|
1
|
Maghsoudi H, Sheikhnia F, Hajmalek N, Gholipour FD, Alipour S, Ghorbanpour M, Farzanegan S, Mir SM, Memar MY. Multifaceted roles of melatonin in oncology: an insight into its therapeutic potential in cancer management. Inflammopharmacology 2025:10.1007/s10787-025-01751-9. [PMID: 40263172 DOI: 10.1007/s10787-025-01751-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Accepted: 04/04/2025] [Indexed: 04/24/2025]
Abstract
Cancer remains the leading cause of death worldwide. The treatment of cancer has become increasing complex. Current treatment options for cancer include surgical resection, chemotherapy, radiotherapy, nanomedicine, and immunotherapy. Recent experimental and clinical studies have provided substantial evidence supporting the potential use of melatonin as a preventive and therapeutic agent in oncology. Melatonin (N-acetyl-5-methoxy-tryptamine), a pleiotropic and multitasking molecule, is secreted from the pineal gland during the night under normal light-dark conditions. Beyond its role in circadian regulation, melatonin exhibits antioxidant, anti-aging, immunomodulatory, and anti-cancer properties. Melatonin exerts significant apoptotic, angiogenic, oncostatic, and anti-proliferative effects on a variety of cancer cells. This review discusses the influence of melatonin on cancer cells through mechanisms involving cell cycle regulation, stimulation of apoptosis, autophagy induction, epigenetic modification, and transcriptional regulation.
Collapse
Affiliation(s)
- Hossein Maghsoudi
- Student Research Committee, Urmia University of Medical Sciences, Urmia, 57147-83734, Iran
- Department of Clinical Biochemistry and Applied Cell Sciences, School of Medicine, Urmia University of Medical Sciences, Urmia, 57147-83734, Iran
| | - Farhad Sheikhnia
- Student Research Committee, Urmia University of Medical Sciences, Urmia, 57147-83734, Iran
- Department of Clinical Biochemistry and Applied Cell Sciences, School of Medicine, Urmia University of Medical Sciences, Urmia, 57147-83734, Iran
| | - Nooshin Hajmalek
- Department of Clinical Biochemistry, School of Medicine, Babol University of Medical Sciences, Babol, 47176-47754, Iran
| | - Fatemeh Dadash Gholipour
- Department of Clinical Biochemistry, School of Medicine, Babol University of Medical Sciences, Babol, 47176-47754, Iran
- Student Research Committee, Babol University of Medical Sciences, Babol, 47176-47754, Iran
| | - Shahriar Alipour
- Student Research Committee, Urmia University of Medical Sciences, Urmia, 57147-83734, Iran
- Department of Clinical Biochemistry and Applied Cell Sciences, School of Medicine, Urmia University of Medical Sciences, Urmia, 57147-83734, Iran
| | - Mansour Ghorbanpour
- Department of Medicinal Plants, Faculty of Agriculture and Natural Resources, Arak University, Arak, 38156-88349, Iran
| | - Sara Farzanegan
- Metabolic Disorders Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Seyed Mostafa Mir
- Metabolic Disorders Research Center, Golestan University of Medical Sciences, Gorgan, Iran.
| | - Mohammad Yousef Memar
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
| |
Collapse
|
|
2
|
Devinat M, Thevenard-Devy J, Ghilane F, Devy J, Chazee L, Terryn C, Duca L, Devarenne-Charpentier E, El Btaouri H. Xanthohumol Sensitizes Melanoma Cells to Vemurafenib by Lowering Membrane Cholesterol and Increasing Membrane Fluidity. Int J Mol Sci 2025; 26:2290. [PMID: 40076912 PMCID: PMC11901044 DOI: 10.3390/ijms26052290] [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: 02/05/2025] [Revised: 02/26/2025] [Accepted: 02/28/2025] [Indexed: 03/14/2025] Open
Abstract
Chemoresistance remains one of the major obstacles to cancer treatment. The search for specific molecules that could improve cancer treatment has become one of the objectives of biomedical research. Identifying new natural molecules to enhance chemotherapy treatment or improve sensitization to conventional therapies has become a key objective. Here, we evaluated the effect of Xanthohumol (XN) extracted from hop on SKMEL-28 melanoma cells and their sensitization to vemurafenib (VEM) treatment. We measured the XN effect on cell viability and apoptosis. We also assessed the effect of XN on membrane fluidity and membrane cholesterol levels. Finally, we studied the impact of XN on cell sensitization to VEM. Here, we showed that XN reduced SKMEL-28 cell viability through an apoptotic mechanism. Our results demonstrated the potential role of XN in sensitizing cancer cells to VEM with a less toxic effect on non-tumor cells. A study of XN's molecular mechanism showed that XN was able to induce cholesterol depletion and increased fluidity in SKMEL-28 cancer cells. This leads to an increase in VEM incorporation. Here, we describe the importance of the strategy to modulate membrane fluidity by XN in order to significantly improve anticancer therapy.
Collapse
Affiliation(s)
- Marine Devinat
- UMR-CNRS 7369 Matrice Extracellulaire et Dynamique Cellulaire (MEDyC), UFR Sciences Exactes et Naturelles, Université de Reims Champagne Ardenne, Moulin de la Housse, BP 1039, 51687 Reims, CEDEX, France; (M.D.); (J.T.-D.); (J.D.); (L.C.); (L.D.); (E.D.-C.)
| | - Jessica Thevenard-Devy
- UMR-CNRS 7369 Matrice Extracellulaire et Dynamique Cellulaire (MEDyC), UFR Sciences Exactes et Naturelles, Université de Reims Champagne Ardenne, Moulin de la Housse, BP 1039, 51687 Reims, CEDEX, France; (M.D.); (J.T.-D.); (J.D.); (L.C.); (L.D.); (E.D.-C.)
| | - Fatiha Ghilane
- Laboratoire de Biologie des Pathologies Humaines, Université Mohammed V de Rabat, 4 Avenue Ibn Battouta, Rabat B.P. 1014 RP, Morocco;
| | - Jerome Devy
- UMR-CNRS 7369 Matrice Extracellulaire et Dynamique Cellulaire (MEDyC), UFR Sciences Exactes et Naturelles, Université de Reims Champagne Ardenne, Moulin de la Housse, BP 1039, 51687 Reims, CEDEX, France; (M.D.); (J.T.-D.); (J.D.); (L.C.); (L.D.); (E.D.-C.)
| | - Lise Chazee
- UMR-CNRS 7369 Matrice Extracellulaire et Dynamique Cellulaire (MEDyC), UFR Sciences Exactes et Naturelles, Université de Reims Champagne Ardenne, Moulin de la Housse, BP 1039, 51687 Reims, CEDEX, France; (M.D.); (J.T.-D.); (J.D.); (L.C.); (L.D.); (E.D.-C.)
| | - Christine Terryn
- Plateau Technique en Imagerie Cellulaire et Tissulaire (PICT) Pôle Santé, UFR Pharmacie, Université de Reims Champagne Ardenne, 51 Rue Cognacq Jay, 51096 Reims, France;
| | - Laurent Duca
- UMR-CNRS 7369 Matrice Extracellulaire et Dynamique Cellulaire (MEDyC), UFR Sciences Exactes et Naturelles, Université de Reims Champagne Ardenne, Moulin de la Housse, BP 1039, 51687 Reims, CEDEX, France; (M.D.); (J.T.-D.); (J.D.); (L.C.); (L.D.); (E.D.-C.)
| | - Emmanuelle Devarenne-Charpentier
- UMR-CNRS 7369 Matrice Extracellulaire et Dynamique Cellulaire (MEDyC), UFR Sciences Exactes et Naturelles, Université de Reims Champagne Ardenne, Moulin de la Housse, BP 1039, 51687 Reims, CEDEX, France; (M.D.); (J.T.-D.); (J.D.); (L.C.); (L.D.); (E.D.-C.)
| | - Hassan El Btaouri
- UMR-CNRS 7369 Matrice Extracellulaire et Dynamique Cellulaire (MEDyC), UFR Sciences Exactes et Naturelles, Université de Reims Champagne Ardenne, Moulin de la Housse, BP 1039, 51687 Reims, CEDEX, France; (M.D.); (J.T.-D.); (J.D.); (L.C.); (L.D.); (E.D.-C.)
| |
Collapse
|
|
3
|
Jagirdar K, Portuallo ME, Wei M, Wilhide M, Bravo Narula JA, Robertson BM, Alicea GM, Aguh C, Xiao M, Godok T, Fingerman D, Brown GS, Herlyn M, Elad VM, Guo X, Toska E, Zabransky DJ, Wubbenhorst B, Nathanson KL, Kwatra S, Goyal Y, Ji H, Liu Q, Rebecca VW. ERK hyperactivation serves as a unified mechanism of escape in intrinsic and acquired CDK4/6 inhibitor resistance in acral lentiginous melanoma. Oncogene 2024; 43:395-405. [PMID: 38066089 PMCID: PMC10837073 DOI: 10.1038/s41388-023-02900-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Revised: 10/27/2023] [Accepted: 11/15/2023] [Indexed: 12/19/2023]
Abstract
Patients with metastatic acral lentiginous melanoma (ALM) suffer worse outcomes relative to patients with other forms of cutaneous melanoma (CM), and do not benefit as well to approved melanoma therapies. Identification of cyclin-dependent kinase 4 and 6 (CDK4/6) pathway gene alterations in >60% of ALMs has led to clinical trials of the CDK4/6 inhibitor (CDK4i/6i) palbociclib for ALM; however, median progression free survival with CDK4i/6i treatment was only 2.2 months, suggesting existence of resistance mechanisms. Therapy resistance in ALM remains poorly understood; here we report hyperactivation of MAPK signaling and elevated cyclin D1 expression serve as a mechanism of intrinsic early/adaptive CDK4i/6i resistance. ALM cells that have acquired CDK4i/6i resistance following chronic treatment exposure also exhibit hyperactivation of the MAPK pathway. MEK and/or ERK inhibition increases CDK4i/6i efficacy against therapy naïve and CDK4i/6i-resistant AM cells in xenograft and patient-derived xenograft (PDX) models and promotes a defective DNA repair, cell cycle arrested and apoptotic program. Notably, gene alterations poorly correlate with protein expression of cell cycle proteins in ALM or efficacy of CDK4i/6i, urging additional strategies when stratifying patients for CDK4i/6i trial inclusion. Concurrent targeting of the MAPK pathway and CDK4/6 represents a new approach for patients with metastatic ALM to improve outcomes.
Collapse
Affiliation(s)
- Kasturee Jagirdar
- Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - Marie E Portuallo
- Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - Meihan Wei
- Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - Matthew Wilhide
- Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - Jeremy A Bravo Narula
- Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - Bailey M Robertson
- Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - Gretchen M Alicea
- Department of Chemical and Biomolecular Engineering, The Johns Hopkins Whiting School of Engineering, Baltimore, MD, USA
| | - Crystal Aguh
- Department of Dermatology, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Min Xiao
- The Wistar Institute, Molecular and Cellular Oncogenesis Program and Melanoma Research Center, Philadelphia, PA, USA
| | - Tetiana Godok
- The Wistar Institute, Molecular and Cellular Oncogenesis Program and Melanoma Research Center, Philadelphia, PA, USA
| | - Dylan Fingerman
- The Wistar Institute, Molecular and Cellular Oncogenesis Program and Melanoma Research Center, Philadelphia, PA, USA
| | - Gregory Schuyler Brown
- The Wistar Institute, Molecular and Cellular Oncogenesis Program and Melanoma Research Center, Philadelphia, PA, USA
| | - Meenhard Herlyn
- The Wistar Institute, Molecular and Cellular Oncogenesis Program and Melanoma Research Center, Philadelphia, PA, USA
| | - Vissy M Elad
- Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - Xinyu Guo
- Sidney Kimmel Comprehensive Cancer Center and Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Eneda Toska
- Sidney Kimmel Comprehensive Cancer Center and Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Daniel J Zabransky
- Sidney Kimmel Comprehensive Cancer Center and Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Bradley Wubbenhorst
- Department of Medicine, Division of Translational Medicine and Human Genetics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
| | - Katherine L Nathanson
- Department of Medicine, Division of Translational Medicine and Human Genetics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
| | - Shawn Kwatra
- Department of Dermatology, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Yogesh Goyal
- Department of Cell and Developmental Biology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA
| | - Hongkai Ji
- Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - Qin Liu
- The Wistar Institute, Molecular and Cellular Oncogenesis Program and Melanoma Research Center, Philadelphia, PA, USA
| | - Vito W Rebecca
- Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
- Sidney Kimmel Comprehensive Cancer Center and Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
| |
Collapse
|
|
4
|
Kharouf N, Flanagan TW, Alamodi AA, Al Hmada Y, Hassan SY, Shalaby H, Santourlidis S, Hassan SL, Haikel Y, Megahed M, Brodell RT, Hassan M. CD133-Dependent Activation of Phosphoinositide 3-Kinase /AKT/Mammalian Target of Rapamycin Signaling in Melanoma Progression and Drug Resistance. Cells 2024; 13:240. [PMID: 38334632 PMCID: PMC10854812 DOI: 10.3390/cells13030240] [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: 11/29/2023] [Revised: 01/24/2024] [Accepted: 01/25/2024] [Indexed: 02/10/2024] Open
Abstract
Melanoma frequently harbors genetic alterations in key molecules leading to the aberrant activation of PI3K and its downstream pathways. Although the role of PI3K/AKT/mTOR in melanoma progression and drug resistance is well documented, targeting the PI3K/AKT/mTOR pathway showed less efficiency in clinical trials than might have been expected, since the suppression of the PI3K/mTOR signaling pathway-induced feedback loops is mostly associated with the activation of compensatory pathways such as MAPK/MEK/ERK. Consequently, the development of intrinsic and acquired resistance can occur. As a solid tumor, melanoma is notorious for its heterogeneity. This can be expressed in the form of genetically divergent subpopulations including a small fraction of cancer stem-like cells (CSCs) and non-cancer stem cells (non-CSCs) that make the most of the tumor mass. Like other CSCs, melanoma stem-like cells (MSCs) are characterized by their unique cell surface proteins/stemness markers and aberrant signaling pathways. In addition to its function as a robust marker for stemness properties, CD133 is crucial for the maintenance of stemness properties and drug resistance. Herein, the role of CD133-dependent activation of PI3K/mTOR in the regulation of melanoma progression, drug resistance, and recurrence is reviewed.
Collapse
Affiliation(s)
- Naji Kharouf
- Institut National de la Santé et de la Recherche Médicale, University of Strasbourg, 67000 Strasbourg, France; (N.K.); (Y.H.)
- Department of Operative Dentistry and Endodontics, Dental Faculty, University of Strasbourg, 67000 Strasbourg, France
| | - Thomas W. Flanagan
- Department of Pharmacology and Experimental Therapeutics, LSU Health Sciences Center, New Orleans, LA 70112, USA;
| | | | - Youssef Al Hmada
- Department of Pathology, University of Mississippi Medical Center, Jackson, MS 39216, USA; (Y.A.H.); (R.T.B.)
| | - Sofie-Yasmin Hassan
- Department of Pharmacy, Faculty of Science, Heinrich-Heine University Duesseldorf, 40225 Dusseldorf, Germany;
| | - Hosam Shalaby
- Department of Urology, School of Medicine, Tulane University, New Orleans, LA 70112, USA;
| | - Simeon Santourlidis
- Epigenetics Core Laboratory, Institute of Transplantation Diagnostics and Cell Therapeutics, Medical Faculty, Heinrich-Heine University Duesseldorf, 40225 Duesseldorf, Germany;
| | - Sarah-Lilly Hassan
- Department of Chemistry, Faculty of Science, Heinrich-Heine University Duesseldorf, 40225 Dusseldorf, Germany;
| | - Youssef Haikel
- Institut National de la Santé et de la Recherche Médicale, University of Strasbourg, 67000 Strasbourg, France; (N.K.); (Y.H.)
