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Croley CR, Pumarol J, Delgadillo BE, Cook AC, Day F, Kaceli T, Ward CC, Husain I, Husain A, Banerjee S, Bishayee A. Signaling pathways driving ocular malignancies and their targeting by bioactive phytochemicals. Pharmacol Ther 2023:108479. [PMID: 37330112 DOI: 10.1016/j.pharmthera.2023.108479] [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: 04/21/2023] [Revised: 06/05/2023] [Accepted: 06/12/2023] [Indexed: 06/19/2023]
Abstract
Ocular cancers represent a rare pathology. The American Cancer Society estimates that 3,360 cases of ocular cancer occur annually in the United States. The major types of cancers of the eye include ocular melanoma (also known as uveal melanoma), ocular lymphoma, retinoblastoma, and squamous cell carcinoma. While uveal melanoma is one of the primary intraocular cancers with the highest occurrence in adults, retinoblastoma remains the most common primary intraocular cancer in children, and squamous cell carcinoma presents as the most common conjunctival cancer. The pathophysiology of these diseases involves specific cell signaling pathways. Oncogene mutations, tumor suppressor mutations, chromosome deletions/translocations and altered proteins are all described as causal events in developing ocular cancer. Without proper identification and treatment of these cancers, vision loss, cancer spread, and even death can occur. The current treatments for these cancers involve enucleation, radiation, excision, laser treatment, cryotherapy, immunotherapy, and chemotherapy. These treatments present a significant burden to the patient that includes a possible loss of vision and a myriad of side effects. Therefore, alternatives to traditional therapy are urgently needed. Intercepting the signaling pathways for these cancers with the use of naturally occurring phytochemicals could be a way to relieve both cancer burden and perhaps even prevent cancer occurrence. This research aims to present a comprehensive review of the signaling pathways involved in various ocular cancers, discuss current therapeutic options, and examine the potential of bioactive phytocompounds in the prevention and targeted treatment of ocular neoplasms. The current limitations, challenges, pitfalls, and future research directions are also discussed.
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Affiliation(s)
- Courtney R Croley
- Healthcare Corporation of America, Department of Ophthalmology, Morsani College of Medicine, University of South Florida, Hudson, FL 34667, USA
| | - Joshua Pumarol
- Ross University School of Medicine, Miramar, FL 33027, USA
| | - Blake E Delgadillo
- College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, FL 34211, USA
| | - Andrew C Cook
- College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, FL 34211, USA
| | - Faith Day
- College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, FL 34211, USA
| | - Tea Kaceli
- College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, FL 34211, USA
| | - Caroline C Ward
- Morsani College of Medicine, University of South Florida, Tampa, FL 33602, USA
| | - Imran Husain
- College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Erie, PA 16509, USA
| | - Ali Husain
- College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Erie, PA 16509, USA
| | - Sabyasachi Banerjee
- Department of Pharmaceutical Chemistry, Gupta College of Technological Sciences, Asansol 713 301, India
| | - Anupam Bishayee
- College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, FL 34211, USA.
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Chan PY, Phillips MM, Ellis S, Johnston A, Feng X, Arora A, Hay G, Cohen VML, Sagoo MS, Bomalaski JS, Sheaff MT, Szlosarek PW. A Phase 1 study of ADI-PEG20 (pegargiminase) combined with cisplatin and pemetrexed in ASS1-negative metastatic uveal melanoma. Pigment Cell Melanoma Res 2022; 35:461-470. [PMID: 35466524 PMCID: PMC9322321 DOI: 10.1111/pcmr.13042] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 04/19/2022] [Accepted: 04/21/2022] [Indexed: 12/14/2022]
Abstract
Metastatic uveal melanoma (UM) is a devastating disease with few treatment options. We evaluated the safety, tolerability and preliminary activity of arginine depletion using pegylated arginine deiminase (ADI‐PEG20; pegargiminase) combined with pemetrexed (Pem) and cisplatin (Cis) chemotherapy in a phase 1 dose‐expansion study of patients with argininosuccinate synthetase (ASS1)‐deficient metastatic UM. Eligible patients received up to six cycles of Pem (500 mg/m2) and Cis (75 mg/m2) every 3 weeks plus weekly intramuscular ADI (36 mg/m2), followed by maintenance ADI until progression (NCT02029690). Ten of fourteen ASS1‐deficient patients with UM liver metastases and a median of one line of prior immunotherapy received ADIPemCis. Only one ≥ grade 3 adverse event of febrile neutropenia was reported. Seven patients had stable disease with a median progression‐free survival of 3.0 months (range, 1.3–8.1) and a median overall survival of 11.5 months (range, 3.2–36.9). Despite anti‐ADI‐PEG20 antibody emergence, plasma arginine concentrations remained suppressed by 18 weeks with a reciprocal increase in plasma citrulline. Tumour rebiopsies at progression revealed ASS1 re‐expression as an escape mechanism. ADIPemCis was well tolerated with modest disease stabilisation in metastatic UM. Further investigation of arginine deprivation is indicated in UM including combinations with immune checkpoint blockade and additional anti‐metabolite strategies.
