genes were discovered, background information that led to their discovery will also be discussed, which will hopefully be a useful guide for readers seeking to build on the work of others.
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Affiliation(s)
- Ramon Parsons
- Department of Oncological Sciences, Tisch Cancer Institute at Mount Sinai, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA
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Alonso-González C, González A, Menéndez-Menéndez J, Martínez-Campa C, Cos S. Melatonin as a Radio-Sensitizer in Cancer. Biomedicines 2020; 8:247. [PMID: 32726912 PMCID: PMC7460067 DOI: 10.3390/biomedicines8080247] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 07/15/2020] [Accepted: 07/22/2020] [Indexed: 02/07/2023] Open
Abstract
Radiotherapy is one of the treatments of choice in many types of cancer. Adjuvant treatments to radiotherapy try, on one hand, to enhance the response of tumor cells to radiation and, on the other hand, to reduce the side effects to normal cells. Radiosensitizers are agents that increase the effect of radiation in tumor cells by trying not to increase side effects in normal tissues. Melatonin is a hormone produced mainly by the pineal gland which has an important role in the regulation of cancer growth, especially in hormone-dependent mammary tumors. Different studies have showed that melatonin administered with radiotherapy is able to enhance its therapeutic effects and can protect normal cells against side effects of this treatment. Several mechanisms are involved in the radiosensitization induced by melatonin: increase of reactive oxygen species production, modulation of proteins involved in estrogen biosynthesis, impairment of tumor cells to DNA repair, modulation of angiogenesis, abolition of inflammation, induction of apoptosis, stimulation of preadipocytes differentiation and modulation of metabolism. At this moment, there are very few clinical trials that study the therapeutic usefulness to associate melatonin and radiotherapy in humans. All findings point to melatonin as an effective adjuvant molecule to radiotherapy in cancer treatment.
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Affiliation(s)
| | - Alicia González
- Department of Physiology and Pharmacology, School of Medicine, University of Cantabria and Instituto de Investigación Sanitaria Valdecilla (IDIVAL), 39011 Santander, Spain; (C.A.-G.); (J.M.-M.); (S.C.)
| | | | - Carlos Martínez-Campa
- Department of Physiology and Pharmacology, School of Medicine, University of Cantabria and Instituto de Investigación Sanitaria Valdecilla (IDIVAL), 39011 Santander, Spain; (C.A.-G.); (J.M.-M.); (S.C.)
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Genetic Analysis of Small Well-differentiated Pancreatic Neuroendocrine Tumors Identifies Subgroups With Differing Risks of Liver Metastases. Ann Surg 2020; 271:566-573. [PMID: 30339629 DOI: 10.1097/sla.0000000000003022] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
OBJECTIVE The aim of this study was to investigate the key molecular alterations in small primary pancreatic neuroendocrine tumors (PanNETs) associated with the development of liver metastases. BACKGROUND Well-differentiated PanNETs with small size are typically indolent; however, a limited subset metastasize to the liver. METHODS A total of 87 small primary PanNETs (<3 cm), including 32 metastatic cases and 55 nonmetastatic cases after a 5-year follow-up, were immunolabeled for DAXX/ATRX and analyzed for alternative lengthening of telomeres (ALT) by Fluorescence In Situ Hybridization. A subset of these cases, 24 that metastasized and 24 that did not metastasize, were assessed by targeted next-generation sequencing and whole-genome copy number variation. RESULTS In the entire cohort, high Ki-67 (OR 1.369; 95% CI 1.121-1.673; P = 0.002), N-stage (OR 4.568; 95% CI 1.458-14.312; P = 0.009), and ALT-positivity (OR 3.486; 95% CI 1.093-11.115; P = 0.035) were independently associated with liver metastases. In the subset assessed by next-generation sequencing and copy number variation analysis, 3 molecular subtypes with differing risks of liver metastases were identified. Group 1 (n = 15; 73% metastasized) was characterized by recurrent chromosomal gains, CN-LOH, DAXX mutations, and ALT-positivity. Group 2 (n = 19; 42% metastasized, including 5 G1 tumors) was characterized by limited copy number alterations and mutations. Group 3 (n = 14; 35% metastasized) were defined by chromosome 11 loss. CONCLUSIONS We identified genomic patterns of small PanNETs associated with a different risk for liver metastases. Molecular alterations, such as DAXX mutations, chromosomal gains, and ALT, are associated with an increased risk of metastasis in small PanNETs. Therefore, targeted sequencing and/or ALT analysis may help in the clinical decisions for these small PanNETs.
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Mukherjee S, Haubner J, Chakraborty A. Targeting the Inositol Pyrophosphate Biosynthetic Enzymes in Metabolic Diseases. Molecules 2020; 25:molecules25061403. [PMID: 32204420 PMCID: PMC7144392 DOI: 10.3390/molecules25061403] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Revised: 03/09/2020] [Accepted: 03/11/2020] [Indexed: 12/12/2022] Open
Abstract
In mammals, a family of three inositol hexakisphosphate kinases (IP6Ks) synthesizes the inositol pyrophosphate 5-IP7 from IP6. Genetic deletion of Ip6k1 protects mice from high fat diet induced obesity, insulin resistance and fatty liver. IP6K1 generated 5-IP7 promotes insulin secretion from pancreatic β-cells, whereas it reduces insulin signaling in metabolic tissues by inhibiting the protein kinase Akt. Thus, IP6K1 promotes high fat diet induced hyperinsulinemia and insulin resistance in mice while its deletion has the opposite effects. IP6K1 also promotes fat accumulation in the adipose tissue by inhibiting the protein kinase AMPK mediated energy expenditure. Genetic deletion of Ip6k3 protects mice from age induced fat accumulation and insulin resistance. Accordingly, the pan IP6K inhibitor TNP [N2-(m-trifluorobenzyl), N6-(p-nitrobenzyl)purine] ameliorates obesity, insulin resistance and fatty liver in diet induced obese mice by improving Akt and AMPK mediated insulin sensitivity and energy expenditure. TNP also protects mice from bone loss, myocardial infarction and ischemia reperfusion injury. Thus, the IP6K pathway is a potential target in obesity and other metabolic diseases. Here, we summarize the studies that established IP6Ks as a potential target in metabolic diseases. Further studies will reveal whether inhibition of this pathway has similar pleiotropic benefits on metabolic health of humans.