- Department of Operative Dentistry and Endodontics, Dental Faculty, University of Strasbourg, 67000 Strasbourg, France
- Pôle de Médecine et Chirurgie Bucco-Dentaire, Hôpital Civil, Hôpitaux Universitaire de Strasbourg, 67000 Strasbourg, France
| | - Mossad Megahed
- Clinic of Dermatology, University Hospital of Aachen, 52074 Aachen, Germany;
| | - Robert T. Brodell
- Department of Pathology, University of Mississippi Medical Center, Jackson, MS 39216, USA; (Y.A.H.); (R.T.B.)
| | - Mohamed Hassan
- Institut National de la Santé et de la Recherche Médicale, University of Strasbourg, 67000 Strasbourg, France; (N.K.); (Y.H.)
- Department of Operative Dentistry and Endodontics, Dental Faculty, University of Strasbourg, 67000 Strasbourg, France
- Research Laboratory of Surgery-Oncology, Department of Surgery, Tulane University School of Medicine, New Orleans, LA 70112, USA
| |
Collapse
|
|
5
|
Neuendorf HM, Simmons JL, Boyle GM. Therapeutic targeting of anoikis resistance in cutaneous melanoma metastasis. Front Cell Dev Biol 2023; 11:1183328. [PMID: 37181747 PMCID: PMC10169659 DOI: 10.3389/fcell.2023.1183328] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Accepted: 04/14/2023] [Indexed: 05/16/2023] Open
Abstract
The acquisition of resistance to anoikis, the cell death induced by loss of adhesion to the extracellular matrix, is an absolute requirement for the survival of disseminating and circulating tumour cells (CTCs), and for the seeding of metastatic lesions. In melanoma, a range of intracellular signalling cascades have been identified as potential drivers of anoikis resistance, however a full understanding of the process is yet to be attained. Mechanisms of anoikis resistance pose an attractive target for the therapeutic treatment of disseminating and circulating melanoma cells. This review explores the range of small molecule, peptide and antibody inhibitors targeting molecules involved in anoikis resistance in melanoma, and may be repurposed to prevent metastatic melanoma prior to its initiation, potentially improving the prognosis for patients.
Collapse
Affiliation(s)
- Hannah M. Neuendorf
- Cancer Drug Mechanisms Group, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
- School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, QLD, Australia
| | - Jacinta L. Simmons
- Cancer Drug Mechanisms Group, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
- School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, QLD, Australia
- School of Biomedical Sciences, Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia
| | - Glen M. Boyle
- Cancer Drug Mechanisms Group, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
- School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, QLD, Australia
- School of Biomedical Sciences, Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia
| |
Collapse
|
|
6
|
Rebecca V, Jagirdar K, Portuallo M, Wei M, Wilhide M, Bravo J, Robertson B, Alicea G, Aguh C, Xiao M, Godok T, Fingerman D, Brown G, Herlyn M, Guo B, Toska E, Zabransky D, Wubbenhorst B, Nathanson K, Kwatra S, Goyal Y, Ji H, Liu Q. ERK Hyperactivation Serves as a Unified Mechanism of Escape in Intrinsic and Acquired CDK4/6 Inhibitor Resistance in Acral Lentiginous Melanoma. RESEARCH SQUARE 2023:rs.3.rs-2817876. [PMID: 37131684 PMCID: PMC10153386 DOI: 10.21203/rs.3.rs-2817876/v1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/04/2023]
Abstract
Patients with metastatic acral lentiginous melanoma (ALM) suffer worse outcomes relative to patients with other forms of cutaneous melanoma (CM), and do not benefit as well to approved melanoma therapies. Identification of cyclin-dependent kinase 4 and 6 (CDK4/6) pathway gene alterations in > 60% of ALMs has led to clinical trials of the CDK4/6 inhibitor (CDK4i/6i) palbociclib for ALM; however, median progression free survival with CDK4i/6i treatment was only 2.2 months, suggesting existence of resistance mechanisms. Therapy resistance in ALM remains poorly understood; here we report hyperactivation of MAPK signaling and elevated cyclin D1 expression are a unified mechanism of both intrinsic and acquired CDK4i/6i resistance. MEK and/or ERK inhibition increases CDK4i/6i efficacy in a patient-derived xenograft (PDX) model of ALM and promotes a defective DNA repair, cell cycle arrested and apoptotic program. Notably, gene alterations poorly correlate with protein expression of cell cycle proteins in ALM or efficacy of CDK4i/6i, urging additional strategies when stratifying patients for CDK4i/6i trial inclusion. Concurrent targeting of the MAPK pathway and CDK4/6 represents a new approach to improve outcomes for patients with advanced ALM.
Collapse
|
|
7
|
Degan S, May BL, Jin YJ, Hammouda MB, Sun H, Zhang G, Wang Y, Erdmann D, Warren W, Zhang JY. Co-Treatment of Chloroquine and Trametinib Inhibits Melanoma Cell Proliferation and Decreases Immune Cell Infiltration. Front Oncol 2022; 12:782877. [PMID: 35847840 PMCID: PMC9282877 DOI: 10.3389/fonc.2022.782877] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Accepted: 05/25/2022] [Indexed: 12/02/2022] Open
Abstract
Autophagy is characterized as a cytoprotective process and inhibition of autophagy with medicinally active agents, such as chloroquine (CQ) is proposed as a prospective adjuvant therapy for cancer. Here, we examined the preclinical effects of CQ combined with the MEK inhibitor trametinib (TRA) on melanoma. We found that cotreatment of CQ and TRA markedly slowed melanoma growth induced in Tyr-CreER.BrafCa.Ptenfl/fl mice. Immunostaining showed that trametinib decreased Ki-67+ proliferating cells, and increased TUNEL+ apoptotic cells. The combo treatment induced a further decrease of Ki-67+ proliferating cells. Consistent with the in vivo findings, CQ and TRA inhibited melanoma cell proliferation in vitro, which was correlated by decreased cyclin D1 expression. In addition, we found that tissues treated with CQ and TRA had significantly decreased numbers of CD4+ and CD8+ T-lymphocytes and F4/80+ macrophages. Together, these results indicate that cotreatment of CQ and TRA decreases cancer cell proliferation, but also dampens immune cell infiltration. Further study is warranted to understand whether CQ-induced immune suppression inadvertently affects therapeutic benefits.
Collapse
Affiliation(s)
- Simone Degan
- Department of Dermatology, Duke University Medical Center, Durham, NC, United States
- Department of Chemistry, Duke University, Durham, NC, United States
| | - Brian L. May
- Department of Surgery, Duke University, Durham, NC, United States
| | - Yingai J. Jin
- Department of Dermatology, Duke University Medical Center, Durham, NC, United States
| | - Manel Ben Hammouda
- Department of Dermatology, Duke University Medical Center, Durham, NC, United States
| | - Huiying Sun
- Department of Dermatology, Duke University Medical Center, Durham, NC, United States
| | - Guoqiang Zhang
- Department of Dermatology, Duke University Medical Center, Durham, NC, United States
| | - Yan Wang
- Department of Dermatology, Duke University Medical Center, Durham, NC, United States
| | - Detlev Erdmann
- Division of Plastic, Maxillofacial and Oral Surgery, Duke University Medical Center, Durham, NC, United States
| | - Warren Warren
- Department of Chemistry, Duke University, Durham, NC, United States
| | - Jennifer Y. Zhang
- Department of Dermatology, Duke University Medical Center, Durham, NC, United States
- Department of Pathology, Duke University Medical Center, Durham, NC, United States
| |
Collapse
|
|
8
|
Fatemi I, Dehdashtian E, Pourhanifeh MH, Mehrzadi S, Hosseinzadeh A. Therapeutic Application of Melatonin in the Treatment of Melanoma: A Review. CURRENT CANCER THERAPY REVIEWS 2021. [DOI: 10.2174/1573394717666210526140950] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Melanoma is an aggressive type of skin cancer, which is responsible for more deaths
than nonmelanoma skin cancers. Therapeutic strategies include targeted therapy, biochemotherapy,
immunotherapy, photodynamic therapy, chemotherapy, and surgical resection. Depending on the
clinical stage, single or combination therapy may be used to prevent and treat cancer. Due to resistance
development during treatment courses, the efficacy of mentioned therapies can be reduced.
In addition to resistance, these treatments have serious side effects for melanoma patients. According
to available reports, melatonin, a pineal indolamine with a wide spectrum of biological potentials,
has anticancer features. Furthermore, melatonin could protect against chemotherapy- and radiation-
induced adverse events and can sensitize cancer cells to therapy. The present review discusses
the therapeutic application of melatonin in the treatment of melanoma. This review was carried
out in PubMed, Web of Science, and Scopus databases comprising the date of publication period
from January 1976 to March 2021.
Collapse
Affiliation(s)
- Iman Fatemi
- Research Center of Tropical and Infectious Diseases, Kerman University of Medical Sciences, Kerman,Iran
| | - Ehsan Dehdashtian
- Razi Drug Research Center, Iran University of Medical Sciences, Tehran,Iran
| | | | - Saeed Mehrzadi
- Razi Drug Research Center, Iran University of Medical Sciences, Tehran,Iran
| | - Azam Hosseinzadeh
- Razi Drug Research Center, Iran University of Medical Sciences, Tehran,Iran
| |
Collapse
|
|
9
|
Lee J, Lee D, Kim Y. Mathematical model of STAT signalling pathways in cancer development and optimal control approaches. ROYAL SOCIETY OPEN SCIENCE 2021; 8:210594. [PMID: 34631119 PMCID: PMC8479343 DOI: 10.1098/rsos.210594] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Accepted: 09/03/2021] [Indexed: 06/10/2023]
Abstract
In various diseases, the STAT family display various cellular controls over various challenges faced by the immune system and cell death programs. In this study, we investigate how an intracellular signalling network (STAT1, STAT3, Bcl-2 and BAX) regulates important cellular states, either anti-apoptosis or apoptosis of cancer cells. We adapt a mathematical framework to illustrate how the signalling network can generate a bi-stability condition so that it will induce either apoptosis or anti-apoptosis status of tumour cells. Then, we use this model to develop several anti-tumour strategies including IFN-β infusion. The roles of JAK-STATs signalling in regulation of the cell death program in cancer cells and tumour growth are poorly understood. The mathematical model unveils the structure and functions of the intracellular signalling and cellular outcomes of the anti-tumour drugs in the presence of IFN-β and JAK stimuli. We identify the best injection order of IFN-β and DDP among many possible combinations, which may suggest better infusion strategies of multiple anti-cancer agents at clinics. We finally use an optimal control theory in order to maximize anti-tumour efficacy and minimize administrative costs. In particular, we minimize tumour volume and maximize the apoptotic potential by minimizing the Bcl-2 concentration and maximizing the BAX level while minimizing total injection amount of both IFN-β and JAK2 inhibitors (DDP).
Collapse
Affiliation(s)
- Jonggul Lee
- Pierre Louis Institute of Epidemiology and Public Health, Paris 75012, France
| | - Donggu Lee
- Department of Mathematics, Konkuk University, Seoul 05029, Republic of Korea
| | - Yangjin Kim
- Department of Mathematics, Konkuk University, Seoul 05029, Republic of Korea
- Mathematical Biosciences Institute, Columbus, OH 43210, USA
- Department of Neurosurgery, Harvard Medical School & Brigham and Women’s Hospital, Boston MA 02115, USA
| |
Collapse
|
|
10
|
Autophagy Inhibition in BRAF-Driven Cancers. Cancers (Basel) 2021; 13:cancers13143498. [PMID: 34298710 PMCID: PMC8306561 DOI: 10.3390/cancers13143498] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 07/10/2021] [Accepted: 07/11/2021] [Indexed: 12/13/2022] Open
Abstract
Simple Summary BRAF is a protein kinase that is frequently mutationally activated in cancer. Mutant BRAF can be pharmacologically inhibited, which in combination with blockade of its direct effector, MEK1/2, is an FDA-approved therapeutic strategy for several BRAF-mutated cancer patients, such as melanoma, non-small-cell lung carcinoma, and thyroid cancer. However, therapy resistance is a major clinical challenge, highlighting the need for comprehensive investigations on the biological causes of such resistance, as well as to develop novel therapeutic strategies to improve patient survival. Autophagy is a cellular recycling process, which has been shown to allow cancer cells to escape from BRAF inhibition. Combined blockade of autophagy and BRAF signaling is a novel therapeutic strategy that is currently being tested in clinical trials. This review describes the relationship between BRAF-targeted therapy and autophagy regulation and discusses possible future treatment strategies. Abstract Several BRAF-driven cancers, including advanced BRAFV600E/K-driven melanoma, non-small-cell lung carcinoma, and thyroid cancer, are currently treated using first-line inhibitor combinations of BRAFV600E plus MEK1/2. However, despite the success of this vertical inhibition strategy, the durability of patient response is often limited by the phenomenon of primary or acquired drug resistance. It has recently been shown that autophagy, a conserved cellular recycling process, is increased in BRAF-driven melanoma upon inhibition of BRAFV600E signaling. Autophagy is believed to promote tumor progression of established tumors and also to protect cancer cells from the cytotoxic effects of chemotherapy. To this end, BRAF inhibitor (BRAFi)-resistant cells often display increased autophagy compared to responsive lines. Several mechanisms have been proposed for BRAFi-induced autophagy, such as activation of the endoplasmic reticulum (ER) stress gatekeeper GRP78, AMP-activated protein kinase, and transcriptional regulation of the autophagy regulating transcription factors TFEB and TFE3 via ERK1/2 or mTOR inhibition. This review describes the relationship between BRAF-targeted therapy and autophagy regulation, and discusses possible future treatment strategies of combined inhibition of oncogenic signaling plus autophagy for BRAF-driven cancers.
Collapse
|
|
11
|
Gong B, Zhang J, Hua Z, Liu Z, Thiele CJ, Li Z. Downregulation of ATXN3 Enhances the Sensitivity to AKT Inhibitors (Perifosine or MK-2206), but Decreases the Sensitivity to Chemotherapeutic Drugs (Etoposide or Cisplatin) in Neuroblastoma Cells. Front Oncol 2021; 11:686898. [PMID: 34322387 PMCID: PMC8311598 DOI: 10.3389/fonc.2021.686898] [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: 03/28/2021] [Accepted: 06/23/2021] [Indexed: 12/14/2022] Open
Abstract
Background Chemotherapy resistance is the major cause of failure in neuroblastoma (NB) treatment. ATXN3 has been linked to various types of cancer and neurodegenerative diseases; however, its roles in NB have not been established. The aim of our study was to explore the role of ATXN3 in the cell death induced by AKT inhibitor (perifosine or MK-2206) or chemotherapy drugs (etoposide or cisplatin) in NB cells. Methods The expressions of ATXN3 and BCL-2 family members were detected by Western blot. Cell survival was evaluated by CCK8, cell confluence was measured by IncuCyte, and apoptosis was detected by flow cytometry. AS and BE2 were treated with AKT inhibitors or chemotherapeutics, respectively. Results Downregulation of ATXN3 did not block, but significantly increased the perifosine/MK-2206-induced cell death. Among the BCL-2 family members, the expression of pro-apoptotic protein BIM and anti-proapoptotic protein Bcl-xl expression increased significantly when ATXN3 was down-regulated. Downregulation of BIM protected NB cells from the combination of perifosine/MK-2206 and ATXN3 downregulation. Downregulation of ATXN3 did not increase, but decrease the sensitivity of NB cells to etoposide/cisplatin, and knockdown of Bcl-xl attenuated this decrease in sensitivity. Conclusion Downregulation of ATXN3 enhanced AKT inhibitors (perifosine or MK-2206) induced cell death by BIM, but decreased the cell death induced by chemotherapeutic drugs (etoposide or cisplatin) via Bcl-xl. The expression of ATXN3 may be an indicator in selecting different treatment regimen.
