Chang Chao-Hsiang, Lee Chao-Ying, Lu Chi-Cheng, Tsai Fuu-Jen, Hsu Yuan-Man, Tsao Je-Wei, Juan Yu-Ning, Chiu Hong-Yi, Yang Jai-Sing, Wang Ching-Chiung
School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 110, Taiwan, R.O.C.
School of Pharmacy, China Medical University, Taichung 404, Taiwan, R.O.C.
Int J Oncol. 2017 Mar;50(3):873-882. doi: 10.3892/ijo.2017.3866. Epub 2017 Jan 30.
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.
白藜芦醇是一种有效的化学预防植物化学物质，对多种肿瘤细胞具有活性。然而，耐药性的增加给口腔癌的治疗带来了挑战。在本研究中，我们探讨了白藜芦醇在顺铂耐药的人口腔癌细胞CAR中的口腔抗肿瘤活性及其机制。我们的结果表明，白藜芦醇对正常口腔细胞的毒性极低，并通过吖啶橙（AO）和单丹磺酰尸胺（MDC）染色诱导CAR细胞发生自噬性细胞死亡，形成酸性囊泡细胞器（AVO）和自噬泡。白藜芦醇诱导的CAR细胞凋亡过程中出现了DNA片段化或DNA凝聚。III类磷脂酰肌醇3激酶（3-MA）和AMP激活的蛋白激酶（AMPK）（化合物c）的抑制剂抑制了白藜芦醇诱导的自噬泡形成、LC3-II蛋白水平和自噬。泛半胱天冬酶抑制剂Z-VAD-FMK减弱了白藜芦醇诱导的半胱天冬酶-9切割、半胱天冬酶-3切割和细胞凋亡。白藜芦醇还增强了AMPK的磷酸化，并调节了白藜芦醇处理的CAR细胞中自噬和促凋亡相关信号。重要的是，白藜芦醇还刺激了CAR细胞中自噬mRNA基因的表达，包括Atg5、Atg12、Beclin-1和LC3-II。总体而言，我们的研究结果表明，白藜芦醇可能诱导耐药口腔癌细胞发生自噬和凋亡死亡，并可能在不久的将来成为口腔癌治疗的新方法。