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Affiliation(s)
- Pui Ying Chan
- Department of Medical Oncology, St Bartholomew's Hospital, Barts Health NHS Trust, London, UK.,Wellcome Sanger Institute, Hinxton, Cambridgeshire, UK
| | - Melissa M Phillips
- Department of Medical Oncology, St Bartholomew's Hospital, Barts Health NHS Trust, London, UK
| | - Stephen Ellis
- Department of Medical Oncology, St Bartholomew's Hospital, Barts Health NHS Trust, London, UK
| | | | - Xiaoxing Feng
- Polaris Pharmaceuticals Inc, San Diego, California, USA
| | - Amit Arora
- Department of Ocular Oncology, Moorfields Eye Hospital, Moorfields Eye Hospital NHS Foundation Trust, London, UK
| | - Gordon Hay
- Department of Ocular Oncology, Moorfields Eye Hospital, Moorfields Eye Hospital NHS Foundation Trust, London, UK
| | - Victoria M L Cohen
- Department of Ocular Oncology, Moorfields Eye Hospital, Moorfields Eye Hospital NHS Foundation Trust, London, UK
| | - Mandeep S Sagoo
- Department of Ocular Oncology, Moorfields Eye Hospital, Moorfields Eye Hospital NHS Foundation Trust, London, UK.,NIHR Biomedical Research Centre for Ophthalmology at Moorfields Eye Hospital and University College London Institute of Ophthalmology, London, UK
| | | | - Michael T Sheaff
- Department of Histopathology, Royal London Hospital, Barts Health NHS Trust, London, UK
| | - Peter W Szlosarek
- Department of Medical Oncology, St Bartholomew's Hospital, Barts Health NHS Trust, London, UK.,Centre for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, UK
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Ren Y, Yan C, Wu L, Zhao J, Chen M, Zhou M, Wang X, Liu T, Yi Q, Sun J. iUMRG: multi-layered network-guided propagation modeling for the inference of susceptibility genes and potential drugs against uveal melanoma. NPJ Syst Biol Appl 2022; 8:18. [PMID: 35610253 PMCID: PMC9130324 DOI: 10.1038/s41540-022-00227-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Accepted: 04/28/2022] [Indexed: 11/17/2022] Open
Abstract
Uveal melanoma (UM) is the most common primary malignant intraocular tumor. The use of precision medicine for UM to enable personalized diagnosis, prognosis, and treatment require the development of computer-aided strategies and predictive tools that can identify novel high-confidence susceptibility genes (HSGs) and potential therapeutic drugs. In the present study, a computational framework via propagation modeling on integrated multi-layered molecular networks (abbreviated as iUMRG) was proposed for the systematic inference of HSGs in UM. Under the leave-one-out cross-validation experiments, the iUMRG achieved superior predictive performance and yielded a higher area under the receiver operating characteristic curve value (0.8825) for experimentally verified SGs. In addition, using the experimentally verified SGs as seeds, genome-wide screening was performed to detect candidate HSGs using the iUMRG. Multi-perspective validation analysis indicated that most of the top 50 candidate HSGs were indeed markedly associated with UM carcinogenesis, progression, and outcome. Finally, drug repositioning experiments performed on the HSGs revealed 17 potential targets and 10 potential drugs, of which six have been approved for UM treatment. In conclusion, the proposed iUMRG is an effective supplementary tool in UM precision medicine, which may assist the development of new medical therapies and discover new SGs.
