7 results on '"Amaravadi, Ravi K."'
Search Results
2. Targeting the unfolded protein response in cancer.
- Author
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Ojha, Rani and Amaravadi, Ravi K.
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CANCER cells , *CELLULAR pathology , *ENDOPLASMIC reticulum , *HOMEOSTASIS , *DENATURATION of proteins , *PROTEIN renaturation - Abstract
Cancer cells are exposed to various intrinsic and extrinsic factors that disrupt protein homeostasis, producing endoplasmic reticulum (ER) stress. To cope with these situations, cancer cells evoke a highly conserved adaptive mechanism called the unfolded protein response (UPR) to restore the ER homeostasis. Recently, several pharmacological agents have been found to exhibit anti-tumor activity by targeting the UPR components. The development of potent and specific compounds that target the UPR components has not only shed light on the regulation of the UPR in cancer cells, but also brought the field closer to clinical drug candidates. Here we present an overview of the milestones in the field of UPR biology in cancer with a focus on new strategies for pharmacological inhibition. [ABSTRACT FROM AUTHOR]
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- 2017
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3. Recent advances in targeting autophagy in cancer.
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Jain, Vaibhav, Singh, Mahendra Pal, and Amaravadi, Ravi K.
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AUTOPHAGY , *WASTE recycling , *TUMOR growth , *DRUG development , *CANCER cells - Abstract
Autophagy is a degradative and recycling process that is upregulated in cancer cells. New advances in understanding the mechanism of autophagy have uncovered novel potential targets for drug development. Clinical trials involving hydroxychloroquine have demonstrated the safety of targeting autophagy, but efficacy could be improved. Autophagy regulates tumor immunity. Novel autophagy inhibitors are entering clinical trials. Autophagy is a cellular homeostasis mechanism that fuels the proliferation and survival of advanced cancers by degrading and recycling organelles and proteins. Preclinical studies have identified that within an established tumor, tumor cell autophagy and host cell autophagy conspire to support tumor growth. A growing body of evidence suggests that autophagy inhibition can augment the efficacy of chemotherapy, targeted therapy, or immunotherapy to enhance tumor shrinkage. First-generation autophagy inhibition trials in cancer using the lysosomal inhibitor hydroxychloroquine (HCQ) have produced mixed results but have guided the way for the development of more potent and specific autophagy inhibitors in clinical trials. In this review, we will discuss the role of autophagy in cancer, newly discovered molecular mechanisms of the autophagy pathway, the effects of autophagy modulation in cancer and host cells, and novel autophagy inhibitors that are entering clinical trials. [ABSTRACT FROM AUTHOR]
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- 2023
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4. Autophagy: a targetable linchpin of cancer cell metabolism
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Leone, Robert D. and Amaravadi, Ravi K.
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AUTOPHAGY , *CANCER cells , *CELL metabolism , *CELLULAR signal transduction , *ORGANELLES , *ONCOGENES - Abstract
Cancer cells display several features of aberrant cellular metabolism. Two consequences of this dysregulated metabolism are rapid depletion of intracellular nutrients and a buildup of aggregated proteins and damaged organelles. Autophagy provides a mechanism for recycling proteins, lipids, and organelles. In cancer cells, oncogenes and conditions of severe stress drive profound upregulation of autophagy. In this setting, autophagy ameliorates the ill effects of dysregulated cellular metabolism, allowing a steady supply of nutrients and removal of damaged organelles. Although therapeutic strategies targeting cancer cell metabolism and autophagy are already entering clinical trials, further study of the precise mechanisms of interplay between oncogenic signaling, cellular metabolism, and autophagy will provide more effective strategies in the future. [ABSTRACT FROM AUTHOR]
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- 2013
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5. Autophagy inhibitor Lys05 has single-agent antitumor activity and reproduces the phenotype of a genetic autophagy deficiency.
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McAfee, Quentin, Zhihui Zhang, Samanta, Arabinda, Levi, Samuel M., Xiao-Hong Ma, Shengfu Piao, Lynch, John P., Uehara, Takeshi, Sepulveda, Antonia R., Davis, Lisa E., Winkler, Jeffrey D., and Amaravadi, Ravi K.