Collapse
Affiliation(s)
- Baocheng Gong
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, China.,Medical Research Center, Liaoning Key Laboratory of Research and Application of Animal Models for Environment and Metabolic Diseases, Shengjing Hospital of China Medical University, Shenyang, China
| | - Jinhua Zhang
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, China
| | - Zhongyan Hua
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, China.,Medical Research Center, Liaoning Key Laboratory of Research and Application of Animal Models for Environment and Metabolic Diseases, Shengjing Hospital of China Medical University, Shenyang, China
| | - Zhihui Liu
- Cellular and Molecular Biology Section, Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
| | - Carol J Thiele
- Cellular and Molecular Biology Section, Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
| | - Zhijie Li
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, China.,Medical Research Center, Liaoning Key Laboratory of Research and Application of Animal Models for Environment and Metabolic Diseases, Shengjing Hospital of China Medical University, Shenyang, China
| |
Collapse
|
|
12
|
Martins WK, Silva MDND, Pandey K, Maejima I, Ramalho E, Olivon VC, Diniz SN, Grasso D. Autophagy-targeted therapy to modulate age-related diseases: Success, pitfalls, and new directions. CURRENT RESEARCH IN PHARMACOLOGY AND DRUG DISCOVERY 2021; 2:100033. [PMID: 34909664 PMCID: PMC8663935 DOI: 10.1016/j.crphar.2021.100033] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 04/15/2021] [Accepted: 05/02/2021] [Indexed: 02/08/2023] Open
Abstract
Autophagy is a critical metabolic process that supports homeostasis at a basal level and is dynamically regulated in response to various physiological and pathological processes. Autophagy has some etiologic implications that support certain pathological processes due to alterations in the lysosomal-degradative pathway. Some of the conditions related to autophagy play key roles in highly relevant human diseases, e.g., cardiovascular diseases (15.5%), malignant and other neoplasms (9.4%), and neurodegenerative conditions (3.7%). Despite advances in the discovery of new strategies to treat these age-related diseases, autophagy has emerged as a therapeutic option after preclinical and clinical studies. Here, we discuss the pitfalls and success in regulating autophagy initiation and its lysosome-dependent pathway to restore its homeostatic role and mediate therapeutic effects for cancer, neurodegenerative, and cardiac diseases. The main challenge for the development of autophagy regulators for clinical application is the lack of specificity of the repurposed drugs, due to the low pharmacological uniqueness of their target, including those that target the PI3K/AKT/mTOR and AMPK pathway. Then, future efforts must be conducted to deal with this scenery, including the disclosure of key components in the autophagy machinery that may intervene in its therapeutic regulation. Among all efforts, those focusing on the development of novel allosteric inhibitors against autophagy inducers, as well as those targeting autolysosomal function, and their integration into therapeutic regimens should remain a priority for the field.
Collapse
Affiliation(s)
- Waleska Kerllen Martins
- Laboratory of Cell and Membrane (LCM), Anhanguera University of São Paulo (UNIAN), Rua Raimundo Pereira de Magalhães, 3,305. Pirituba, São Paulo, 05145-200, Brazil
| | - Maryana do Nascimento da Silva
- Laboratory of Cell and Membrane (LCM), Anhanguera University of São Paulo (UNIAN), Rua Raimundo Pereira de Magalhães, 3,305. Pirituba, São Paulo, 05145-200, Brazil
| | - Kiran Pandey
- Center for Neural Science, New York University, Meyer Building, Room 823, 4 Washington Place, New York, NY, 10003, USA
| | - Ikuko Maejima
- Laboratory of Molecular Traffic, Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa Machi, Maebashi, Gunma, 3718512, Japan
| | - Ercília Ramalho
- Laboratory of Cell and Membrane (LCM), Anhanguera University of São Paulo (UNIAN), Rua Raimundo Pereira de Magalhães, 3,305. Pirituba, São Paulo, 05145-200, Brazil
| | - Vania Claudia Olivon
- Laboratory of Pharmacology and Physiology, UNIDERP, Av. Ceará, 333. Vila Miguel Couto, Campo Grande, MS, 79003-010, Brazil
| | - Susana Nogueira Diniz
- Laboratory of Molecular Biology and Functional Genomics, Anhanguera University of São Paulo (UNIAN), Rua Raimundo Pereira de Magalhães, 3,305. Pirituba, São Paulo, 05145-200, Brazil
| | - Daniel Grasso
- Instituto de Estudios de la Inmunidad Humoral (IDEHU), Universidad de Buenos Aires, CONICET, Junín 954 p4, Buenos Aires, C1113AAD, Argentina
| |
Collapse
|
|
13
|
Gao F, Chen X, Lu J, Hu S, Xu H, Shi Y, Feng M, Ding J, Liu H, Luo C, Xie Z, Wang J. Discovery of novel ceramide analogs with favorable pharmacokinetic properties and combination with AKT inhibitor against colon cancer. Eur J Med Chem 2021; 215:113274. [PMID: 33592537 DOI: 10.1016/j.ejmech.2021.113274] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Revised: 02/01/2021] [Accepted: 02/01/2021] [Indexed: 10/22/2022]
Abstract
Ceramides have emerged as potential therapeutic option with novel mechanism to affect the proliferation, differentiation, senescence, and apoptosis of cancer cells through regulation of multiple signal transduction. Aiming at the improvement of the apoptosis activity and pharmacokinetic profiles of ceramides, a novel series of ceramide analogs were developed through structure simplification and conformation restriction. Among them, compound 12 bearing an alkoxyl naphthyl motif, with favorable rat pharmacokinetic properties, showed better anti-proliferative activity against various colon cancer cells (IC50 ∼20 μM) than other ceramide analogues, as well as the synergistic effect combined with AKT inhibitor MK2206. Additionally, we demonstrated that this combination therapy promoted caspase 3-dependent apoptotic pathway and intensified cell cycle arrest in the G0/G1 phase. Furthermore, the combination of compound 12 and MK2206 displayed synergistic anti-tumor effect in vivo.
Collapse
Affiliation(s)
- Feng Gao
- State Key Laboratory of Drug Research and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Xiaoxu Chen
- State Key Laboratory of Drug Research and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China; School of Life Science and Technology, ShanghaiTech University, Shanghai, 200031, China
| | - Junyan Lu
- State Key Laboratory of Drug Research and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Shulei Hu
- State Key Laboratory of Drug Research and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Hui Xu
- State Key Laboratory of Drug Research and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Yuqiang Shi
- State Key Laboratory of Drug Research and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Mingshun Feng
- State Key Laboratory of Drug Research and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; School of Life Science and Technology, ShanghaiTech University, Shanghai, 200031, China
| | - Jian Ding
- State Key Laboratory of Drug Research and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China; School of Life Science and Technology, ShanghaiTech University, Shanghai, 200031, China
| | - Hong Liu
- State Key Laboratory of Drug Research and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China; School of Life Science and Technology, ShanghaiTech University, Shanghai, 200031, China
| | - Cheng Luo
- State Key Laboratory of Drug Research and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
| | - Zuoquan Xie
- State Key Laboratory of Drug Research and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
| | - Jiang Wang
- State Key Laboratory of Drug Research and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
| |
Collapse
|
|
14
|
McClure E, Carr MJ, Zager JS. The MAP kinase signal transduction pathway: promising therapeutic targets used in the treatment of melanoma. Expert Rev Anticancer Ther 2020; 20:687-701. [PMID: 32667249 DOI: 10.1080/14737140.2020.1796646] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
INTRODUCTION Mitogen-activated protein kinase (MAPK) signal transduction pathway inhibition through the use of agents binding to signal cascade kinases BRAF and MEK has become a key treatment strategy of patients with BRAF-mutant, unresectable melanoma. AREAS COVERED Detailed analysis is undertaken of the current data, presenting the efficacy and safety of recently developed therapies targeting BRAF and MEK inhibition in the setting of unresectable melanoma. MAPK signal transduction, translational findings, current phase I, II and III clinical trials, and ongoing studies are explored, including use of MAPK pathway inhibition in the neoadjuvant and adjuvant settings as well as in combination with immunotherapy and other therapies. EXPERT OPINION Inhibition of the MAPK pathway significantly improves response, progression-free survival, disease specific survival, and overall survival for patients with BRAF-mutant, unresectable melanoma. The concurrent administration of BRAF and MEK inhibiting agents improves response rate and outcomes and reduces serious adverse effects, including development of new cutaneous malignancies. Triplet therapy with BRAK/MEK combination and immunotherapy has shown in early results to increase duration of response and may be best used sequentially as opposed to concurrently to avoid treatment limiting toxicities. Current clinical trials will further define these therapies and their impact on treatment of melanoma.
Collapse
Affiliation(s)
- Erin McClure
- University of South Florida Morsani College of Medicine , Tampa, FL, USA
| | - Michael J Carr
- Department of Cutaneous Oncology, Moffitt Cancer Center , Tampa, FL, USA
| | - Jonathan S Zager
- Department of Cutaneous Oncology, Moffitt Cancer Center , Tampa, FL, USA.,Department of Oncological Sciences, University of South Florida Morsani College of Medicine , Tampa, FL, USA
| |
Collapse
|
|
15
|
Mobasheri T, Rayzan E, Shabani M, Hosseini M, Mahmoodi Chalbatani G, Rezaei N. Neuroblastoma-targeted nanoparticles and novel nanotechnology-based treatment methods. J Cell Physiol 2020; 236:1751-1775. [PMID: 32735058 DOI: 10.1002/jcp.29979] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Revised: 07/11/2020] [Accepted: 07/16/2020] [Indexed: 12/17/2022]
Abstract
Neuroblastoma is a complicated pediatric tumor, originating from the neural crest, which is the most prevalent in adrenal glands, but may rarely be seen in some other tissues as well. Studies are focused on developing new strategies through novel chemo- and immuno-therapeutic drug targets. Different types of oncogenes such as MYCN, tumor suppressor genes such as p53, and some structural genes such as vascular endothelial growth factor are considered as targets for neuroblastoma therapy. The individual expression patterns in NB cells make them appropriate for this purpose. The combined effect of nano-drug delivery systems and specific drug targets will result in lower systemic side effects, prolonged therapeutic effects, and improvements in the pharmacokinetic properties of the drugs. Some of these novel drug delivery systems with a focus on liposomes as carriers are also discussed. In this review, genes and protein products that are beneficial as drug targets in the treatment of neuroblastoma have been discussed.
Collapse
Affiliation(s)
- Taranom Mobasheri
- International Hematology/Oncology of Pediatrics Experts (IHOPE), Universal Scientific Education and Research Network (USERN), Tehran, Iran.,School of Pharmacy, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Elham Rayzan
- International Hematology/Oncology of Pediatrics Experts (IHOPE), Universal Scientific Education and Research Network (USERN), Tehran, Iran.,Research Center for Immunodeficiencies (RCID), Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahsima Shabani
- Research Center for Immunodeficiencies (RCID), Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.,International Hematology/Oncology of Pediatrics Experts (IHOPE), Universal Scientific Education and Research Network (USERN), Baltimore, Maryland
| | - Mina Hosseini
- Department of Pharmaceutical Biotechnology, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Nima Rezaei
- Research Center for Immunodeficiencies (RCID), Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.,Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.,Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| |
Collapse
|
|
16
|
Rebecca VW, Herlyn M. Nongenetic Mechanisms of Drug Resistance in Melanoma. ANNUAL REVIEW OF CANCER BIOLOGY 2020. [DOI: 10.1146/annurev-cancerbio-030419-033533] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Resistance to targeted and immune-based therapies limits cures in patients with metastatic melanoma. A growing number of reports have identified nongenetic primary resistance mechanisms including intrinsic microenvironment- and lineage plasticity–mediated processes serving critical functions in the persistence of disease throughout therapy. There is a temporally shifting spectrum of cellular identities fluidly occupied by therapy-persisting melanoma cells responsible for driving therapeutic resistance and metastasis. The key epigenetic, metabolic, and phenotypic reprogramming events requisite for the manifestation and maintenance of so-called persister melanoma populations remain poorly understood and underscore the need to comprehensively investigate actionable vulnerabilities. Here we attempt to integrate the field's observations on nongenetic mechanisms of drug resistance in melanoma. We postulate that the future design of therapeutic strategies specifically addressing therapy-persisting subpopulations of melanoma will improve the curative potential of therapy for patients with metastatic disease.
Collapse
Affiliation(s)
- Vito W. Rebecca
- Molecular and Cellular Oncogenesis Program and Melanoma Research Center, The Wistar Institute, Philadelphia, Pennsylvania 19104, USA
| | - Meenhard Herlyn
- Molecular and Cellular Oncogenesis Program and Melanoma Research Center, The Wistar Institute, Philadelphia, Pennsylvania 19104, USA
| |
Collapse
|
|
17
|
A phase I trial of MK-2206 and hydroxychloroquine in patients with advanced solid tumors. Cancer Chemother Pharmacol 2019; 84:899-907. [PMID: 31463691 DOI: 10.1007/s00280-019-03919-x] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Accepted: 07/29/2019] [Indexed: 12/31/2022]
Abstract
PURPOSE Given the evidence that coordinate inhibition of AKT induces autophagy, we studied the combination of the AKT inhibitor, MK-2206 with hydroxychloroquine (HCQ) in patients with advanced solid tumors. METHODS Patients were treated with weekly MK-2206 (135 mg or 200 mg) plus HCQ (200 mg, 400 mg or 600 mg BID). RESULTS Thirty-five patients were enrolled across 5 dose levels. Two DLTs of grade 3 maculo-papular rash were observed at dose level 2 (MK-2206 200 mg weekly plus HCQ at 400 mg BID) and 1 DLT of grade 3 fatigue at dose level 2B (MK-2206 135 mg weekly plus HCQ 600 mg BID). The maximum tolerated dose (MTD) was declared as dose level 2B. The most common adverse events attributed to MK-2206 were hyperglycemia (N = 18; 51%), fatigue (N = 17; 49%), maculo-papular rash (N = 16; 46%), diarrhea (N = 12; 34%), anorexia (N = 11; 31%), and nausea (N = 11; 31%). Patients experiencing adverse events attributed to HCQ were small in number (N = 13) and primarily included fatigue (N = 5; 14%) and maculo-papular rashes (N = 3; 9%). Statistically significant effects on the pharmacokinetic properties of MK-2206 were observed in combination with HCQ. In addition, the plasma concentrations of HCQ in the combination with MK-2206 were significantly higher than the plasma levels of HCQ as monotherapy in prior studies. The best overall response of stable disease was observed in 5/34 (15%) patients. CONCLUSION The combination of MK-2206 and hydroxychloroquine was tolerable, but with substantial number of drug-related AEs and minimal evidence of antitumor activity.
Collapse
|
|
18
|
Xie X, Lin J, Zhong Y, Fu M, Tang A. FGFR 3S249C mutation promotes chemoresistance by activating Akt signaling in bladder cancer cells. Exp Ther Med 2019; 18:1226-1234. [PMID: 31316618 PMCID: PMC6601368 DOI: 10.3892/etm.2019.7672] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2018] [Accepted: 05/09/2019] [Indexed: 12/15/2022] Open
Abstract
Fibroblast growth factor receptor 3 (FGFR3) is a high frequency mutant gene in bladder cancer (BCa) and has become a promising therapeutic target due to its involvement in cell proliferation and migration. However, whether and how FGFR3 mutations affects BCa cell chemosensitivity is unknown. The current study aimed to elucidate the role of the FGFR3S249C mutation in the development of chemoresistance in BCa cells. The results revealed that 97-7 (FGFR3S249C) cells had decreased sensitivity to cisplatin compared with 5637 (FGFR3WT) and T24 (FGFR3WT) cells. The ratio of phosphorylated-Akt/total-Akt was higher in 97-7 (FGFR3S249C) cells, which was reversed by knockdown of FGFR3. Furthermore, inhibition of Akt signaling by GDC0068 or LY294002 increased the cisplatin sensitivity of 97-7 (FGFR3S249C) cells. GDC0068 or LY294002 was also revealed to augment the effects of cisplatin on 97-7 (FGFR3S249C) cell proliferation and apoptosis. The results of the present study demonstrated that the FGFR3S249C mutation promotes chemoresistance in BCa cells by activating the Akt signaling pathway. The FGFR3S249C mutation may therefore be used as a predictor of chemosensitivity in patients with BCa.
