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

Li Han,Xiaojuan Guo,Hua Bian,Lei Yang,Wenhua Zang,Jingke Yang,Zhong Chen

doi:10.1155/2016/4651949

Abstract

The aim of the study was to explore the possible mechanisms that Guizhi Fuling Wan (GFW) enhances the sensitivity of the SKOV3/DDP ovarian cancer cells and the resistant xenograft tumours to cisplatin. Rat medicated sera containing GFW were prepared by administering GFW to rats, and the primary bioactive constituents of the sera were gallic acid, paeonol, and paeoniflorin analysed by HPLC/QqQ MS. Cell counting kit-8 analysis was shown that coincubation of the sera with cisplatin/paclitaxel enhanced significantly the cytotoxic effect of cisplatin or paclitaxel in SKOV3/DDP cells. The presence of the rat medicated sera containing GFW resulted in an increase in rhodamine 123 accumulation by flow cytometric assays and a decrease in the protein levels of P-gp, phosphorylation of AKT at Ser473, and mTOR in a dose-dependent manner in SKOV3/DDP cells by western blot analysis, but the sera had no effect on the protein levels of PI3K p110α and total AKT. The low dose of GFW enhanced the anticancer efficacy of cisplatin and paclitaxel treatment in resistant SKOV3/DDP xenograft tumours. GFW could sensitize cisplatin-resistant SKOV3/DDP cells by inhibiting the protein level and function of P-gp, which may be medicated through inactivation of the PI3K/AKT/mTOR pathway.

Highlights

Ovarian cancer (OC) is the most lethal of the gynaecological malignancies, largely due to the concealed pathogenesis of OC and advanced stage (FIGO stages III and IV) at diagnosis in most patients [1]
Stordal et al demonstrated that the recurrence/drug resistance in OC patients treated with first-line platinum/taxane chemotherapy was related to the overexpression of Pglycoprotein (P-gp) [4]
Blank sera samples were screened and found to be free of interference from endogenous components or other sources at the same mass transitions (Figure 1(a)); the retention times (RTs) for gallic acid, paeonol, and paeoniflorin standards (Figure 1(b)) in the spiked sera samples were the same as those detected for three bioactive constituents in the rat medicated sera (Figure 1(c)), indicating that the 3 potent multidrug resistance (MDR) inhibitors were present in the rat medicated sera

Summary

Introduction

Ovarian cancer (OC) is the most lethal of the gynaecological malignancies, largely due to the concealed pathogenesis of OC and advanced stage (FIGO stages III and IV) at diagnosis in most patients [1]. Most ovarian cancer patients will respond to initial chemotherapy, but the long-term survival remains poor as a result of recurrence and drug resistance, leading to a 5-year survival rate of 46% [3]. Stordal et al demonstrated that the recurrence/drug resistance in OC patients treated with first-line platinum/taxane chemotherapy was related to the overexpression of Pglycoprotein (P-gp) [4]. Other studies have shown that the main mechanism of drug resistance was due to Pgp expression in doxorubicin-, vincristine-, and paclitaxelresistant OC cell lines [5] and in OC patients [6]. Because Pgp overexpression plays an important role in the recurrence or drug resistance in OC chemotherapy, it is a problem that should be solved quickly to identify P-gp inhibitors and improve the chemotherapy sensitivity for OC patients

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