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Affiliation(s)
- Yueping Ren
- School of Biomedical Engineering, School of Ophthalmology & Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, P. R. China
| | - Congcong Yan
- School of Biomedical Engineering, School of Ophthalmology & Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, P. R. China
| | - Lili Wu
- Tibet Medical College, Beijing University of Chinese Medicine, Tibet, 850010, P. R. China
| | - Jingting Zhao
- School of Biomedical Engineering, School of Ophthalmology & Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, P. R. China
| | - Mingwei Chen
- Department of Human Anatomy, Harbin Medical University, Harbin, 150081, P. R. China
| | - Meng Zhou
- School of Biomedical Engineering, School of Ophthalmology & Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, P. R. China
| | - Xiaoyan Wang
- The Affiliated Ningbo Eye Hospital of Wenzhou Medical University, Ningbo, 315042, P. R. China
| | - Tonghua Liu
- Tibet Medical College, Beijing University of Chinese Medicine, Tibet, 850010, P. R. China.
| | - Quanyong Yi
- The Affiliated Ningbo Eye Hospital of Wenzhou Medical University, Ningbo, 315042, P. R. China.
| | - Jie Sun
- School of Biomedical Engineering, School of Ophthalmology & Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, P. R. China.
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Toro MD, Gozzo L, Tracia L, Cicciù M, Drago F, Bucolo C, Avitabile T, Rejdak R, Nowomiejska K, Zweifel S, Yousef YA, Nazzal R, Romano GL. New Therapeutic Perspectives in the Treatment of Uveal Melanoma: A Systematic Review. Biomedicines 2021; 9:biomedicines9101311. [PMID: 34680428 PMCID: PMC8533164 DOI: 10.3390/biomedicines9101311] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 09/15/2021] [Accepted: 09/21/2021] [Indexed: 12/13/2022] Open
Abstract
Uveal melanoma (UM) is a rare disease, but the most common primary intraocular cancer, mostly localized in the choroid. Currently, the first-line treatment options for UM are radiation therapy, resection, and enucleation. However, although these treatments could potentially be curative, half of all patients will develop metastatic disease, whose prognosis is still poor. Indeed, effective therapeutic options for patients with advanced or metastatic disease are still lacking. Recently, the development of new treatment modalities with a lower incidence of adverse events, a better disease control rate, and new therapeutic approaches, have merged as new potential and promising therapeutic strategies. Additionally, several clinical trials are ongoing to find new therapeutic options, mainly for those with metastatic disease. Many interventions are still in the preliminary phases of clinical development, being investigated in phase I trial or phase I/II. The success of these trials could be crucial for changing the prognosis of patients with advanced/metastatic UM. In this systematic review, we analyzed all emerging and available literature on the new perspectives in the treatment of UM and patient outcomes; furthermore, their current limitations and more common adverse events are summarized.
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Affiliation(s)
- Mario Damiano Toro
- Department of Ophthalmology, University of Zurich, 8091 Zurich, Switzerland; (M.D.T.); (S.Z.)
- Department of General and Pediatric Ophthalmology, Medical University of Lublin, 20079 Lublin, Poland; (R.R.); (K.N.)
| | - Lucia Gozzo
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy; (F.D.); (C.B.); (G.L.R.)
- Clinical Pharmacology Unit, Regional Pharmacovigilance Centre, University Hospital of Catania, 95123 Catania, Italy
- Correspondence: ; Tel.: +39-095-3781757
| | - Luciano Tracia
- Plastic and Reconstructive Surgery Department, American Hospital Dubai, Dubai, United Arab Emirates;
| | - Marco Cicciù
- Department of Biomedical and Dental Sciences, Morphological and Functional Images, University of Messina, AOU ‘G. Martino’, 98124 Messina, Italy;
| | - Filippo Drago
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy; (F.D.); (C.B.); (G.L.R.)
- Clinical Pharmacology Unit, Regional Pharmacovigilance Centre, University Hospital of Catania, 95123 Catania, Italy
- Centre for Research and Consultancy in HTA and Drug Regulatory Affairs (CERD), University of Catania, 95123 Catania, Italy
| | - Claudio Bucolo
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy; (F.D.); (C.B.); (G.L.R.)
