Autophagy inhibition enhances colorectal cancer apoptosis induced by dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235

Yang, Xiaoyu; Niu, Bingxuan; Wang, Libo; Chen, Mei‐Ling; Kang, Xiao-Chun; Wang, Luonan; Ji, Yinghua; Zhong, Jiateng

doi:10.3892/ol.2016.4590

Cited by 24 publications

(13 citation statements)

References 41 publications

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“…It is an imidazo [4,5-c] quinoline derivative compound that binds to the ATP-binding cleft of PI3K and mTOR kinase, inhibiting their catalytic activities [25]. BEZ235 exhibited satisfactory anticancer effects in preclinical studies in several types of cancer, including the following: triple-negative breast cancer, lung cancer, melanoma, colorectal cancer, renal cancer, prostate cancer, lymphoma, and mucinous adenocarcinoma of the ovary [73][74][75][76][77][78][79][80][81][82][83][84][85]. However, the clinical trials of BEZ235 were not satisfactory.…”

Section: Dual Pi3k/mtor Inhibitors Nvp-bez235 (Dactolisib)mentioning

confidence: 99%

Targeting PI3K in cancer: mechanisms and advances in clinical trials

et al. 2019

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Phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling is one of the most important intracellular pathways, which can be considered as a master regulator for cancer. Enormous efforts have been dedicated to the development of drugs targeting PI3K signaling, many of which are currently employed in clinical trials evaluation, and it is becoming increasingly clear that PI3K inhibitors are effective in inhibiting tumor progression. PI3K inhibitors are subdivided into dual PI3K/mTOR inhibitors, pan-PI3K inhibitors and isoform-specific inhibitors. In this review, we performed a critical review to summarize the role of the PI3K pathway in tumor development, recent PI3K inhibitors development based on clinical trials, and the mechanisms of resistance to PI3K inhibition.

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Section: Dual Pi3k/mtor Inhibitors Nvp-bez235 (Dactolisib)mentioning

confidence: 99%

Targeting PI3K in cancer: mechanisms and advances in clinical trials

et al. 2019

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“…Hence, inhibition of mTORC1 unleashes autophagy and provides salvaged metabolites to cancer cells thereby allowing their growth and proliferation. Pre-clinical studies combining mTOR and autophagy inhibition displayed synergistic cytotoxic effects [315]. In a phase I clinical trial, significant anti-tumor activity was observed in melanoma patients treated with both temsirolimus and hydroxychloroquine, an autophagy inhibitor [316].…”

Section: Co-targeting Mtor and Metabolismmentioning

confidence: 99%

Targeting mTOR and Metabolism in Cancer: Lessons and Innovations

Magaway

Kim

Jacinto

2019

Cells

165

128

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Cancer cells support their growth and proliferation by reprogramming their metabolism in order to gain access to nutrients. Despite the heterogeneity in genetic mutations that lead to tumorigenesis, a common alteration in tumors occurs in pathways that upregulate nutrient acquisition. A central signaling pathway that controls metabolic processes is the mTOR pathway. The elucidation of the regulation and functions of mTOR can be traced to the discovery of the natural compound, rapamycin. Studies using rapamycin have unraveled the role of mTOR in the control of cell growth and metabolism. By sensing the intracellular nutrient status, mTOR orchestrates metabolic reprogramming by controlling nutrient uptake and flux through various metabolic pathways. The central role of mTOR in metabolic rewiring makes it a promising target for cancer therapy. Numerous clinical trials are ongoing to evaluate the efficacy of mTOR inhibition for cancer treatment. Rapamycin analogs have been approved to treat specific types of cancer. Since rapamycin does not fully inhibit mTOR activity, new compounds have been engineered to inhibit the catalytic activity of mTOR to more potently block its functions. Despite highly promising pre-clinical studies, early clinical trial results of these second generation mTOR inhibitors revealed increased toxicity and modest antitumor activity. The plasticity of metabolic processes and seemingly enormous capacity of malignant cells to salvage nutrients through various mechanisms make cancer therapy extremely challenging. Therefore, identifying metabolic vulnerabilities in different types of tumors would present opportunities for rational therapeutic strategies. Understanding how the different sources of nutrients are metabolized not just by the growing tumor but also by other cells from the microenvironment, in particular, immune cells, will also facilitate the design of more sophisticated and effective therapeutic regimen. In this review, we discuss the functions of mTOR in cancer metabolism that have been illuminated from pre-clinical studies. We then review key findings from clinical trials that target mTOR and the lessons we have learned from both pre-clinical and clinical studies that could provide insights on innovative therapeutic strategies, including immunotherapy to target mTOR signaling and the metabolic network in cancer.

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“…oxaliplatin [ 24 , 25 ]), targeted therapy (e.g. celecoxib and an antagonist of Bcl-2/Bcl-xL [ 26 ], PI3K/mTOR inhibitor [ 27 ], BRAF inhibitor [ 28 ], niacin and tumor necrosis factor-related apoptosis-inducing ligand [ 29 ], store-operated Ca 2+ entry inhibitor [ 30 ], SN-38/CPT-11 [ 31 ]), other compounds or extracts (e.g. icaritin [ 32 ], tetrandrine [ 33 ], apigenin [ 34 ], purvalanol [ 35 ]), radiation therapy [ 36 ] and photodynamic therapy [ 37 ].…”

Section: Introductionmentioning

confidence: 99%

Interplay between apoptosis and autophagy in colorectal cancer

et al. 2017

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Autophagy and apoptosis are two pivotal mechanisms in mediating cell survival and death. Cross-talk of autophagy and apoptosis has been documented in the tumorigenesis and progression of cancer, while the interplay between the two pathways in colorectal cancer (CRC) has not yet been comprehensively summarized. In this study, we outlined the basis of apoptosis and autophagy machinery firstly, and then reviewed the recent evidence in cellular settings or animal studies regarding the interplay between them in CRC. In addition, several key factors that modulate the cross-talk between autophagy and apoptosis as well as its significance in clinical practice were discussed. Understanding of the interplay between the cell death mechanisms may benefit the translation of CRC treatment from basic research to clinical use.

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Autophagy inhibition enhances colorectal cancer apoptosis induced by dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235

Cited by 24 publications

References 41 publications

Targeting PI3K in cancer: mechanisms and advances in clinical trials

Targeting PI3K in cancer: mechanisms and advances in clinical trials

Targeting mTOR and Metabolism in Cancer: Lessons and Innovations

Interplay between apoptosis and autophagy in colorectal cancer

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