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AUTOPHAGY ,TUMOR growth ,ANTINEOPLASTIC agents ,CANCER cells ,CLINICAL medicine ,MEDICAL research - Abstract
Autophagy is a lysosome-dependent degradative process that protects cancer cells from multiple stresses. In preclinical models, autophagy inhibition with chloroquine (CQ) derivatives augments the efficacy of many anticancer therapies, but CQ has limited activity as a single agent. Clinical trials are underway combining anticancer agents with hydroxychloroquine (HCQ), but concentrations of HCQ required to inhibit autophagy are not consistently achievable in the clinic. We report the synthesis and characterization of bisaminoquinoline autophagy inhibitors that potently inhibit autophagy and impair tumor growth in vivo. The structural motifs that are necessary for improved autophagy inhibition compared with CQ include the presence of two aminoquinoline rings and a triamine linker and C-7 chlorine. The lead compound, Lys01, is a 10-fold more potent autophagy inhibitor than HCQ. Compared with HCQ, Lys05, a water-soluble salt of Lys01, more potently accumulates within and deacidifies the lysosome, resulting in impaired autophagy and tumor growth. At the highest dose administered, some mice develop Paneth cell dysfunction that resembles the intestinal phenotype of mice and humans with genetic defects in the autophagy gene ATG16L1, providing in vivo evidence that Lys05 targets autophagy. Unlike HCQ, significant single-agent antitumor activity is observed without toxicity in mice treated with lower doses of Lys05, establishing the therapeutic potential of this compound in cancer. [ABSTRACT FROM AUTHOR]
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- 2012
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6. PUMA: A Puzzle Piece in Chloroquine's Antimelanoma Activity.
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Amaravadi, Ravi K
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CHLOROQUINE , *CANCER cells , *MELANOMA , *GENE targeting , *LYSOSOMES , *AUTOPHAGY - Abstract
Chloroquine (CQ) can induce cell death in a subset of cancer cell lines, and some melanoma cell lines are quite susceptible. Although it is well known that CQ impairs lysosomal function and can serve as an autophagy inhibitor, the molecular target of CQ and the subsequent cascade of events that lead to cell death are not fully understood. Recent evidence indicates that in melanoma cell lines, CQ induces apoptosis by preventing degradation of the pro-apoptotic BH3-only protein p53-upregulated modulator of apoptosis. This finding adds to the unfolding story of CQ's mechanism of action as a cancer therapeutic agent. [ABSTRACT FROM AUTHOR]
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- 2013
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7. A Potent Autophagy Inhibitor (Lys05) Enhances the Impact of Ionizing Radiation on Human Lung Cancer Cells H1299.
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Cechakova, Lucie, Ondrej, Martin, Pavlik, Vojtech, Jost, Petr, Cizkova, Dana, Bezrouk, Ales, Pejchal, Jaroslav, Amaravadi, Ravi K., Winkler, Jeffrey D., and Tichy, Ales
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IONIZING radiation ,CANCER cells ,LUNG cancer ,LYSOSOMES ,TRANSMISSION electron microscopy ,FLUORESCENCE microscopy - Abstract
Autophagy inhibition through small-molecule inhibitors is one of the approaches to increase the efficiency of radiotherapy in oncological patients. A new inhibitor—Lys05—with the potential to accumulate within lysosomes and to block autophagy was discovered a few years ago. Several studies have addressed its chemosensitizing effects but nothing is known about its impact in the context of ionizing radiation (IR). To describe its role in radiosensitization, we employed radioresistant human non-small cell lung carcinoma cells (H1299, p53-negative). Combined treatment of H1299 cells by Lys05 together with IR decreased cell survival in the clonogenic assay and real-time monitoring of cell growth more than either Lys05 or IR alone. Immunodetection of LC3 and p62/SQSTM1 indicated that autophagy was inhibited, which correlated with increased SQSTM1 and decreased BNIP3 gene expression determined by qRT-PCR. Fluorescence microscopy and flow cytometry uncovered an accumulation of lysosomes. Similarly, transmission electron microscopy demonstrated the accumulation of autophagosomes confirming the ability of Lys05 to potentiate autophagy inhibition in H1299 cells. We report here for the first time that Lys05 could be utilized in combination with IR as a promising future strategy in the eradication of lung cancer cells. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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