Babao Dan Reverses Multiple-Drug Resistance in Gastric Cancer Cells via Triggering Apoptosis and Autophagy and Inhibiting PI3K/AKT/mTOR Signaling

Jinyan Zhao,Jie Liu,Min Zhang,Zhixue Zhan,Jiumao Lin,Weilan Lan,Bin Guan,Jun Peng,Daniela Russo

doi:10.1155/2021/5631942

Abstract

Multidrug resistance (MDR) is a critical reason for cancer chemotherapy failure. Babaodan (BBD) is a famous traditional Chinese patent medicine reported to have antigastric cancer activity. However, the roles and molecular mechanisms of the reversal of MDR of gastric cancer by BBD have not been well described until now. Therefore, the purpose of this study was to elucidate further the role of BBD in reversing the MDR of gastric cancer cells and its specific regulatory mechanism via in vitro experiments. To verify our results, MTT, Doxorubicin (DOX) staining, Rhodamin123 (Rho123) staining, DAPI staining, Annexin V-FITC, propidium iodide (PI), Cyto-ID, and western blot assays were performed. To determine whether BBD triggers apoptosis and autophagy through the PI3K/AKT/mTOR signaling, we also applied 3-methyladenine (3-MA), chloroquine (CQ), and 740Y-P (an activator of PI3K). The results showed that BBD reversed the MDR and induced apoptosis and autophagy of SGC7901/DDP cells. Pathway analyses suggested BBD inhibits PI3K/AKT/mTOR pathway activity and subsequent apoptosis-autophagy induction. Inhibition of autophagy with 3-MA and chloroquine (CQ) was performed to confirm that BBD promoted autophagy. PI3K agonist, 740Y-P, further verified BBD inhibition of PI3K/AKT/mTOR pathway activation. In conclusion, BBD may reverse the MDR of gastric cancer cells, induce apoptosis, and promote autophagy via inactivation of the PI3K/AKT/mTOR signaling pathway.

Highlights

Gastric cancer (GC) is the third most common cancer worldwide and is associated with high mortality [1, 2]
Western blot results showed that treatment with BBD (0.25, 0.5, or 1.0 mg/mL) significantly reduced the expressions of ABCB1, ABCC1, and ABCG2 compared with the control group (P < 0.05)
We examined whether BBD affects the PI3K/AKT/mammalian target of rapamycin (mTOR) signaling pathway as a mechanism for its effects on the Multidrug resistance (MDR) of GC

Summary

Introduction

Gastric cancer (GC) is the third most common cancer worldwide and is associated with high mortality [1, 2]. Medical advances in gastric cancer have improved, patients’ predictive and overall survival rates remain poor due to their limited and complex response to chemotherapy [5]. Multidrug resistance is the leading cause of low survival time, which leads to the failure of chemotherapy for tumors and limited efficacy in most patients with gastric cancer. One mechanism mediating MDR is through the regulation of cancer cell apoptosis and autophagy by anticancer medications [9]. Another critical mechanism involves the increased outflow of drugs from cancer cells by upregulated transport proteins that rely on specific energy sources such as ABCB1, ABCC1, and ABCG2 [10]. Other mechanisms that may contribute to drug resistance include EMT, DNA damage repair, drug target mutations, and stem cell modification [11, 12]

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