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Augmenting Tumor-Starvation Therapy by Cancer Cell Autophagy Inhibition.

ABSTRACT: It was recently recognized that cancer therapeutic efficacy may be greatly compromised by an intrinsic protective mechanism called autophagy, by which cancer cells survive in harsh conditions such as starvation. Here, a synergetic strategy is described for cancer treatment by suppressing such a protective mechanism for augmenting tumor-starvation therapy. The synergetic therapy is achieved by restraining glucose metabolism using an antiglycolytic agent to predispose cancer cells to severe energy deprivation; concurrently the downstream autophagic flux and compensatory energy supplies are blocked by the autophagy inhibitor black phosphorus nanosheet. Cancer cells fail to extract their own nutrient to feed themselves, finally succumbing to therapeutic interventions and starving to death. Both in vitro and in vivo results evidence the cooperative effect between the autophagy inhibitor and antiglycolytic agent, which leads to remarkable synergetic antineoplastic outcome. It is expected that such a combinational approach by concurrently blocking exogenous and endogenous nutrition supplies will be beneficial to the design of effective tumor-specific cancer therapies in the future.

SUBMITTER: Yang B

PROVIDER: S-EPMC7080508 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Augmenting Tumor-Starvation Therapy by Cancer Cell Autophagy Inhibition.

Yang Bowen B Ding Li L Chen Yu Y Shi Jianlin J

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20200127 6

It was recently recognized that cancer therapeutic efficacy may be greatly compromised by an intrinsic protective mechanism called autophagy, by which cancer cells survive in harsh conditions such as starvation. Here, a synergetic strategy is described for cancer treatment by suppressing such a protective mechanism for augmenting tumor-starvation therapy. The synergetic therapy is achieved by restraining glucose metabolism using an antiglycolytic agent to predispose cancer cells to severe energy ...[more]

PMID: 32195096

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Project description:BackgroundCancer cells through autophagy-mediated recycling to meet the metabolic demands of growth and proliferation. The steroidal saponin 20(S)-ginsenoside Rh2 effectively inhibits the growth and survival of a variety of tumor cell lines and animal models, but the effects of Rh2 on autophagy remain elusive.MethodsCell viability was measured by CCK-8 (cell counting kit-8) assays. Apoptosis, ROS generation and mitochondrial membrane potential were analyzed by flow cytometry. Western blot analyses were used to determine changes in protein levels. Morphology of apoptotic cells and autophagosome accumulation were analyzed by DAPI staining and transmission electron microscopy. Autophagy induction was monitored by acidic vesicular organelle staining, EGFP-LC3 and mRFP-GFP-LC3 transfection. Atg7 siRNA and autophagy regulator was used to assess the effect of autophagy on apoptosis induced by G-Rh2.ResultsIn this study, we found that low concentration G-Rh2 attenuated cancer cell growth and induced apoptosis upon serum-free starvation. Caspase 3 inhibitors failed to block apoptosis in G-Rh2-treated cells, indicating a caspase-independent mechanism. G-Rh2-treated cells in serum-deprived conditions showed impaired mitochondrial function, increased release and nuclear translocation of apoptosis-inducing factor, but little changes in the mitochondrial and cytoplasmic distributions of cytochrome C. Annexin A2 overexpression in 293T cells inhibited G-Rh2-induced apoptosis under serum-starved conditions. Meanwhile, G-Rh2 reduced lysosomal activity and inhibited the fusion of autophagosome and lysosome, leading to a block of autophagic flux. Knockdown Atg7 significantly inhibited autophagy and triggered AIF-induced apoptosis in serm free condition. The autophagy inducer significantly decreased the apoptosis levels of G-Rh2-treated cells in serum-free conditions.ConclusionsUnder nutrient deficient conditions, G-Rh2 represses autophagy in cervical cancer cells and enhanced apoptosis through an apoptosis-inducing factor mediated pathway.

Dataset Information

Augmenting Tumor-Starvation Therapy by Cancer Cell Autophagy Inhibition.

Publications

Augmenting Tumor-Starvation Therapy by Cancer Cell Autophagy Inhibition.

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