Collapse
Affiliation(s)
- Xina Xie
- Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China.,Institute of Translational Medicine, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Health Science Center, Shenzhen, Guangdong 518035, P.R. China
| | - Jiatian Lin
- Department of Minimally Invasive Intervention, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China
| | - Yuantang Zhong
- Department of Urinary Surgery, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Health Science Center, Shenzhen, Guangdong 518035, P.R. China
| | - Mianheng Fu
- Institute of Translational Medicine, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Health Science Center, Shenzhen, Guangdong 518035, P.R. China
| | - Aifa Tang
- Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China.,Institute of Translational Medicine, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Health Science Center, Shenzhen, Guangdong 518035, P.R. China
| |
Collapse
|
|
19
|
Wolff C, Zoschke C, Kalangi SK, Reddanna P, Schäfer-Korting M. Tumor microenvironment determines drug efficacy in vitro - apoptotic and anti-inflammatory effects of 15-lipoxygenase metabolite, 13-HpOTrE. Eur J Pharm Biopharm 2019; 142:1-7. [PMID: 31176725 DOI: 10.1016/j.ejpb.2019.06.003] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2019] [Revised: 05/14/2019] [Accepted: 06/06/2019] [Indexed: 01/09/2023]
Abstract
Recent studies using 3D scaffolds have emphasized the importance of the surrounding stroma on chemoresistance in drug efficacy screenings. Since 15-lipoxygenase (15-LOX) metabolites reduced growth of breast, colon, prostate, lung and leukemia cancer cells in 2D cell culture, we were intrigued by the direct comparison of 15-LOX metabolite efficacy in 2D and 3D culture including a stroma equivalent. Herein, we studied the effects of 15-LOX metabolites 13-HpOTrE, 13-HpODE, and 15-HpETE on cutaneous squamous cell carcinoma cells. All metabolites reduced the viability of cancer cells in 2D culture below 10% at 100 µM of each substance. 13-HpOTrE, being the most active agent with respect to cytotoxicity and apoptosis was selected for further experiments. Other than with the 2D culture, we did not obverse cell death, neither from lactate dehydrogenase release, nor from morphology when applying 13-HpOTrE onto the surface of the 3D tumor constructs for one week. Next, we investigated the protein expression of peroxisome proliferator activated receptor gamma, for which the ligand is 13-HpOTrE, and Bcl-2 protein, an apoptosis regulator, but did not find any change following 13-HpOTrE administration. However, 13-HpOTrE treatment reduced the release of interleukin-6, bringing it closer to the level of tumor-free constructs. In conclusion, 13-HpOTrE reduces viability of skin cancer cells in 2D cultures only but modulates inflammatory cytokine levels in the corresponding 3D tumor constructs, too. These studies highlight the need for screening of anticancer drugs employing 3D tumors and including tumor microenvironment in the screening process to increase the low success rate of clinical trials in oncology.
Collapse
Affiliation(s)
- Christopher Wolff
- Freie Universität Berlin, Institute of Pharmacy (Pharmacology & Toxicology), Königin-Luise-Str. 2+4, D-14195 Berlin, Germany
| | - Christian Zoschke
- Freie Universität Berlin, Institute of Pharmacy (Pharmacology & Toxicology), Königin-Luise-Str. 2+4, D-14195 Berlin, Germany
| | - Suresh Kumar Kalangi
- University of Hyderabad, Department of Animal Biology, School of Life Sciences, Hyderabad, 500046, India
| | - Pallu Reddanna
- University of Hyderabad, Department of Animal Biology, School of Life Sciences, Hyderabad, 500046, India
| | - Monika Schäfer-Korting
- Freie Universität Berlin, Institute of Pharmacy (Pharmacology & Toxicology), Königin-Luise-Str. 2+4, D-14195 Berlin, Germany.
| |
Collapse
|
|
20
|
HSP90 inhibitor DPB induces autophagy and more effectively apoptosis in A549 cells combined with autophagy inhibitors. In Vitro Cell Dev Biol Anim 2019; 55:349-354. [PMID: 30989449 DOI: 10.1007/s11626-019-00327-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2018] [Accepted: 01/25/2019] [Indexed: 01/10/2023]
Abstract
In our previous study, we proved that a novel Heat shock protein 90 (HSP90) inhibitor 4-(3-(7-(diethylamino)-2-oxo-2H-chromen-3-yl)-5-phenyl-4,5-dihydro-1H-pyrazol-1-yl) benzoic acid (DPB) could inhibit A549 lung cancer cell growth via inducing apoptosis. However, whether DPB affects autophagy is still unknown. Here, we investigated the effects of DPB on autophagy and the improved anti-cancer activity in A549 lung cancer cells. Aggregation of LC3-II was observed using laser scanning confocal microscopy in GFP-LC3 stably transfected U87 cells. Autophagy and apoptosis-related protein levels were examined by Western blot analysis. It is suggested that treatment with DPB (5-20 μmol/L) induced mTOR-independent autophagy in dose- and time-dependent manners. Pre-treatment A549 cells with autophagy inhibitor 3-methyladenine (3-MA, 5 mmol/L) enhanced DPB-induced apoptosis. And, DPB inhibited A549 cell growth more effectively in combination with autophagy inhibitors 3-MA (5 mmol/L) or 3-benzyl-5-((2-nitrophenoxy) methyl)-dihydrofuran-2(3H)-one (3BDO, 30 μmol/L). These results illustrated that as a potential and promising HSP90 inhibitor, DPB could be utilized in the treatment of cancer combined with the autophagy inhibitor.
Collapse
|
|
21
|
Zhang M, Zhang W, Tang G, Wang H, Wu M, Yu W, Zhou Z, Mou Y, Liu X. Targeted Codelivery of Docetaxel and Atg7 siRNA for Autophagy Inhibition and Pancreatic Cancer Treatment. ACS APPLIED BIO MATERIALS 2019; 2:1168-1176. [PMID: 35021365 DOI: 10.1021/acsabm.8b00764] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Affiliation(s)
- Miaozun Zhang
- Department of General Surgery, Ningbo Medical Center Lihuili Hospital, Ningbo 315041, China
| | - Wei Zhang
- Department of Gastroenterology, Ningbo No.2 Hospital, Ningbo 315010, China
| | - Guping Tang
- Department of Chemistry, Zhejiang University, Hangzhou 310028, China
| | - Hebin Wang
- College of Life Sciences, Tarim University, Alar 843300, China
| | - Min Wu
- Department of Chemistry, Zhejiang University, Hangzhou 310028, China
| | - Weiming Yu
- Department of General Surgery, Ningbo Medical Center Lihuili Hospital, Ningbo 315041, China
| | - Zhenfeng Zhou
- Department of Anesthesiology, Zhejiang Provincial People’s Hospital, Hangzhou 310014, China
| | - Yiping Mou
- Department of General Surgery, Zhejiang Provincial People’s Hospital, Hangzhou 310014, China
| | - Xingang Liu
- Department of Chemistry, Zhejiang University, Hangzhou 310028, China
| |
Collapse
|
|
22
|
Matsuzaki S, Pouly JL, Canis M. In vitro and in vivo effects of MK2206 and chloroquine combination therapy on endometriosis: autophagy may be required for regrowth of endometriosis. Br J Pharmacol 2018; 175:1637-1653. [PMID: 29457968 DOI: 10.1111/bph.14170] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2017] [Revised: 12/18/2017] [Accepted: 01/31/2018] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND AND PURPOSE A high recurrence rate after medical treatment is a major clinical problem for patients with endometriosis. Here, we have evaluated the in vitro effects of combined treatment with MK2206 (an AKT inhibitor) + chloroquine on cell growth and regrowth of endometriotic stromal cells and the in vivo effects on endometriotic implants in a mouse xenograft model of endometriosis. EXPERIMENTAL APPROACH We evaluated the effects of autophagy inhibition by knockdown of the ATG13, Beclin-1 and ATG12 genes and pharmacological agents (chloroquine, bafilomycin A1 or 3-methyalanine) individually and in combination with MK2206 on cell growth and/or cell regrowth of endometriotic stromal cells in vitro. Furthermore, we evaluated treatment with MK2206 + chloroquine on endometriotic implants in a mouse xenograft model of endometriosis. KEY RESULTS Combined treatment with MK2206 and chloroquine markedly reduced cell growth and regrowth after discontinuation of treatment in endometriotic stromal cells compared with cells treated with either drug alone. Autophagy inhibition by ATG13, Beclin-1 or ATG12 gene knockdown only affected regrowth of endometriotic stromal cells, but not endometrial stromal cells from the same patients, after a 72 h discontinuation of the combined treatment. Furthermore, combined treatment reduced the size of endometriotic implants, whereas no effects on endometriotic implants treated with either drug alone were observed in a mouse xenograft model of endometriosis. CONCLUSIONS AND IMPLICATIONS The present findings suggest that a novel strategy for treatment of endometriosis may involve decreasing the number of endometriotic cells that can survive treatment and then preventing regrowth by autophagy inhibition.
Collapse
Affiliation(s)
- Sachiko Matsuzaki
- Chirurgie Gynécologique, CHU Clermont-Ferrand, Clermont-Ferrand, France.,Institut Pascal, UMR6602, Université Clermont Auvergne, CNRS/UCA/SIGMA, Clermont-Ferrand, France
| | - Jean-Luc Pouly
- Chirurgie Gynécologique, CHU Clermont-Ferrand, Clermont-Ferrand, France.,Institut Pascal, UMR6602, Université Clermont Auvergne, CNRS/UCA/SIGMA, Clermont-Ferrand, France
| | - Michel Canis
- Chirurgie Gynécologique, CHU Clermont-Ferrand, Clermont-Ferrand, France.,Institut Pascal, UMR6602, Université Clermont Auvergne, CNRS/UCA/SIGMA, Clermont-Ferrand, France
| |
Collapse
|
|
23
|
Massaro RR, Brohem CA, Almeida RLD, Rivelli DP, Miyake JA, Colquhoun A, Barros SBDM, Maria-Engler SS. 4-Nerolidylcatechol induces autophagy in human glioblastoma cells. BRAZ J PHARM SCI 2018. [DOI: 10.1590/s2175-97902017000300169] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
|
|
24
|
Cervia D, Assi E, De Palma C, Giovarelli M, Bizzozero L, Pambianco S, Di Renzo I, Zecchini S, Moscheni C, Vantaggiato C, Procacci P, Clementi E, Perrotta C. Essential role for acid sphingomyelinase-inhibited autophagy in melanoma response to cisplatin. Oncotarget 2018; 7:24995-5009. [PMID: 27107419 PMCID: PMC5041885 DOI: 10.18632/oncotarget.8735] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2015] [Accepted: 03/28/2016] [Indexed: 01/03/2023] Open
Abstract
The sphingolipid metabolising enzyme Acid Sphingomyelinase (A-SMase) has been recently shown to inhibit melanoma progression and correlate inversely to tumour grade. In this study we have investigated the role of A-SMase in the chemo-resistance to anticancer treatmentusing mice with melanoma allografts and melanoma cells differing in terms of expression/activity of A-SMase. Since autophagy is emerging as a key mechanism in tumour growth and chemo-resistance, we have also investigated whether an action of A-SMase in autophagy can explain its role. Melanoma sensitivity to chemotherapeutic agent cisplatin in terms of cell viability/apoptosis, tumour growth, and animal survival depended directly on the A-SMase levels in tumoural cells. A-SMase action was due to inhibition of autophagy through activation of Akt/mammalian target of rapamycin (mTOR) pathway. Treatment of melanoma-bearing mice with the autophagy inhibitor chloroquine restored sensitivity to cisplatin of tumours expressing low levels of A-SMase while no additive effects were observed in tumours characterised by sustained A-SMase levels. The fact that A-SMase in melanomas affects mTOR-regulated autophagy and plays a central role in cisplatin efficacy encourages pre-clinical testing on the modulation of A-SMase levels/activity as possible novel anti-neoplastic strategy.
Collapse
Affiliation(s)
- Davide Cervia
- Department for Innovation in Biological, Agro-food and Forest Systems (DIBAF), Università degli Studi della Tuscia, Viterbo, Italy.,Department of Biomedical and Clinical Sciences "Luigi Sacco" (DIBIC), Università degli Studi di Milano, Milano, Italy
| | - Emma Assi
- Scientific Institute IRCCS Eugenio Medea, Bosisio Parini, Italy.,Present address: Division of Experimental Oncology, San Raffaele Scientific Institute, Milano, Italy
| | - Clara De Palma
- Department of Biomedical and Clinical Sciences "Luigi Sacco" (DIBIC), Università degli Studi di Milano, Milano, Italy.,Unit of Clinical Pharmacology, National Research Council-Institute of Neuroscience, University Hospital "Luigi Sacco", Milano, Italy
| | - Matteo Giovarelli
- Department of Biomedical and Clinical Sciences "Luigi Sacco" (DIBIC), Università degli Studi di Milano, Milano, Italy
| | - Laura Bizzozero
- Scientific Institute IRCCS Eugenio Medea, Bosisio Parini, Italy.,Present address: Department of Oncology, Università degli Studi di Torino and Laboratory of Neurovascular Biology, Candiolo Cancer Institute, Candiolo, Italy
| | - Sarah Pambianco
- Department of Biomedical and Clinical Sciences "Luigi Sacco" (DIBIC), Università degli Studi di Milano, Milano, Italy
| | - Ilaria Di Renzo
- Department of Biomedical and Clinical Sciences "Luigi Sacco" (DIBIC), Università degli Studi di Milano, Milano, Italy
| | - Silvia Zecchini
- Department of Biomedical and Clinical Sciences "Luigi Sacco" (DIBIC), Università degli Studi di Milano, Milano, Italy
| | - Claudia Moscheni
- Department of Biomedical and Clinical Sciences "Luigi Sacco" (DIBIC), Università degli Studi di Milano, Milano, Italy
| | | | - Patrizia Procacci
- Department of Biomedical Sciences for Health (SCIBIS), Università degli Studi di Milano, Milano, Italy
| | - Emilio Clementi
- Department of Biomedical and Clinical Sciences "Luigi Sacco" (DIBIC), Università degli Studi di Milano, Milano, Italy.,Scientific Institute IRCCS Eugenio Medea, Bosisio Parini, Italy.,Unit of Clinical Pharmacology, National Research Council-Institute of Neuroscience, University Hospital "Luigi Sacco", Milano, Italy
| | - Cristiana Perrotta
- Department of Biomedical and Clinical Sciences "Luigi Sacco" (DIBIC), Università degli Studi di Milano, Milano, Italy
| |
Collapse
|
|
25
|
Sample A, He YY. Mechanisms and prevention of UV-induced melanoma. PHOTODERMATOLOGY, PHOTOIMMUNOLOGY & PHOTOMEDICINE 2018; 34:13-24. [PMID: 28703311 PMCID: PMC5760354 DOI: 10.1111/phpp.12329] [Citation(s) in RCA: 208] [Impact Index Per Article: 29.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 07/06/2017] [Indexed: 02/06/2023]
Abstract
Melanoma is the deadliest form of skin cancer and its incidence is rising, creating a costly and significant clinical problem. Exposure to ultraviolet (UV) radiation, namely UVA (315-400 nm) and UVB (280-315 nm), is a major risk factor for melanoma development. Cumulative UV radiation exposure from sunlight or tanning beds contributes to UV-induced DNA damage, oxidative stress, and inflammation in the skin. A number of factors, including hair color, skin type, genetic background, location, and history of tanning, determine the skin's response to UV radiation. In melanocytes, dysregulation of this UV radiation response can lead to melanoma. Given the complex origins of melanoma, it is difficult to develop curative therapies and universally effective preventative strategies. Here, we describe and discuss the mechanisms of UV-induced skin damage responsible for inducing melanomagenesis, and explore options for therapeutic and preventative interventions.