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Weidle UH, Birzele F, Nopora A. Pancreatic Ductal Adenocarcinoma: MicroRNAs Affecting Tumor Growth and Metastasis in Preclinical In Vivo Models. Cancer Genomics Proteomics 2020; 16:451-464. [PMID: 31659100 DOI: 10.21873/cgp.20149] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Revised: 07/30/2019] [Accepted: 08/01/2019] [Indexed: 02/08/2023] Open
Abstract
Patients with pancreatic ductal adenocarcinoma have a dismall prognosis because at the time of diagnosis, in the vast majority of patients the tumor has already disseminated to distant organs and the therapeutic benefit of approved agents such as gemcitabine is limited. Therefore, the identification and preclinical and clinical validation of therapeutic agents covering new targets is of paramount importance. In this review we have summarized microRNAs and corresponding targets which affect growth and metastasis of pancreatic tumors in preclinical mouse in vivo models. We identified four up-regulated and 16 down-regulated miRs in PDAC in comparison to corresponding normal tissues. Three sub-categories of miRs have emerged: miRs affecting tumor growth and miRs with an impact on both, tumor growth and metastasis or metastasis only. Finally, we discuss technical and therapeutic aspects of miR-related therapeutic agents for the treatment of pancreatic ductal adenocarcinoma.
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Affiliation(s)
- Ulrich H Weidle
- Roche Innovation Center Munich, Roche Diagnostics GmbH, Penzberg, Germany
| | - Fabian Birzele
- Roche Innovation Center Basel, F. Hofman La Roche, Basel, Switzerland
| | - Adam Nopora
- Roche Innovation Center Munich, Roche Diagnostics GmbH, Penzberg, Germany
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Kobayashi Y, Lim SO, Yamaguchi H. Oncogenic signaling pathways associated with immune evasion and resistance to immune checkpoint inhibitors in cancer. Semin Cancer Biol 2019; 65:51-64. [PMID: 31874279 DOI: 10.1016/j.semcancer.2019.11.011] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Revised: 11/03/2019] [Accepted: 11/15/2019] [Indexed: 12/12/2022]
Abstract
Immune checkpoint inhibitors (ICIs) are novel class of anti-cancer drugs that exhibit significant therapeutic effects even in patients with advanced-stage cancer. However, the efficacy of ICIs is limited due to resistance. Therefore, appropriate biomarkers to select patients who are likely to respond to these drugs as well as combination therapy to overcome the resistance are urgently necessary. Cancer is caused by various genetic alterations that lead to abnormalities in oncogenic signaling pathways. The aberrant oncogenic signaling pathways serve as not only prognostic and predictive biomarkers, but also targets for molecularly targeted therapy. Growing evidence shows that the aberrant oncogenic signaling pathways in cancer cells facilitate the resistance to ICIs by modulating the regulation of immune checkpoint and cancer immune surveillance. Indeed, it has been demonstrated that some molecular targeted therapies significantly improve the efficacy of ICIs in preclinical and clinical studies. In this review, we highlighted several oncogenic signaling pathways including receptor tyrosine kinases (RTKs), MAPK, PI3K-AKT-mTOR, JAK-STAT, Hippo, and Wnt pathways, and summarized the recent findings of the mechanisms underlying the regulation of cancer immunity and the ICI resistance induced by these aberrant oncogenic signaling pathways in cancer cells. Moreover, we discussed potential combination therapies with ICIs and molecularly targeted drugs to overcome the resistance and increase the efficacy of ICIs.
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Affiliation(s)
- Yoshie Kobayashi
- Cancer Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), PO Box 34110, Doha, Qatar
| | - Seung-Oe Lim
- Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, 47907, USA
| | - Hirohito Yamaguchi
- Cancer Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), PO Box 34110, Doha, Qatar.
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Ayres Pereira M, Chio IIC. Metastasis in Pancreatic Ductal Adenocarcinoma: Current Standing and Methodologies. Genes (Basel) 2019; 11:E6. [PMID: 31861620 PMCID: PMC7016631 DOI: 10.3390/genes11010006] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Revised: 12/11/2019] [Accepted: 12/17/2019] [Indexed: 01/18/2023] Open
Abstract
Pancreatic ductal adenocarcinoma is an extremely aggressive disease with a high metastatic potential. Most patients are diagnosed with metastatic disease, at which the five-year survival rate is only 3%. A better understanding of the mechanisms that drive metastasis is imperative for the development of better therapeutic interventions. Here, we take the reader through our current knowledge of the parameters that support metastatic progression in pancreatic ductal adenocarcinoma, and the experimental models that are at our disposal to study this process. We also describe the advantages and limitations of these models to study the different aspects of metastatic dissemination.
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Affiliation(s)
| | - Iok In Christine Chio
- Institute for Cancer Genetics, Department of Genetics and Development, Columbia University Medical Center, New York, NY 10032, USA;
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