- Center of Research in Ocular Pharmacology—CERFO, University of Catania, 95123 Catania, Italy
| | - Teresio Avitabile
- Department of Ophthalmology, University of Catania, 95123 Catania, Italy;
| | - Robert Rejdak
- Department of General and Pediatric Ophthalmology, Medical University of Lublin, 20079 Lublin, Poland; (R.R.); (K.N.)
| | - Katarzyna Nowomiejska
- Department of General and Pediatric Ophthalmology, Medical University of Lublin, 20079 Lublin, Poland; (R.R.); (K.N.)
| | - Sandrine Zweifel
- Department of Ophthalmology, University of Zurich, 8091 Zurich, Switzerland; (M.D.T.); (S.Z.)
| | - Yacoub A. Yousef
- Department of Surgery/Ophthalmology, King Hussein Cancer Center, Amman 11941, Jordan;
| | | | - Giovanni Luca Romano
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy; (F.D.); (C.B.); (G.L.R.)
- Center of Research in Ocular Pharmacology—CERFO, University of Catania, 95123 Catania, Italy
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Comito F, Marchese PV, Ricci AD, Tober N, Peterle C, Sperandi F, Melotti B. Systemic and liver-directed therapies in metastatic uveal melanoma: state-of-the-art and novel perspectives. Future Oncol 2021; 17:4583-4606. [PMID: 34431316 DOI: 10.2217/fon-2021-0318] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Metastatic uveal melanoma (MUM) is the most common form of noncutaneous melanoma. It is different from its cutaneous counterpart and is characterized by a very poor prognosis. Despite groundbreaking improvements in the treatment of cutaneous melanoma, there have been few advances in the treatment of MUM, and standard treatments for MUM have not been defined. We performed a systematic review focusing our attention on all interventional studies, ongoing or already published, concerning the treatment of MUM. We present results from studies of chemotherapy, targeted therapy, immunotherapy and liver-directed therapies. Although the results in this setting have been disappointing until now, trials investigating novel immunotherapeutic strategies alone and in combination with targeted agents and liver-directed therapies are ongoing.
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Affiliation(s)
- Francesca Comito
- Division of Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna.,Department of Experimental, Diagnostic & Specialty Medicine, S. Orsola-Malpighi University Hospital of Bologna 40138, Italy
| | - Paola Valeria Marchese
- Department of Experimental, Diagnostic & Specialty Medicine, S. Orsola-Malpighi University Hospital of Bologna 40138, Italy
| | - Angela Dalia Ricci
- Department of Experimental, Diagnostic & Specialty Medicine, S. Orsola-Malpighi University Hospital of Bologna 40138, Italy
| | - Nastassja Tober
- Department of Experimental, Diagnostic & Specialty Medicine, S. Orsola-Malpighi University Hospital of Bologna 40138, Italy
| | - Chiara Peterle
- Department of Experimental, Diagnostic & Specialty Medicine, S. Orsola-Malpighi University Hospital of Bologna 40138, Italy
| | - Francesca Sperandi
- Division of Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna
| | - Barbara Melotti
- Division of Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna
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6
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Li S, Wu X, Chen P, Pei Y, Zheng K, Wang W, Qiu E, Zhang X. Interferon-α versus interleukin-2 in Chinese patients with malignant melanoma: a randomized, controlled, trial. Anticancer Drugs 2019; 30:402-409. [PMID: 30664008 PMCID: PMC6430598 DOI: 10.1097/cad.0000000000000741] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Accepted: 12/11/2018] [Indexed: 12/13/2022]
Abstract
The US Food and Drug Association has approved interferon-α (IFN-α) and interleukin-2 (IL-2) as adjuvant therapy in malignant melanoma. The objective of the study was to compare efficacy and safety of subcutaneous interferon-α with continuous intravenous IL-2 in Chinese patients with malignant melanoma. A total of 250 patients with unresectable malignant melanoma were subjected to randomized in 1 : 1 ratio. Patients received subcutaneous 9×10 IU/m IFN-α (IFN-α group, n=125) or continuous intravenous 9×10 IU/m IL-2 (IL-2 group, n=125) at every 21 days for 4 months. The response, progression-free survival, overall survival, adverse effects, and cost were evaluated by experts in the field. IL-2 and IFN-α were effective in improvement of malignant melanoma after 4 months of intervention. IL-2 was effective in improving brain metastasis. Patients of the IL-2 group had a higher overall survival (P<0.0001) and a higher progression-free survival (P=0.002) than those of IFN-α group. The IL-2 group reported hypotension, kidney dysfunction, liver dysfunctions, flu-like symptoms, and capillary leak syndrome as adverse effects. IFN-α group reported thrombocytopenia and neutropenia as adverse effects. Healthcare management and expert charges lead to increase in the cost of treatment for IL-2 group patients than IFN-α group (P<0.0001). Continuous intravenous IL-2 should be recommended in relapse-free Chinese patients with malignant melanoma. Level of Evidence: I.