Collapse
Affiliation(s)
- Ashley Sample
- Department of Medicine, Section of Dermatology, University of Chicago, Chicago, IL
- Committee on Cancer Biology, University of Chicago, Chicago, IL
| | - Yu-Ying He
- Department of Medicine, Section of Dermatology, University of Chicago, Chicago, IL
- Committee on Cancer Biology, University of Chicago, Chicago, IL
| |
Collapse
|
|
26
|
Rebecca VW, Nicastri MC, McLaughlin N, Fennelly C, McAfee Q, Ronghe A, Nofal M, Lim CY, Witze E, Chude CI, Zhang G, Alicea GM, Piao S, Murugan S, Ojha R, Levi SM, Wei Z, Barber-Rotenberg JS, Murphy ME, Mills GB, Lu Y, Rabinowitz J, Marmorstein R, Liu Q, Liu S, Xu X, Herlyn M, Zoncu R, Brady DC, Speicher DW, Winkler JD, Amaravadi RK. A Unified Approach to Targeting the Lysosome's Degradative and Growth Signaling Roles. Cancer Discov 2017; 7:1266-1283. [PMID: 28899863 PMCID: PMC5833978 DOI: 10.1158/2159-8290.cd-17-0741] [Citation(s) in RCA: 148] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2017] [Revised: 08/24/2017] [Accepted: 09/06/2017] [Indexed: 01/01/2023]
Abstract
Lysosomes serve dual roles in cancer metabolism, executing catabolic programs (i.e., autophagy and macropinocytosis) while promoting mTORC1-dependent anabolism. Antimalarial compounds such as chloroquine or quinacrine have been used as lysosomal inhibitors, but fail to inhibit mTOR signaling. Further, the molecular target of these agents has not been identified. We report a screen of novel dimeric antimalarials that identifies dimeric quinacrines (DQ) as potent anticancer compounds, which concurrently inhibit mTOR and autophagy. Central nitrogen methylation of the DQ linker enhances lysosomal localization and potency. An in situ photoaffinity pulldown identified palmitoyl-protein thioesterase 1 (PPT1) as the molecular target of DQ661. PPT1 inhibition concurrently impairs mTOR and lysosomal catabolism through the rapid accumulation of palmitoylated proteins. DQ661 inhibits the in vivo tumor growth of melanoma, pancreatic cancer, and colorectal cancer mouse models and can be safely combined with chemotherapy. Thus, lysosome-directed PPT1 inhibitors represent a new approach to concurrently targeting mTORC1 and lysosomal catabolism in cancer.Significance: This study identifies chemical features of dimeric compounds that increase their lysosomal specificity, and a new molecular target for these compounds, reclassifying these compounds as targeted therapies. Targeting PPT1 blocks mTOR signaling in a manner distinct from catalytic inhibitors, while concurrently inhibiting autophagy, thereby providing a new strategy for cancer therapy. Cancer Discov; 7(11); 1266-83. ©2017 AACR.See related commentary by Towers and Thorburn, p. 1218This article is highlighted in the In This Issue feature, p. 1201.
Collapse
Affiliation(s)
- Vito W Rebecca
- Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Michael C Nicastri
- Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Noel McLaughlin
- Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Colin Fennelly
- Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Quentin McAfee
- Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Amruta Ronghe
- Molecular and Cellular Oncogenesis Program and Melanoma Research Center, Wistar Institute, Philadelphia, Pennsylvania
| | - Michel Nofal
- Department of Chemistry and Integrative Genomics, Princeton University, Princeton, New Jersey
| | - Chun-Yan Lim
- Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, California
| | - Eric Witze
- Department of Cancer Biology, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Cynthia I Chude
- Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Gao Zhang
- Molecular and Cellular Oncogenesis Program and Melanoma Research Center, Wistar Institute, Philadelphia, Pennsylvania
| | - Gretchen M Alicea
- Molecular and Cellular Oncogenesis Program and Melanoma Research Center, Wistar Institute, Philadelphia, Pennsylvania
| | - Shengfu Piao
- Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | | | - Rani Ojha
- Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Samuel M Levi
- Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Zhi Wei
- Department of Computer Science, New Jersey Institute of Technology, Newark, New Jersey
| | - Julie S Barber-Rotenberg
- Department of Biochemistry and Biophysics, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Maureen E Murphy
- Molecular and Cellular Oncogenesis Program and Melanoma Research Center, Wistar Institute, Philadelphia, Pennsylvania
| | - Gordon B Mills
- Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Yiling Lu
- Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Joshua Rabinowitz
- Department of Chemistry and Integrative Genomics, Princeton University, Princeton, New Jersey
| | - Ronen Marmorstein
- Department of Biochemistry and Biophysics, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Qin Liu
- Molecular and Cellular Oncogenesis Program and Melanoma Research Center, Wistar Institute, Philadelphia, Pennsylvania
| | - Shujing Liu
- Department of Pathology, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Xiaowei Xu
- Department of Pathology, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Meenhard Herlyn
- Molecular and Cellular Oncogenesis Program and Melanoma Research Center, Wistar Institute, Philadelphia, Pennsylvania
| | - Roberto Zoncu
- Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, California
| | - Donita C Brady
- Department of Cancer Biology, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania
| | - David W Speicher
- Molecular and Cellular Oncogenesis Program and Melanoma Research Center, Wistar Institute, Philadelphia, Pennsylvania
| | - Jeffrey D Winkler
- Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania.
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Ravi K Amaravadi
- Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania
| |
Collapse
|
|
27
|
Bingel C, Koeneke E, Ridinger J, Bittmann A, Sill M, Peterziel H, Wrobel JK, Rettig I, Milde T, Fernekorn U, Weise F, Schober A, Witt O, Oehme I. Three-dimensional tumor cell growth stimulates autophagic flux and recapitulates chemotherapy resistance. Cell Death Dis 2017; 8:e3013. [PMID: 28837150 PMCID: PMC5596581 DOI: 10.1038/cddis.2017.398] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2017] [Revised: 07/10/2017] [Accepted: 07/10/2017] [Indexed: 12/18/2022]
Abstract
Current preclinical models in tumor biology are limited in their ability to recapitulate relevant (patho-) physiological processes, including autophagy. Three-dimensional (3D) growth cultures have frequently been proposed to overcome the lack of correlation between two-dimensional (2D) monolayer cell cultures and human tumors in preclinical drug testing. Besides 3D growth, it is also advantageous to simulate shear stress, compound flux and removal of metabolites, e.g., via bioreactor systems, through which culture medium is constantly pumped at a flow rate reflecting physiological conditions. Here we show that both static 3D growth and 3D growth within a bioreactor system modulate key hallmarks of cancer cells, including proliferation and cell death as well as macroautophagy, a recycling pathway often activated by highly proliferative tumors to cope with metabolic stress. The autophagy-related gene expression profiles of 2D-grown cells are substantially different from those of 3D-grown cells and tumor tissue. Autophagy-controlling transcription factors, such as TFEB and FOXO3, are upregulated in tumors, and 3D-grown cells have increased expression compared with cells grown in 2D conditions. Three-dimensional cultures depleted of the autophagy mediators BECN1, ATG5 or ATG7 or the transcription factor FOXO3, are more sensitive to cytotoxic treatment. Accordingly, combining cytotoxic treatment with compounds affecting late autophagic flux, such as chloroquine, renders the 3D-grown cells more susceptible to therapy. Altogether, 3D cultures are a valuable tool to study drug response of tumor cells, as these models more closely mimic tumor (patho-)physiology, including the upregulation of tumor relevant pathways, such as autophagy.
Collapse
Affiliation(s)
- Corinna Bingel
- Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ), INF 280, D-69120 Heidelberg, Germany
| | - Emily Koeneke
- Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ), INF 280, D-69120 Heidelberg, Germany.,Translational Program, Hopp Children's Cancer Center at NCT Heidelberg (KiTZ), Heidelberg, Germany
| | - Johannes Ridinger
- Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ), INF 280, D-69120 Heidelberg, Germany.,Translational Program, Hopp Children's Cancer Center at NCT Heidelberg (KiTZ), Heidelberg, Germany
| | - Annika Bittmann
- Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ), INF 280, D-69120 Heidelberg, Germany.,Translational Program, Hopp Children's Cancer Center at NCT Heidelberg (KiTZ), Heidelberg, Germany
| | - Martin Sill
- Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Heike Peterziel
- Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ), INF 280, D-69120 Heidelberg, Germany.,Translational Program, Hopp Children's Cancer Center at NCT Heidelberg (KiTZ), Heidelberg, Germany
| | - Jagoda K Wrobel
- Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ), INF 280, D-69120 Heidelberg, Germany.,Translational Program, Hopp Children's Cancer Center at NCT Heidelberg (KiTZ), Heidelberg, Germany
| | - Inga Rettig
- Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ), INF 280, D-69120 Heidelberg, Germany
| | - Till Milde
- Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ), INF 280, D-69120 Heidelberg, Germany.,Translational Program, Hopp Children's Cancer Center at NCT Heidelberg (KiTZ), Heidelberg, Germany.,Center for Individualized Pediatric Oncology (ZIPO) and Brain Tumors, Department of Pediatric Oncology, Hematology and Immunology, University Hospital Heidelberg, Heidelberg, Germany
| | - Uta Fernekorn
- Department of Nano-Biosystem Technology, Technische Universität Ilmenau, Ilmenau, Germany
| | - Frank Weise
- Department of Nano-Biosystem Technology, Technische Universität Ilmenau, Ilmenau, Germany
| | - Andreas Schober
- Department of Nano-Biosystem Technology, Technische Universität Ilmenau, Ilmenau, Germany
| | - Olaf Witt
- Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ), INF 280, D-69120 Heidelberg, Germany.,Translational Program, Hopp Children's Cancer Center at NCT Heidelberg (KiTZ), Heidelberg, Germany
| | - Ina Oehme
- Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ), INF 280, D-69120 Heidelberg, Germany.,Translational Program, Hopp Children's Cancer Center at NCT Heidelberg (KiTZ), Heidelberg, Germany
| |
Collapse
|
|
28
|
Maslinic acid promotes autophagy by disrupting the interaction between Bcl2 and Beclin1 in rat pheochromocytoma PC12 cells. Oncotarget 2017; 8:74527-74538. [PMID: 29088805 PMCID: PMC5650360 DOI: 10.18632/oncotarget.20210] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2017] [Accepted: 06/24/2017] [Indexed: 12/23/2022] Open
Abstract
Maslinic acid (2α, 3β-dihydroxyolean-12-en-28-oic acid, MA) was isolated from natural plants and showed anti-cancer activity in rat Pheochromocytoma PC12 cells in our previous studies. We now discover that MA disrupts the interaction between Bcl2 and autophagy scaffold protein Beclin1 in the above cell line, leading to the up-regulation of autophagy. We investigated the effect of MA on the interaction between Bcl2 and Beclin1 by biochemical and biophysical methods in combination with autophagy characterization in the above cell line. Our results suggest that MA may serve as an autophagy activator by directly blocking the Bcl2-Beclin1 interaction to release free Beclin1 required for the recruitment of autophagy positive regulators, implying MA may exert its anti-cancer activity by regulating autophagy.
Collapse
|
|
29
|
Prêtre V, Wicki A. Inhibition of Akt and other AGC kinases: A target for clinical cancer therapy? Semin Cancer Biol 2017; 48:70-77. [PMID: 28473255 DOI: 10.1016/j.semcancer.2017.04.011] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2016] [Revised: 04/04/2017] [Accepted: 04/25/2017] [Indexed: 01/27/2023]
Abstract
AGC kinases have been identified to contribute to cancer development and progression. Currently, most AGC inhibitors in clinical development are Akt inhibitors such as MK-2206 or GDC-0068, which are known to promote cell growth arrest and to sensitize cancer cells to radiotherapy. Response rates in clinical trials with single agent Akt inhibitors are typically low. The observed adverse events are within the expected limits for compounds inhibiting the PI3K-mTOR axis. Preclinical and early clinical data for combination therapies are accumulating. Based on these data, several Akt inhibitors are about to enter phase 3 trials. Besides drugs that target Akt, p70S6K inhibitors have entered clinical development. Again, the response rates were rather low. In addition, relevant toxicities were identified, including a risk for coagulopathies with these compounds. Multi-AGC kinase inhibitors are also in early clinical development but the data is not sufficient yet to draw conclusions regarding their efficacy and side-effect profile. PKC inhibitors have been tested in the phase 3 setting but were found to lack efficacy. More trials with isoform-specific PKC inhibitors are expected. Taken together, therapies with AGC kinase inhibitors as single agents are unlikely to meet success. However, combination therapies and a precise stratification of patients according to the activation of signaling axes may increase the probability to see relevant efficacy with these compounds. The emergence of onco-immunotherapies holds some new challenges for these agents.
Collapse
Affiliation(s)
- Vincent Prêtre
- Department of Biomedicine, University of Basel, 4031 Basel, Switzerland
| | - Andreas Wicki
- Department of Biomedicine, University of Basel, 4031 Basel, Switzerland; Department of Medical Oncology, University Hospital Basel, 4031 Basel, Switzerland.
| |
Collapse
|
|
30
|
Narayan RS, Fedrigo CA, Brands E, Dik R, Stalpers LJ, Baumert BG, Slotman BJ, Westerman BA, Peters GJ, Sminia P. The allosteric AKT inhibitor MK2206 shows a synergistic interaction with chemotherapy and radiotherapy in glioblastoma spheroid cultures. BMC Cancer 2017; 17:204. [PMID: 28320338 PMCID: PMC5359921 DOI: 10.1186/s12885-017-3193-9] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2016] [Accepted: 03/11/2017] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Glioblastoma multiforme (GBM) is the most common, invasive and deadly primary type of malignant brain tumor. The Phosphatidylinositol-3-Kinase/AKT (PI3K/AKT) pathway is highly active in GBM and has been associated with increased survival and resistance to therapy. The aim of this study is to investigate the effects of AKT inhibition in combination with the current standard of care which consists of irradiation and temozolomide (TMZ) on human malignant glioma cells growing adherent and as multicellular spheroids in vitro. METHODS The effects of the allosteric inhibitor MK2206 combined with irradiation and TMZ were assessed on glioma cells growing adherent and as multicellular 3D spheroids. The interaction was studied on proliferation, clonogenic cell survival, cell invasion, -migration and on expression of key proteins in the PI3K-AKT pathway by western blot. RESULTS A differential effect was found at low- (1 μM) and high dose (10 μM) MK2206. At 1 μM, the inhibitor reduced phosphorylation of Thr308 and Ser473 residues of AKT in both adherent cells and spheroids. Low dose MK2206 delayed spheroid growth and sensitized spheroids to both irradiation and TMZ in a synergistic way (Combination index <0.35). In contrast, neither low nor high dose MK2206 did enhance therapy sensitivity in adherent growing cells. Effective inhibition of invasion and migration was observed only at higher doses of MK2206 (>5 μM). CONCLUSIONS The data show that a 3D spheroid model show different sensitivity to irradiation when combined with AKT inhibition. Thereby we show that MK2206 has potential synergistic efficacy to the current standard of care for glioma patients.
