Resveratrol-induced autophagy and apoptosis in cisplatin-resistant human oral cancer CAR cells: A key role of AMPK and Akt/mTOR signaling

Abstract

Resveratrol is known to be an effective chemo-preventive phytochemical against multiple tumor cells. However, the increasing drug resistance avoids the cancer treatment in oral cavity cancer. In this study, we investigated the oral antitumor activity of resveratrol and its mechanism in cisplatin-resistant human oral cancer CAR cells. Our results demonstrated that resveratrol had an extremely low toxicity in normal oral cells and provoked autophagic cell death to form acidic vesicular organelles (AVOs) and autophagic vacuoles in CAR cells by acridine orange (AO) and monodansylcadaverine (MDC) staining. Either DNA fragmentation or DNA condensation occurred in resveratrol-triggered CAR cell apoptosis. These inhibitors of PI3K class III (3-MA) and AMP-activated protein kinase (AMPK) (compound c) suppressed the autophagic vesicle formation, LC3-II protein levels and autophagy induced by resveratrol. The pan-caspase inhibitor Z-VAD-FMK attenuated resveratrol-triggered cleaved caspase-9, cleaved caspase-3 and cell apoptosis. Resveratrol also enhanced phosphorylation of AMPK and regulated autophagy- and pro-apoptosis-related signals in resveratrol-treated CAR cells. Importantly, resveratrol also stimulated the autophagic mRNA gene expression, including Atg5, Atg12, Beclin-1 and LC3-II in CAR cells. Overall, our findings indicate that resveratrol is likely to induce autophagic and apoptotic death in drug-resistant oral cancer cells and might become a new approach for oral cancer treatment in the near future.

Autophagy and its link to type II diabetes mellitus

“…(5) Pepstatin A inhibits lysosomal protein degradation. (6) Resveratrol induces autophagy through activation of AMPK and (7) Tunicamycin is a glycosylation inhibitor that induces autophagy [55, 90, 91]. …”

Autophagy: A Role in the Apoptosis, Survival, Inflammation, and Development of the Retina

“…For example, Torin1 and the mTOR inhibitor rapamycin can induce autophagy [22,23]. 3-Methyladenine (3-MA) blocks the formation of autophagosomes by inhibiting class III PI3K [24]. Bafilomycin A1 inhibits lysosome acidification and lysosome degradation by inhibiting V-ATPase.…”

YC-1 induces G0/G1phase arrest and mitochondria-dependent apoptosis in cisplatin-resistant human oral cancer CAR cells

“…However, surgery, radiotherapy and chemotherapy did not significantly improve the overall survival rate of oral cancer patients. On top of that, the development of drug resistance in the duration of chemotherapy remains as a clinical obstacle [18, 19]. To meet the need, designing novel compounds as well as discovering new targeting molecules that can overcome the resistance to chemotherapeutic drugs in oral cancer are clinically important.…”