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Affiliation(s)
- Shenglong Li
- Department of Bone and Soft Tissue Tumor Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute
| | - Xixi Wu
- School of Medicine, Ross University School of Medicine, Miramar, Florida, USA
| | - Peng Chen
- The Graduate School, China Medical University, Shenyang, China
| | - Yi Pei
- Department of Bone and Soft Tissue Tumor Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute
| | - Ke Zheng
- Department of Bone and Soft Tissue Tumor Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute
| | - Wei Wang
- Department of Bone and Soft Tissue Tumor Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute
| | - Enduo Qiu
- Department of Bone and Soft Tissue Tumor Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute
| | - Xiaojing Zhang
- Department of Bone and Soft Tissue Tumor Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute
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7
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Shen B, Mao W, Ahn JC, Chung PS, He P. Mechanism of HN‑3 cell apoptosis induced by carboplatin: Combination of mitochondrial pathway associated with Ca2+ and the nucleus pathways. Mol Med Rep 2018; 18:4978-4986. [PMID: 30272304 PMCID: PMC6236313 DOI: 10.3892/mmr.2018.9507] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2018] [Accepted: 08/31/2018] [Indexed: 12/24/2022] Open
Abstract
Laryngeal carcinomas have been recognized as a serious health threat worldwide. In the present study, the mechanism of apoptosis in HN-3 cells induced by carboplatin (CBCDA), a widely used anti-cancer drug, was investigated. The pro-apoptotic effect of CBCDA in HN-3 cells was demonstrated to be time- and dose-dependent. Therefore, the stages of apoptosis were investigated in chronological order. The results demonstrated that excessive generation of cytosolic Ca2+ in HN-3 cells was initially triggered when cells were exposed to CBCDA, followed by the appearance of mitochondrial depolarization and oxidative stress, leading to the release of apoptosis-inducing factor. At later stages, expression of caspase-8 was increased due to the apoptotic signals originating from CBCDA-induced DNA damage, as well as caspase-9 and poly ADP ribose polymerase (PARP) expression upregulation. Glutathione decreased the available CBDCA concentration, decreased apoptosis and alleviating oxidative stress, thus reducing the actual effective concentration. Mechanistic research may benefit the rational design of more efficient therapeutic strategies as well as development of novel platinum-based agents.
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Affiliation(s)
- Bo Shen
- Institute of Radiation Medicine, Fudan University, Shanghai 200032, P.R. China
| | - Wenjing Mao
- Department of Otolaryngology‑Head and Neck Surgery, Shanghai Key Clinical Disciplines of Otorhinolaryngology, Eye and ENT Hospital of Fudan University, Shanghai 200031, P.R. China
| | - Jin-Chul Ahn
- Department of Otolaryngology‑Head and Neck Surgery, Dankook University, Cheonan, Chungcheongnam 330‑715, Republic of Korea
| | - Phil-Sang Chung
- Department of Otolaryngology‑Head and Neck Surgery, Dankook University, Cheonan, Chungcheongnam 330‑715, Republic of Korea
| | - Peijie He
- Department of Otolaryngology‑Head and Neck Surgery, Shanghai Key Clinical Disciplines of Otorhinolaryngology, Eye and ENT Hospital of Fudan University, Shanghai 200031, P.R. China
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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.
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