Collapse
Affiliation(s)
- Ravi S. Narayan
- Department of Radiation Oncology, VU University Medical Center/Cancer Center Amsterdam, P.O. Box 7057, Amsterdam, 1007 MB The Netherlands
| | - Carlos A. Fedrigo
- Department of Radiation Oncology, VU University Medical Center/Cancer Center Amsterdam, P.O. Box 7057, Amsterdam, 1007 MB The Netherlands
| | - Eelke Brands
- Department of Radiation Oncology, VU University Medical Center/Cancer Center Amsterdam, P.O. Box 7057, Amsterdam, 1007 MB The Netherlands
| | - Rogier Dik
- Department of Radiation Oncology, VU University Medical Center/Cancer Center Amsterdam, P.O. Box 7057, Amsterdam, 1007 MB The Netherlands
| | - Lukas J.A. Stalpers
- Department of Radiation Oncology, Academic Medical Center, Amsterdam, The Netherlands
| | - Brigitta G. Baumert
- Clinical Cooperation Unit Neurooncology, MediClin Robert Janker Klinik & University of Bonn Medical Center, Bonn, Germany
- Department of Radiation Oncology, Maastro Clinic, Maastricht, The Netherlands
| | - Ben J. Slotman
- Department of Radiation Oncology, VU University Medical Center/Cancer Center Amsterdam, P.O. Box 7057, Amsterdam, 1007 MB The Netherlands
| | - Bart A. Westerman
- Department of Neurosurgery, Neuro Oncology Research Group, VU University Medical Center, Amsterdam, The Netherlands
| | - Godefridus J. Peters
- Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands
| | - Peter Sminia
- Department of Radiation Oncology, VU University Medical Center/Cancer Center Amsterdam, P.O. Box 7057, Amsterdam, 1007 MB The Netherlands
| |
Collapse
|
|
31
|
Matsuzaki S, Pouly JL, Canis M. Effects of U0126 and MK2206 on cell growth and re-growth of endometriotic stromal cells grown on substrates of varying stiffness. Sci Rep 2017; 7:42939. [PMID: 28218307 PMCID: PMC5317159 DOI: 10.1038/srep42939] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2016] [Accepted: 01/17/2017] [Indexed: 12/28/2022] Open
Abstract
Endometriosis is a common gynecological disorder responsible for infertility and pelvic pain. A complete cure for patients with endometriosis awaits new targets and strategies. Here we show that U0126 (a MEK inhibitor) and MK2206 (an AKT inhibitor) synergistically inhibit cell growth of deep endometriotic stromal cells (DES) grown on polyacrylamide gel substrates (PGS) of varying stiffness (2 or 30 kilopascal [kPa]) or plastic in vitro. No significant differences in cell proliferation were observed among DES, endometrial stromal cells of patients with endometriosis (EES) from the proliferative phase (P), EES-S (secretory phase) and EES-M (menstrual phase) compared to cells grown on a substrate of the same stiffness at both higher (U0126 [30 μM] and MK2206 [9 μM]) and lower (U0126 [15 μM] and MK2206 [4.5 μM]) combined doses. However, cell re-growth of DES after drug discontinuation was higher than that of EES-P and EES-S when cells were grown on rigid substrates at both combined doses. Combination U0126 and MK2206 treatment is more effective than each drug alone in cell growth inhibition of DES. However, further studies are required to investigate the mechanisms underlying high cell survival and proliferation after drug discontinuation for developing target therapies that prevent recurrence.
Collapse
Affiliation(s)
- Sachiko Matsuzaki
- CHU Clermont-Ferrand, CHU Estaing, Chirurgie Gynécologique, Clermont-Ferrand, France.,Clermont Université, Université d'Auvergne, ISIT UMR6284, Clermont-Ferrand, France.,CNRS, ISIT UMR6284, Clermont-Ferrand, France
| | - Jean-Luc Pouly
- CHU Clermont-Ferrand, CHU Estaing, Chirurgie Gynécologique, Clermont-Ferrand, France
| | - Michel Canis
- CHU Clermont-Ferrand, CHU Estaing, Chirurgie Gynécologique, Clermont-Ferrand, France.,Clermont Université, Université d'Auvergne, ISIT UMR6284, Clermont-Ferrand, France.,CNRS, ISIT UMR6284, Clermont-Ferrand, France
| |
Collapse
|
|
32
|
Xie G, Wang Z, Chen Y, Zhang S, Feng L, Meng F, Yu Z. Dual blocking of PI3K and mTOR signaling by NVP-BEZ235 inhibits proliferation in cervical carcinoma cells and enhances therapeutic response. Cancer Lett 2016; 388:12-20. [PMID: 27894954 DOI: 10.1016/j.canlet.2016.11.024] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2016] [Revised: 11/19/2016] [Accepted: 11/22/2016] [Indexed: 02/06/2023]
Abstract
NVP-BEZ235 is a novel dual PI3K/mTOR inhibitor that shows dramatic effects on many tumors, but its effects on cervical carcinoma cells are largely unknown. In the present study, we investigated the effects of NVP-BEZ235 on the proliferation and invasion of cervical carcinoma cells in vitro and clarified its mechanism of action. In cellular settings with human cervical carcinoma cell lines, this molecule effectively and specifically blocked dysfunctional PI3K/mTOR pathway activation, suppressed cell growth in a time- and concentration-dependent manner, led to G1 cell cycle arrest, and induced apoptosis. NVP-BEZ235 suppressed HeLa cell invasiveness and metastasis by inhibiting the PI3K/Akt/MMP-2 pathway. We further demonstrated that NVP-BEZ235 treatment in combination with cisplatin or carboplatin induced a synergistic anti-tumoral response in cervical carcinoma cells. These findings suggested that NVP-BEZ235 could regulate growth and invasion of cervical carcinoma cells; thus it may provide a potential therapy for cervical carcinoma.
Collapse
Affiliation(s)
- Guifang Xie
- Department of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Department of Obstetrics and Gynecology, The First Hospital of Jilin University, Changchun, China
| | - Zhaoyong Wang
- Department of Pathology, The Second Hospital of Jilin University, Changchun, China
| | - Yong Chen
- Department of Neurosurgery, The First Hospital of Jilin University, Changchun, China
| | - Shuya Zhang
- Department of Obstetrics and Gynecology, The First Hospital of Jilin University, Changchun, China
| | - Lu Feng
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Fanhui Meng
- Department of Obstetrics and Gynecology, The First Hospital of Jilin University, Changchun, China
| | - Zhiyun Yu
- Department of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
| |
Collapse
|
|
33
|
Kim E, Rebecca VW, Smalley KSM, Anderson ARA. Phase i trials in melanoma: A framework to translate preclinical findings to the clinic. Eur J Cancer 2016; 67:213-222. [PMID: 27689717 PMCID: PMC5658204 DOI: 10.1016/j.ejca.2016.07.024] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2016] [Revised: 07/20/2016] [Accepted: 07/25/2016] [Indexed: 01/30/2023]
Abstract
BACKGROUND One of major issues in clinical trials in oncology is their high failure rate, despite the fact that the trials were designed based on the data from successful equivalent preclinical studies. This is in part due to the intrinsic homogeneity of preclinical model systems and the contrasting heterogeneity of actual patient responses. METHODS We present a mathematical model-driven framework, phase i (virtual/imaginary) trials, that integrates the heterogeneity of actual patient responses and preclinical studies through a cohort of virtual patients. The framework includes an experimentally calibrated mathematical model, a cohort of heterogeneous virtual patients, an assessment of stratification factors, and treatment optimisation. We show the detailed process through the lens of melanoma combination therapy (chemotherapy and an AKT inhibitor), using both preclinical and clinical data. RESULTS The mathematical model predicts melanoma treatment response and resistance to mono and combination therapies and was calibrated and then validated with in vitro experimental data. The validated model and a genetic algorithm were used to generate virtual patients whose tumour volume responses to the combination therapy matched statistically the actual heterogeneous patient responses in the clinical trial. Analyses on simulated cohorts revealed key model parameters such as a tumour volume doubling rate and a therapy-induced phenotypic switch rate that may have clinical correlates. Finally, our approach predicts optimal AKT inhibitor scheduling suggesting more effective but less toxic treatment strategies. CONCLUSION Our proposed computational framework to implement phase i trials in cancer can readily capture observed heterogeneous clinical outcomes and predict patient survival. Importantly, phase i trials can be used to optimise future clinical trial design.
Collapse
Affiliation(s)
- Eunjung Kim
- Integrated Mathematical Oncology Department, Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
| | - Vito W Rebecca
- The Department of Tumor Biology, Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Keiran S M Smalley
- The Department of Tumor Biology, Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Alexander R A Anderson
- Integrated Mathematical Oncology Department, Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| |
Collapse
|
|
34
|
Avan A, Narayan R, Giovannetti E, Peters GJ. Role of Akt signaling in resistance to DNA-targeted therapy. World J Clin Oncol 2016; 7:352-369. [PMID: 27777878 PMCID: PMC5056327 DOI: 10.5306/wjco.v7.i5.352] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2016] [Revised: 06/06/2016] [Accepted: 08/01/2016] [Indexed: 02/06/2023] Open
Abstract
The Akt signal transduction pathway controls most hallmarks of cancer. Activation of the Akt cascade promotes a malignant phenotype and is also widely implicated in drug resistance. Therefore, the modulation of Akt activity is regarded as an attractive strategy to enhance the efficacy of cancer therapy and irradiation. This pathway consists of phosphatidylinositol 3 kinase (PI3K), mammalian target of rapamycin, and the transforming serine-threonine kinase Akt protein isoforms, also known as protein kinase B. DNA-targeted agents, such as platinum agents, taxanes, and antimetabolites, as well as radiation have had a significant impact on cancer treatment by affecting DNA replication, which is aberrantly activated in malignancies. However, the caveat is that they may also trigger the activation of repairing mechanisms, such as upstream and downstream cascade of Akt survival pathway. Thus, each target can theoretically be inhibited in view of improving the potency of conventional treatment. Akt inhibitors, e.g., MK-2206 and perifosine, or PI3K modulators, e.g., LY294002 and Wortmannin, have shown some promising results in favor of sensitizing the cancer cells to the therapy in vitro and in vivo, which have provided the rationale for incorporation of these novel agents into multimodality treatment of different malignancies. Nevertheless, despite the acceptable safety profile of some of these agents in the clinical studies, with regard to the efficacy, the results are still too preliminary. Hence, we need to wait for the upcoming data from the ongoing trials before utilizing them into the standard care of cancer patients.
Collapse
|
|
35
|
Wang C, Wang R, Zhou K, Wang S, Wang J, Shi H, Dou Y, Yang D, Chang L, Shi X, Liu Y, Xu X, Zhang X, Ke Y, Liu H. JD enhances the anti-tumour effects of low-dose paclitaxel on gastric cancer MKN45 cells both in vitro and in vivo. Cancer Chemother Pharmacol 2016; 78:971-982. [PMID: 27620208 DOI: 10.1007/s00280-016-3149-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2016] [Accepted: 08/26/2016] [Indexed: 10/21/2022]
Abstract
BACKGROUND Gastric cancer is the third most common cause of cancer mortality worldwide, and paclitaxel (PTX) is one of the most widely used traditional drugs in gastric cancer therapy. However, the response to traditional therapy is limited by acquired chemo-resistance and side effects. Here, we establish a newly designed combination therapy consisting of a compound that is a structural variant of oridonin, i.e. Jesridonin (JD), and low-dose PTX for gastric cancer cells (MKN45) to investigate whether the anti-tumour activity of low-dose PTX could be enhanced when combined with JD. METHODS The interaction of JD and low-dose PTX was detected in MKN45 cells using the median-effect analysis method. The synergistic effect on cell viability and apoptosis was measured by MTT assay, colony formation assay, transient transfection, flow cytometry and Western blotting. The synergistic in vivo effect of JD plus low-dose PTX was evaluated in nude mouse xenograft models using H&E and TUNEL staining and Western blotting. RESULTS JD plus low-dose PTX showed a synergistic effect, as the combination indexes were less than 1. Additionally, a synergistic anti-proliferative and pro-apoptotic effect was detected for the combination of JD and low-dose PTX. The apoptotic mechanism induced by JD plus PTX revealed that the combination therapy synergistically activated the mitochondrial pathway. CONCLUSION Our findings suggest that JD enhances the anti-tumour effect of low-dose PTX on gastric carcinoma cancer cells in both vitro and in vivo, accompanied by activation of the mitochondrial pathway, which may present a more effective therapeutic strategy in gastric cancer treatment.
Collapse
Affiliation(s)
- Cong Wang
- Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Zhengzhou University School of Pharmaceutical Sciences, 100 Kexue Avenue, Zhengzhou, 450001, Henan, People's Republic of China
| | - Ran Wang
- Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Zhengzhou University School of Pharmaceutical Sciences, 100 Kexue Avenue, Zhengzhou, 450001, Henan, People's Republic of China
| | - Kairui Zhou
- Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Zhengzhou University School of Pharmaceutical Sciences, 100 Kexue Avenue, Zhengzhou, 450001, Henan, People's Republic of China
| | - Saiqi Wang
- Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Zhengzhou University School of Pharmaceutical Sciences, 100 Kexue Avenue, Zhengzhou, 450001, Henan, People's Republic of China
| | - Junwei Wang
- Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Zhengzhou University School of Pharmaceutical Sciences, 100 Kexue Avenue, Zhengzhou, 450001, Henan, People's Republic of China
| | - Hongge Shi
- Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Zhengzhou University School of Pharmaceutical Sciences, 100 Kexue Avenue, Zhengzhou, 450001, Henan, People's Republic of China
| | - Yinhui Dou
- Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Zhengzhou University School of Pharmaceutical Sciences, 100 Kexue Avenue, Zhengzhou, 450001, Henan, People's Republic of China
| | - Dongxiao Yang
- Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Zhengzhou University School of Pharmaceutical Sciences, 100 Kexue Avenue, Zhengzhou, 450001, Henan, People's Republic of China
| | - Liming Chang
- Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Zhengzhou University School of Pharmaceutical Sciences, 100 Kexue Avenue, Zhengzhou, 450001, Henan, People's Republic of China
| | - Xiaoli Shi
- Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Zhengzhou University School of Pharmaceutical Sciences, 100 Kexue Avenue, Zhengzhou, 450001, Henan, People's Republic of China
| | - Ying Liu
- Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Zhengzhou University School of Pharmaceutical Sciences, 100 Kexue Avenue, Zhengzhou, 450001, Henan, People's Republic of China
| | - Xiaowei Xu
- Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Zhengzhou University School of Pharmaceutical Sciences, 100 Kexue Avenue, Zhengzhou, 450001, Henan, People's Republic of China
| | - Xiujuan Zhang
- Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Zhengzhou University School of Pharmaceutical Sciences, 100 Kexue Avenue, Zhengzhou, 450001, Henan, People's Republic of China
| | - Yu Ke
- Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Zhengzhou University School of Pharmaceutical Sciences, 100 Kexue Avenue, Zhengzhou, 450001, Henan, People's Republic of China
| | - Hongmin Liu
- Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Zhengzhou University School of Pharmaceutical Sciences, 100 Kexue Avenue, Zhengzhou, 450001, Henan, People's Republic of China.
| |
Collapse
|
|
36
|
Abstract
Macroautophagy (autophagy hereafter) captures intracellular proteins and organelles and degrades them in lysosomes. The degradation breakdown products are released from lysosomes and recycled into metabolic and biosynthetic pathways. Basal autophagy provides protein and organelle quality control by eliminating damaged cellular components. Starvation-induced autophagy recycles intracellular components into metabolic pathways to sustain mitochondrial metabolic function and energy homeostasis. Recycling by autophagy is essential for yeast and mammals to survive starvation through intracellular nutrient scavenging. Autophagy suppresses degenerative diseases and has a context-dependent role in cancer. In some models, cancer initiation is suppressed by autophagy. By preventing the toxic accumulation of damaged protein and organelles, particularly mitochondria, autophagy limits oxidative stress, chronic tissue damage, and oncogenic signaling, which suppresses cancer initiation. This suggests a role for autophagy stimulation in cancer prevention, although the role of autophagy in the suppression of human cancer is unclear. In contrast, some cancers induce autophagy and are dependent on autophagy for survival. Much in the way that autophagy promotes survival in starvation, cancers can use autophagy-mediated recycling to maintain mitochondrial function and energy homeostasis to meet the elevated metabolic demand of growth and proliferation. Thus, autophagy inhibition may be beneficial for cancer therapy. Moreover, tumors are more autophagy-dependent than normal tissues, suggesting that there is a therapeutic window. Despite these insights, many important unanswered questions remain about the exact mechanisms of autophagy-mediated cancer suppression and promotion, how relevant these observations are to humans, and whether the autophagy pathway can be modulated therapeutically in cancer. See all articles in this CCR Focus section, "Cell Death and Cancer Therapy."
