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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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Tangeretin sensitizes cisplatin-resistant human ovarian cancer cells through downregulation of phosphoinositide 3-kinase/Akt signaling pathway.

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Guizhi Fuling Wan, a Traditional Chinese Herbal Formula, Sensitizes Cisplatin-Resistant Human Ovarian Cancer Cells through Inactivation of the PI3K/AKT/mTOR Pathway.

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Project description:Cisplatin (DDP) resistance in patients suffering from ovarian cancer is a considerable hurdle to successful treatment. The present study aimed to identify a possible long non‑coding RNA (lncRNA)‑microRNA (miRNA)‑mRNA axis participating in ovarian cancer DDP‑resistance based on the critical roles of non‑coding RNAs, including lncRNAs and miRNAs, in carcinogenesis. According to online data and experimental results, lncRNA HAND2‑AS1 expression was significantly downregulated within ovarian carcinoma, especially within recurrent and DDP‑resistant ovarian carcinoma. The expression of HAND2‑AS1 was also shown to be markedly inhibited in SKOV3/DDP (DDP) cells with resistance to DDP. In SKOV3/DDP cells, HAND2‑AS1 overexpression inhibited cell viability and promoted cell apoptosis upon DDP treatment through the Bcl‑2/caspase‑3 apoptotic signaling. It was hypothesized that PTEN mRNA expression was also markedly inhibited in SKOV3/DDP ovarian cancer cells, while HAND2‑AS1 overexpression rescued PTEN proteins and blocked PI3K/AKT signaling activation. Moreover, miR‑106a was found to bind directly to PTEN 3' UTR and HAND2‑AS1. Upon DDP treatment, miR‑106a overexpression in SKOV3/DDP cells promoted cell viability. It inhibited cell apoptosis through the Bcl‑2/caspase‑3 apoptotic signaling pathway and downregulated the protein levels of PTEN and upregulated PI3K/AKT signaling activity. Furthermore, miR‑106a overexpression partially reversed the effect of HAND2‑AS1 overexpression upon PTEN proteins and SKOV3/DDP cell proliferation upon DDP treatment. In conclusion, a lncRNA HAND2‑AS1/miR‑106a/PTEN axis that re‑sensitizes DDP‑resistant SKOV3/DDP cells to DDP treatment has been established.

| S-EPMC8436234 | biostudies-literature

Let-7e sensitizes epithelial ovarian cancer to cisplatin through repressing DNA double strand break repair.

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

Tripterygium glycosides sensitizes cisplatin chemotherapeutic potency by modulating gut microbiota in epithelial ovarian cancer.

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| S-EPMC10560985 | biostudies-literature

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