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Triptolide sensitizes cisplatin-resistant human epithelial ovarian cancer by inhibiting the phosphorylation of AKT.

ABSTRACT: Advanced and chemotherapy-resistant ovarian cancer causes high mortality of ovarian cancer, and it is important to find safe and effective drugs to reduce the chemotherapeutic resistance of ovarian cancer. In our study, we attempted to clarify the resistance mechanisms of SKOV3/DDP cells in vitro and evaluated the sensitization to triptolide (TPL) in vivo. Our results indicated that the overexpression of AKT and p-AKT greatly enhanced the cisplatin (DDP) tolerance of SKOV3/DDP, and the combination of DDP+TPL had a significant tumour inhibition effect compared to DDP treatment (p<0.05), via reducing the expressions of p-PI3K, p-Akt, Survivin, VEGF and MMP-2, and the increase of Caspase-3. Collectively, these results suggest that the synergistic anticancer effect of TPL and DDP warrants their potential clinical applications in further.

SUBMITTER: Huang G

PROVIDER: S-EPMC6590046 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Triptolide sensitizes cisplatin-resistant human epithelial ovarian cancer by inhibiting the phosphorylation of AKT.

Huang Genhua G Hu Hui H Zhang Yao Y Zhu Yinfang Y Liu Junli J Tan Buzhen B Chen Tingtao T

Journal of Cancer 20190602 13

Advanced and chemotherapy-resistant ovarian cancer causes high mortality of ovarian cancer, and it is important to find safe and effective drugs to reduce the chemotherapeutic resistance of ovarian cancer. In our study, we attempted to clarify the resistance mechanisms of SKOV3/DDP cells in vitro and evaluated the sensitization to triptolide (TPL) in vivo. Our results indicated that the overexpression of AKT and p-AKT greatly enhanced the cisplatin (DDP) tolerance of SKOV3/DDP, and ...[more]

PMID: 31281478

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| S-EPMC8436234 | biostudies-literature

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Project description:BackgroundResistance to platinum-based chemotherapy remains a great challenge for ovarian cancer treatment. The human let-7 family contains 13 members located on nine different chromosomes, and most members have been implicated in the modulation of drug sensitivity in cancers. Our previous study showed that deregulation of let-7e in epithelial ovarian cancer (EOC) promoted the development of resistance to cisplatin. In the present study, we aimed to investigate the underlying mechanism and further evaluate the clinical value of let-7e in predicting chemo-response and prognosis in EOC.ResultsIn situ hybridization assays revealed a significantly decreased expression of let-7e in chemo-resistant EOC tissues compared with chemo-sensitive cases. Transfection with let-7e agomir sensitized EOC cells to cisplatin, down-regulated BRCA1 and Rad51 expression, and repressed the repair of cisplatin-induced DNA double strand break, while let-7e inhibitor exerted the opposite effects. In human EOC tissues, BRCA1 and Rad51 levels were increased in the chemo-resistant group compared with the sensitive group and were negatively correlated with let-7e. Low let-7e and high Rad51 were significantly associated with poor progression-free survival and overall survival and multivariate regression analyses showed that let-7e was an independent predictor for overall survival and chemotherapy response in EOC. Receiver operating characteristic analysis indicated that let-7e level was highly predictive of resistance to platinum-taxane chemotherapy with an area under the curve of 0.826.ConclusionsIn EOC, low let-7e leads to activation of BRCA1 and Rad51 expression and subsequent enhancement of DSB repair, which in turn results in cisplatin-resistance. Let-7e is a potential predictor for survival and chemo-response in EOC and re-expression of let-7e might be an effective strategy for overcoming chemo-resistance.

| S-EPMC5379542 | biostudies-literature

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| S-EPMC4911881 | biostudies-literature

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