Collapse
Affiliation(s)
- Eileen White
- Rutgers Cancer Institute of New Jersey (CINJ), New Brunswick, New Jersey. Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, New Jersey.
| | - Janice M Mehnert
- Rutgers Cancer Institute of New Jersey (CINJ), New Brunswick, New Jersey. Department of Medicine, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, New Jersey
| | - Chang S Chan
- Rutgers Cancer Institute of New Jersey (CINJ), New Brunswick, New Jersey. Department of Medicine, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, New Jersey
| |
Collapse
|
|
37
|
Saleh T, Cuttino L, Gewirtz DA. Autophagy is not uniformly cytoprotective: a personalized medicine approach for autophagy inhibition as a therapeutic strategy in non-small cell lung cancer. Biochim Biophys Acta Gen Subj 2016; 1860:2130-6. [PMID: 27316314 DOI: 10.1016/j.bbagen.2016.06.012] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2016] [Revised: 06/07/2016] [Accepted: 06/12/2016] [Indexed: 02/06/2023]
Abstract
BACKGROUND Lung cancer is the leading cause of cancer-related death worldwide. In addition to surgical resection, which is considered first-line treatment at early stages of the disease, chemotherapy and radiation are widely used when the disease is advanced. Of multiple responses that may occur in the tumor cells in response to cancer therapy, the functional importance of autophagy remains equivocal; this is likely to restrict current efforts to sensitize this malignancy to chemotherapy and/or radiation by pharmacological interference with the autophagic response. SCOPE OF REVIEW In this review, we attempt to summarize the current state of knowledge based on studies that evaluated the function of autophagy in non-small cell lung cancer (NSCLC) cells in response to radiation and the most commonly used chemotherapeutic agents. MAJOR CONCLUSIONS In addition to the expected prosurvival function of autophagy, where autophagy inhibition enhances the response to therapy, autophagy appears also to have a "non-cytoprotective" function, where autophagy blockade does not affect cell viability, clonogenicity or tumor volume in response to therapy. In other cases, autophagy may actually mediate drug action via expression of its cytotoxic function. GENERAL SIGNIFICANCE These observations emphasize the complexity of autophagy function when examined in different tumor cell lines and in response to different chemotherapeutic agents. A more in-depth understanding of the conditions that promote the unique functions of autophagy is required in order to translate preclinical findings of autophagy inhibition to the clinic for the purpose of improving patient response to chemotherapy and radiation.
Collapse
Affiliation(s)
- Tareq Saleh
- Department of Pharmacology and Toxicology, Massey Cancer Center, Virginia Commonwealth University, 401 College St., Richmond, VA 23298, United States
| | - Laurie Cuttino
- Department of Radiation Oncology, Virginia Commonwealth University, Henrico Doctor's Hospital, 1602 Skipwith Rd, Richmond, VA 23229, United States
| | - David A Gewirtz
- Department of Pharmacology and Toxicology, Massey Cancer Center, Virginia Commonwealth University, 401 College St., Richmond, VA 23298, United States; Department of Medicine, Massey Cancer Center, Virginia Commonwealth University, 401 College St., Richmond, VA 23298, United States.
| |
Collapse
|
|
38
|
Trung NN, Tho NT, Thuy Dung BT, My Nhung HT, Thang ND. Effects of ricin extracted from seeds of the castor bean (ricinuscommunis) on cytotoxicity and tumorigenesis of melanoma cells. BIOMEDICAL RESEARCH AND THERAPY 2016. [DOI: 10.7603/s40730-016-0023-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
|
|
39
|
Roller DG, Capaldo B, Bekiranov S, Mackey AJ, Conaway MR, Petricoin EF, Gioeli D, Weber MJ. Combinatorial drug screening and molecular profiling reveal diverse mechanisms of intrinsic and adaptive resistance to BRAF inhibition in V600E BRAF mutant melanomas. Oncotarget 2016; 7:2734-53. [PMID: 26673621 PMCID: PMC4823068 DOI: 10.18632/oncotarget.6548] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2015] [Accepted: 11/21/2015] [Indexed: 12/28/2022] Open
Abstract
Over half of BRAFV600E melanomas display intrinsic resistance to BRAF inhibitors, in part due to adaptive signaling responses. In this communication we ask whether BRAFV600E melanomas share common adaptive responses to BRAF inhibition that can provide clinically relevant targets for drug combinations. We screened a panel of 12 treatment-naïve BRAFV600E melanoma cell lines with MAP Kinase pathway inhibitors in pairwise combination with 58 signaling inhibitors, assaying for synergistic cytotoxicity. We found enormous diversity in the drug combinations that showed synergy, with no two cell lines having an identical profile. Although the 6 lines most resistant to BRAF inhibition showed synergistic benefit from combination with lapatinib, the signaling mechanisms by which this combination generated synergistic cytotoxicity differed between the cell lines. We conclude that adaptive responses to inhibition of the primary oncogenic driver (BRAFV600E) are determined not only by the primary oncogenic driver but also by diverse secondary genetic and epigenetic changes ("back-seat drivers") and hence optimal drug combinations will be variable. Because upregulation of receptor tyrosine kinases is a major source of drug resistance arising from diverse adaptive responses, we propose that inhibitors of these receptors may have substantial clinical utility in combination with inhibitors of the MAP Kinase pathway.
Collapse
Affiliation(s)
- Devin G. Roller
- Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA, 22908 USA
| | - Brian Capaldo
- Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA, 22908 USA
| | - Stefan Bekiranov
- Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA, 22908 USA
| | - Aaron J. Mackey
- Department of Public Health Sciences, University of Virginia, Charlottesville, VA, 22908 USA
| | - Mark R. Conaway
- Department of Public Health Sciences, University of Virginia, Charlottesville, VA, 22908 USA
| | - Emanuel F. Petricoin
- Center for Applied Proteomics and Molecular Medicine, School of Systems Biology, College of Science, George Mason University, Manassas, VA 20110, USA
| | - Daniel Gioeli
- Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA, 22908 USA
| | - Michael J. Weber
- Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA, 22908 USA
| |
Collapse
|
|
40
|
Thang ND, Nghia PT, Kumasaka MY, Yajima I, Kato M. Treatment of vemurafenib-resistant SKMEL-28 melanoma cells with paclitaxel. Asian Pac J Cancer Prev 2015; 16:699-705. [PMID: 25684511 DOI: 10.7314/apjcp.2015.16.2.699] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Vemurafenib has recently been used as drug for treatment of melanomas with BRAFV600E mutation. Unfortunately, treatment with only vemurafenib has not been sufficiently effective, with recurrence after a short period. In this study, three vemurafenib-resistant BRAFV600E melanoma cell lines, A375PR, A375MR and SKMEL-28R, were established from the original A375P, A375M and SKMEL-28 cell lines. Examination of the molecular mechanisms showed that the phosphorylation levels of MEK and ERK, which play key roles in the RAS/RAF/MEK/ERK signaling pathway, were reduced in these three cell lines, with increased phosphorylation levels of pAKTs limited to SKMEL-28R cells. Treatment of SKMEL-28R cells with 100 nM paclitaxel resulted in increased apoptosis and decreased cellular proliferation, invasion and colony formation via reduction of expression levels of EGFR and pAKTs. Moreover, vemurafenib-induced pAKTs in SKMEL-28R were decreased by treatment with an AKT inhibitor, MK-2206. Taken together, our results revealed that resistance mechanisms of BRAFV600E-mutation melanoma cells to vemurafenib depended on the cell type. Our results suggested that paclitaxel should be considered as a drug in combination with vemurafenib to treat melanoma cells.
Collapse
Affiliation(s)
- Nguyen Dinh Thang
- Department of Biochemistry and Plant Physiology, Key Laboratory of Enzyme and Protein Technology, VNU University of Science, Vietnam National University, Hanoi, Vietnam E-mail :
| | | | | | | | | |
Collapse
|
|
41
|
González-Cao M, Rodón J, Karachaliou N, Sánchez J, Santarpia M, Viteri S, Pilotto S, Teixidó C, Riso A, Rosell R. Other targeted drugs in melanoma. ANNALS OF TRANSLATIONAL MEDICINE 2015; 3:266. [PMID: 26605312 DOI: 10.3978/j.issn.2305-5839.2015.08.12] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Targeted therapy drugs are developed against specific molecular alterations on cancer cells. Because they are "targeted" to the tumor, these therapies are more effective and better tolerated than conventional therapies such as chemotherapy. In the last decade, great advances have been made in understanding of melanoma biology and identification of molecular mechanisms involved in malignant transformation of cells. The identification of oncogenic mutated kinases involved in this process provides an opportunity for development of new target therapies. The dependence of melanoma on BRAF-mutant kinase has provided an opportunity for development of mutation-specific inhibitors with high activity and excellent tolerance that are now being used in clinical practice. This marked a new era in the treatment of metastatic melanoma and much research is now ongoing to identify other "druggable" kinases and transduction signaling networking. It is expected that in the near future the spectrum of target drugs for melanoma treatment will increase. Herein, we review the most relevant potential novel drugs for melanoma treatment based on preclinical data and the results of early clinical trials.
Collapse
Affiliation(s)
- María González-Cao
- 1 Translational Cancer Research Unit, Instituto Oncológico Dr Rosell, Quirón Dexeus University Hospital, Barcelona, Spain ; 2 Vall D'Hebron Institute of Oncology and Universitat Autonoma de Barcelona, Barcelona, Spain ; 3 Immunology Department, CNICV, Madrid, Spain ; 4 Medical Oncology Unit, Human Pathology Department, University of Messina, Messina, Italy ; 5 Department of Medical Oncology, University of Verona, Azienda Ospedaliera Universitaria Integrata, Verona, Italy ; 6 Pangaea Biotech S.L, Barcelona, Spain ; 7 Cancer Biology and Precision Medicine Program, Catalan Institute of Oncology, Germans Trias i Pujol Health Sciences Institute and Hospital, Campus Can Ruti, Badalona, Barcelona, Spain ; 8 Fundación Molecular Oncology Research, Barcelona, Spain
| | - Jordi Rodón
- 1 Translational Cancer Research Unit, Instituto Oncológico Dr Rosell, Quirón Dexeus University Hospital, Barcelona, Spain ; 2 Vall D'Hebron Institute of Oncology and Universitat Autonoma de Barcelona, Barcelona, Spain ; 3 Immunology Department, CNICV, Madrid, Spain ; 4 Medical Oncology Unit, Human Pathology Department, University of Messina, Messina, Italy ; 5 Department of Medical Oncology, University of Verona, Azienda Ospedaliera Universitaria Integrata, Verona, Italy ; 6 Pangaea Biotech S.L, Barcelona, Spain ; 7 Cancer Biology and Precision Medicine Program, Catalan Institute of Oncology, Germans Trias i Pujol Health Sciences Institute and Hospital, Campus Can Ruti, Badalona, Barcelona, Spain ; 8 Fundación Molecular Oncology Research, Barcelona, Spain
| | - Niki Karachaliou
- 1 Translational Cancer Research Unit, Instituto Oncológico Dr Rosell, Quirón Dexeus University Hospital, Barcelona, Spain ; 2 Vall D'Hebron Institute of Oncology and Universitat Autonoma de Barcelona, Barcelona, Spain ; 3 Immunology Department, CNICV, Madrid, Spain ; 4 Medical Oncology Unit, Human Pathology Department, University of Messina, Messina, Italy ; 5 Department of Medical Oncology, University of Verona, Azienda Ospedaliera Universitaria Integrata, Verona, Italy ; 6 Pangaea Biotech S.L, Barcelona, Spain ; 7 Cancer Biology and Precision Medicine Program, Catalan Institute of Oncology, Germans Trias i Pujol Health Sciences Institute and Hospital, Campus Can Ruti, Badalona, Barcelona, Spain ; 8 Fundación Molecular Oncology Research, Barcelona, Spain
| | - Jesús Sánchez
- 1 Translational Cancer Research Unit, Instituto Oncológico Dr Rosell, Quirón Dexeus University Hospital, Barcelona, Spain ; 2 Vall D'Hebron Institute of Oncology and Universitat Autonoma de Barcelona, Barcelona, Spain ; 3 Immunology Department, CNICV, Madrid, Spain ; 4 Medical Oncology Unit, Human Pathology Department, University of Messina, Messina, Italy ; 5 Department of Medical Oncology, University of Verona, Azienda Ospedaliera Universitaria Integrata, Verona, Italy ; 6 Pangaea Biotech S.L, Barcelona, Spain ; 7 Cancer Biology and Precision Medicine Program, Catalan Institute of Oncology, Germans Trias i Pujol Health Sciences Institute and Hospital, Campus Can Ruti, Badalona, Barcelona, Spain ; 8 Fundación Molecular Oncology Research, Barcelona, Spain
| | - Mariacarmela Santarpia
- 1 Translational Cancer Research Unit, Instituto Oncológico Dr Rosell, Quirón Dexeus University Hospital, Barcelona, Spain ; 2 Vall D'Hebron Institute of Oncology and Universitat Autonoma de Barcelona, Barcelona, Spain ; 3 Immunology Department, CNICV, Madrid, Spain ; 4 Medical Oncology Unit, Human Pathology Department, University of Messina, Messina, Italy ; 5 Department of Medical Oncology, University of Verona, Azienda Ospedaliera Universitaria Integrata, Verona, Italy ; 6 Pangaea Biotech S.L, Barcelona, Spain ; 7 Cancer Biology and Precision Medicine Program, Catalan Institute of Oncology, Germans Trias i Pujol Health Sciences Institute and Hospital, Campus Can Ruti, Badalona, Barcelona, Spain ; 8 Fundación Molecular Oncology Research, Barcelona, Spain
| | - Santiago Viteri
- 1 Translational Cancer Research Unit, Instituto Oncológico Dr Rosell, Quirón Dexeus University Hospital, Barcelona, Spain ; 2 Vall D'Hebron Institute of Oncology and Universitat Autonoma de Barcelona, Barcelona, Spain ; 3 Immunology Department, CNICV, Madrid, Spain ; 4 Medical Oncology Unit, Human Pathology Department, University of Messina, Messina, Italy ; 5 Department of Medical Oncology, University of Verona, Azienda Ospedaliera Universitaria Integrata, Verona, Italy ; 6 Pangaea Biotech S.L, Barcelona, Spain ; 7 Cancer Biology and Precision Medicine Program, Catalan Institute of Oncology, Germans Trias i Pujol Health Sciences Institute and Hospital, Campus Can Ruti, Badalona, Barcelona, Spain ; 8 Fundación Molecular Oncology Research, Barcelona, Spain
| | - Sara Pilotto
- 1 Translational Cancer Research Unit, Instituto Oncológico Dr Rosell, Quirón Dexeus University Hospital, Barcelona, Spain ; 2 Vall D'Hebron Institute of Oncology and Universitat Autonoma de Barcelona, Barcelona, Spain ; 3 Immunology Department, CNICV, Madrid, Spain ; 4 Medical Oncology Unit, Human Pathology Department, University of Messina, Messina, Italy ; 5 Department of Medical Oncology, University of Verona, Azienda Ospedaliera Universitaria Integrata, Verona, Italy ; 6 Pangaea Biotech S.L, Barcelona, Spain ; 7 Cancer Biology and Precision Medicine Program, Catalan Institute of Oncology, Germans Trias i Pujol Health Sciences Institute and Hospital, Campus Can Ruti, Badalona, Barcelona, Spain ; 8 Fundación Molecular Oncology Research, Barcelona, Spain
| | - Cristina Teixidó
- 1 Translational Cancer Research Unit, Instituto Oncológico Dr Rosell, Quirón Dexeus University Hospital, Barcelona, Spain ; 2 Vall D'Hebron Institute of Oncology and Universitat Autonoma de Barcelona, Barcelona, Spain ; 3 Immunology Department, CNICV, Madrid, Spain ; 4 Medical Oncology Unit, Human Pathology Department, University of Messina, Messina, Italy ; 5 Department of Medical Oncology, University of Verona, Azienda Ospedaliera Universitaria Integrata, Verona, Italy ; 6 Pangaea Biotech S.L, Barcelona, Spain ; 7 Cancer Biology and Precision Medicine Program, Catalan Institute of Oncology, Germans Trias i Pujol Health Sciences Institute and Hospital, Campus Can Ruti, Badalona, Barcelona, Spain ; 8 Fundación Molecular Oncology Research, Barcelona, Spain
| | - Aldo Riso
- 1 Translational Cancer Research Unit, Instituto Oncológico Dr Rosell, Quirón Dexeus University Hospital, Barcelona, Spain ; 2 Vall D'Hebron Institute of Oncology and Universitat Autonoma de Barcelona, Barcelona, Spain ; 3 Immunology Department, CNICV, Madrid, Spain ; 4 Medical Oncology Unit, Human Pathology Department, University of Messina, Messina, Italy ; 5 Department of Medical Oncology, University of Verona, Azienda Ospedaliera Universitaria Integrata, Verona, Italy ; 6 Pangaea Biotech S.L, Barcelona, Spain ; 7 Cancer Biology and Precision Medicine Program, Catalan Institute of Oncology, Germans Trias i Pujol Health Sciences Institute and Hospital, Campus Can Ruti, Badalona, Barcelona, Spain ; 8 Fundación Molecular Oncology Research, Barcelona, Spain
| | - Rafael Rosell
- 1 Translational Cancer Research Unit, Instituto Oncológico Dr Rosell, Quirón Dexeus University Hospital, Barcelona, Spain ; 2 Vall D'Hebron Institute of Oncology and Universitat Autonoma de Barcelona, Barcelona, Spain ; 3 Immunology Department, CNICV, Madrid, Spain ; 4 Medical Oncology Unit, Human Pathology Department, University of Messina, Messina, Italy ; 5 Department of Medical Oncology, University of Verona, Azienda Ospedaliera Universitaria Integrata, Verona, Italy ; 6 Pangaea Biotech S.L, Barcelona, Spain ; 7 Cancer Biology and Precision Medicine Program, Catalan Institute of Oncology, Germans Trias i Pujol Health Sciences Institute and Hospital, Campus Can Ruti, Badalona, Barcelona, Spain ; 8 Fundación Molecular Oncology Research, Barcelona, Spain
| |
Collapse
|
|
42
|
Hassan M, Selimovic D, Hannig M, Haikel Y, Brodell RT, Megahed M. Endoplasmic reticulum stress-mediated pathways to both apoptosis and autophagy: Significance for melanoma treatment. World J Exp Med 2015; 5:206-217. [PMID: 26618107 PMCID: PMC4655250 DOI: 10.5493/wjem.v5.i4.206] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2015] [Revised: 06/29/2015] [Accepted: 09/08/2015] [Indexed: 02/06/2023] Open
Abstract
Melanoma is the most aggressive form of skin cancer. Disrupted intracellular signaling pathways are responsible for melanoma's extraordinary resistance to current chemotherapeutic modalities. The pathophysiologic basis for resistance to both chemo- and radiation therapy is rooted in altered genetic and epigenetic mechanisms that, in turn, result in the impairing of cell death machinery and/or excessive activation of cell growth and survival-dependent pathways. Although most current melanoma therapies target mitochondrial dysregulation, there is increasing evidence that endoplasmic reticulum (ER) stress-associated pathways play a role in the potentiation, initiation and maintenance of cell death machinery and autophagy. This review focuses on the reliability of ER-associated pathways as therapeutic targets for melanoma treatment.
Collapse
|
|
43
|
Emerging strategies to effectively target autophagy in cancer. Oncogene 2015; 35:1-11. [PMID: 25893285 DOI: 10.1038/onc.2015.99] [Citation(s) in RCA: 199] [Impact Index Per Article: 19.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2014] [Revised: 02/18/2015] [Accepted: 02/18/2015] [Indexed: 02/07/2023]
Abstract
Autophagy serves a dichotomous role in cancer and recent advances have helped delineate the appropriate settings where inhibiting or promoting autophagy may confer therapeutic efficacy in patients. Our evolving understanding of the molecular machinery responsible for the tightly controlled regulation of this homeostatic mechanism has begun to bear fruit in the way of autophagy-oriented clinical trials and promising lead compounds to modulate autophagy for therapeutic benefit. In this manuscript we review the recent preclinical and clinical therapeutic strategies that involve autophagy modulation in cancer.
Collapse
|
|
44
|
Xie X, Koh JY, Price S, White E, Mehnert JM. Atg7 Overcomes Senescence and Promotes Growth of BrafV600E-Driven Melanoma. Cancer Discov 2015; 5:410-23. [PMID: 25673642 DOI: 10.1158/2159-8290.cd-14-1473] [Citation(s) in RCA: 170] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2014] [Accepted: 02/05/2015] [Indexed: 12/31/2022]
Abstract
UNLABELLED Macroautophagy (autophagy hereafter) may promote survival and growth of spontaneous tumors, including melanoma. We utilized a genetically engineered mouse model of melanoma driven by oncogenic BrafV600E and deficiency in the Pten tumor suppressor gene in melanocytes to test the functional consequences of loss of the essential autophagy gene autophagy-related-7, Atg7. Atg7 deficiency prevented melanoma development by BrafV600E and allelic Pten loss, indicating that autophagy is essential for melanomagenesis. Moreover, BrafV600E-mutant, Pten-null, Atg7-deficient melanomas displayed accumulation of autophagy substrates and growth defects, which extended animal survival. Atg7-deleted tumors showed increased oxidative stress and senescence, a known barrier to melanomagenesis. Treatment with the BRAF inhibitor dabrafenib decreased tumor growth and induced senescence that was more pronounced in tumors with Atg7 deficiency. Thus, Atg7 promotes melanoma by limiting oxidative stress and overcoming senescence, and autophagy inhibition may be of therapeutic value by augmenting the antitumor activity of BRAF inhibitors. SIGNIFICANCE The essential autophagy gene Atg7 promotes development of BrafV600E-mutant, Pten-null melanomas by overcoming senescence, and deleting Atg7 facilitated senescence induction and antitumor activity of BRAF inhibition. This suggests that combinatorial BRAFV600E and autophagy inhibition may improve therapeutic outcomes in patients whose tumors have BRAFV600E/K mutations, an approach currently being explored in clinical trials.
Collapse
Affiliation(s)
- Xiaoqi Xie
- Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey. Department of Medicine, Rutgers Robert Wood Johnson Medical School, Piscataway, New Jersey
| | - Ju Yong Koh
- Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey. Department of Medicine, Rutgers Robert Wood Johnson Medical School, Piscataway, New Jersey
| | - Sandy Price
- Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey. Department of Medicine, Rutgers Robert Wood Johnson Medical School, Piscataway, New Jersey
| | - Eileen White
- Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey. Department of Medicine, Rutgers Robert Wood Johnson Medical School, Piscataway, New Jersey. Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, New Jersey.
| | - Janice M Mehnert
- Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey. Department of Medicine, Rutgers Robert Wood Johnson Medical School, Piscataway, New Jersey.
| |
Collapse
|
|
45
|
ROS-mediated EB1 phosphorylation through Akt/GSK3β pathway: implication in cancer cell response to microtubule-targeting agents. Oncotarget 2015; 5:3408-23. [PMID: 24930764 PMCID: PMC4102819 DOI: 10.18632/oncotarget.1982] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Microtubule-targeting agents (MTAs) are largely administered in adults and children cancers. Better deciphering their mechanism of action is of prime importance to develop more convenient therapy strategies. Here, we addressed the question of how reactive oxygen species (ROS) generation by mitochondria can be necessary for MTA efficacy. We showed for the first time that EB1 associates with microtubules in a phosphorylation-dependent manner, under control of ROS. By using phospho-defective mutants, we further characterized the Serine 155 residue as critical for EB1 accumulation at microtubule plus-ends, and both cancer cell migration and proliferation. Phosphorylation of EB1 on the Threonine 166 residue triggered opposite effects, and was identified as a requisite molecular switch in MTA activities. We then showed that GSK3β activation was responsible for MTA-triggered EB1 phosphorylation, resulting from ROS-mediated inhibition of upstream Akt. We thus disclosed here a novel pathway by which generation of mitochondrial ROS modulates microtubule dynamics through phosphorylation of EB1, improving our fundamental knowledge about this oncogenic protein, and pointing out the need to re-examine the current dogma of microtubule targeting by MTAs. The present work also provides a strong mechanistic rational to the promising therapeutic strategies that currently combine MTAs with anti-Akt targeted therapies.
Collapse
|
|
46
|
Zhang FX, Wang BB, Wu CF, Zheng XF, Ma Q. Targeting autophagy for therapy of gastric cancer. Shijie Huaren Xiaohua Zazhi 2015; 23:51-57. [DOI: 10.11569/wcjd.v23.i1.51] [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] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer is one of the most common malignant neoplasms. Surgery represents the main approach for this disease. Notwithstanding the advances in surgical techniques, there has been still a minimal improvement in overall survival with a significant increase in relapse rates. Although the development of new drugs has significantly improved the effectiveness of chemotherapy, the prognosis of patients with unresectable or metastatic gastric carcinoma remains poor. Therefore, it is necessary to find some new ways against gastric carcinogenesis. It has been shown that autophagy plays a dual role in the transformation and progression of gastric cancer; activation and induction of autophagy can lead to gastric carcinogenesis. Recently, several agents targeting autophagy molecules in gastric carcinogenesis have been investigated. This article reviews the regulation of autophagy with inhibitors or inducers to treat gastric cancer, and discusses how they regulate autophagy as a targeted therapy for gastric cancer.
Collapse
|
|
47
|
Fedorenko IV, Fang B, Munko AC, Gibney GT, Koomen JM, Smalley KSM. Phosphoproteomic analysis of basal and therapy-induced adaptive signaling networks in BRAF and NRAS mutant melanoma. Proteomics 2014; 15:327-39. [PMID: 25339196 DOI: 10.1002/pmic.201400200] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2014] [Revised: 09/11/2014] [Accepted: 10/14/2014] [Indexed: 12/30/2022]
Abstract
Basal and kinase inhibitor driven adaptive signaling has been examined in a panel of melanoma cell lines using phosphoproteomics in conjunction with pathway analysis. A considerable divergence in the spectrum of tyrosine-phosphorylated peptides was noted at the cell line level. The unification of genotype-specific cell line data revealed the enrichment for the tyrosine-phosphorylated cytoskeletal proteins to be associated with the presence of a BRAF mutation and oncogenic NRAS to be associated with increased receptor tyrosine kinase phosphorylation. A number of proteins including cell cycle regulators (cyclin dependent kinase 1, cyclin dependent kinase 2, and cyclin dependent kinase 3), MAPK pathway components (Extracellular signal regulated kinase 1 and Extracellular signal regulated kinase 2), interferon regulators (tyrosine kinase-2), GTPase regulators (Ras-Rasb interactor 1), and controllers of protein tyrosine phosphorylation (dual specificity tyrosine (Y) phosphorylation regulated kinase 1A and protein tyrosine phosphatase receptor type A) were common to all genotypes. Treatment of a BRAF-mutant/phosphatase and tensin homologue (PTEN) null melanoma cell line with vemurafenib led to decreased phosphorylation of ERK, phospholipase C1, and β-catenin with increases in receptor tyrosine kinase phosphorylation, signal transduction and activator of signaling 3, and glycogen synthase kinase 3α noted. In NRAS-mutant melanoma, MEK inhibition led to increased phosphorylation of epidermal growth factor receptor signaling pathway components, Src family kinases, and protein kinase Cδ with decreased phosphorylation seen in STAT3 and ERK1/2. Together these data present the first systems level view of adaptive and basal phosphotyrosine signaling in BRAF- and NRAS-mutant melanoma.
Collapse
Affiliation(s)
- Inna V Fedorenko
- The Department of Molecular Oncology, The Moffitt Cancer Center & Research Institute, Tampa, FL, USA
| | | | | | | | | | | |
Collapse
|
|
48
|
Beyond BRAF: where next for melanoma therapy? Br J Cancer 2014; 112:217-26. [PMID: 25180764 PMCID: PMC4453440 DOI: 10.1038/bjc.2014.476] [Citation(s) in RCA: 92] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2014] [Revised: 07/23/2014] [Accepted: 08/04/2014] [Indexed: 12/22/2022] Open
Abstract
In recent years, melanoma has become a poster-child for the development of oncogene-directed targeted therapies. This approach, which has been exemplified by the development of small-molecule BRAF inhibitors and the BRAF/MEK inhibitor combination for BRAF-mutant melanoma, has brought new hope to patients. Despite these successes, treatment failure seems near inevitable in the majority of cases—even in individuals treated with the BRAF/MEK inhibitor doublet. In the current review, we discuss the future of combination strategies for patients with BRAF-mutant melanoma as well as the emerging therapeutic options for patients with NRAS-mutant and BRAF/NRAS-wild-type melanoma. We also outline some of the newest developments in the in-depth personalisation of therapy that should allow melanoma treatment to continue shaping the field precision cancer medicine.
Collapse
|
|
49
|
Nagelkerke A, Bussink J, Geurts-Moespot A, Sweep FCGJ, Span PN. Therapeutic targeting of autophagy in cancer. Part II: pharmacological modulation of treatment-induced autophagy. Semin Cancer Biol 2014; 31:99-105. [PMID: 24933034 DOI: 10.1016/j.semcancer.2014.06.001] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Autophagy, the catabolic pathway in which cells recycle organelles and other parts of their own cytoplasm, is increasingly recognised as an important cytoprotective mechanism in cancer cells. Several cancer treatments stimulate the autophagic process and when autophagy is inhibited, cancer cells show an enhanced response to multiple treatments. These findings have nourished the theory that autophagy provides cancer cells with a survival advantage during stressful conditions, including exposure to therapeutics. Therefore, interference with the autophagic response can potentially enhance the efficacy of cancer therapy. In this review we examine two approaches to modulate autophagy as complementary cancer treatment: inhibition and induction. Inhibition of autophagy during cancer treatment eliminates its cytoprotective effects. Conversely, induction of autophagy combined with conventional cancer therapy exerts severe cytoplasmic degradation that can ultimately lead to cell death. We will discuss how autophagy can be therapeutically manipulated in cancer cells and how interactions between the conventional cancer therapies and autophagy modulation influence treatment outcome.
Collapse
Affiliation(s)
- Anika Nagelkerke
- Department of Laboratory Medicine, Radboud university medical center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands; Department of Radiation Oncology, Radboud university medical center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands.
| | - Johan Bussink
- Department of Radiation Oncology, Radboud university medical center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands.
| | - Anneke Geurts-Moespot
- Department of Laboratory Medicine, Radboud university medical center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands.
| | - Fred C G J Sweep
- Department of Laboratory Medicine, Radboud university medical center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands.
| | - Paul N Span
- Department of Radiation Oncology, Radboud university medical center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands.
| |
Collapse
|