Plumbagin Enhances the Anticancer Efficacy of Cisplatin by Increasing Intracellular ROS in Human Tongue Squamous Cell Carcinoma.

Danfeng Xue,Qun Zhou,Fei He,Hui Yu,Fangfei Ye,Fanzhe Shi,Jiaxuan Qiu,Xiongming Zhou,Shu-Ting Pan

doi:10.1155/2020/5649174

Danfeng Xue, Qun Zhou + Show 7 more

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https://doi.org/10.1155/2020/5649174

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Abstract

Cisplatin is widely used in the treatment of tongue squamous cell carcinoma (TSCC), but its clinical efficacy is limited by drug resistance and toxic side effects. Hence, a novel compound capable of enhancing the anticancer effect of cisplatin while reducing the side effects is urgently needed. We have previously shown that plumbagin (PLB), an anticancer phytochemical, is able to inhibit the growth of TSCC in vitro and in vivo. The objective of this study was to investigate the effect of PLB in reversing the resistance of TSCC to cisplatin as well as its molecular mechanisms. Here, we found that PLB enhances cisplatin-induced cytotoxicity, apoptosis, and autophagy in CAL27 and cisplatin-resistant CAL27/CDDP cells. PLB could inhibit the viability and growth of TSCC cells by increasing the production of intracellular reactive oxygen species (ROS). In addition, the combination treatment of PLB and cisplatin resulted in a synergistic inhibition of TSCC viability, apoptosis, and autophagy by increasing intracellular ROS, which may be achieved by activating JNK and inhibiting AKT/mTOR signaling pathways. Finally, the synergistic treatment was also demonstrated in vivo. Therefore, PLB combined with cisplatin is a potential therapeutic strategy against therapy TSCC cisplatin resistance.

Highlights

Tongue squamous cell carcinoma (TSCC), the most common malignant tumor of the oral region, is well known for its high rate of lymph node metastasis and poor prognosis [1, 2]
We explored whether PLB could synergistically enhance CDDP-mediated cytotoxic effects in TSCC cells
Our findings suggest that PLB combined with CDDP synergistically inhibits the viability of TSCC cells and has a better inhibition on CAL27/CDDP cells

Summary

Introduction

Tongue squamous cell carcinoma (TSCC), the most common malignant tumor of the oral region, is well known for its high rate of lymph node metastasis and poor prognosis [1, 2]. Combination chemotherapy based on cisplatin (cis-diamminedichloroplatinum II, CDDP) is the standard treatment for many types of cancers, including TSCC. In the past few decades, despite the significant development in understanding the chemotherapy resistance mechanisms, no substantial progress has been made in overcoming cisplatin resistance. It is urgent to explore a novel therapeutic strategy to reverse the resistance of cisplatin while minimizing the toxic effect on patients. Phytochemicals are naturally occurring plant-derived compounds that have been widely used to treat a variety of malignant tumors due to their availability, biological activity, and nontoxic effects [4]. Emerging evidence suggests that numerous phytochemicals can reverse the resistance of various malignancies to cisplatin while counteracting organ toxicity caused by cisplatin [5,6,7]. In many types of malignancies, phytochemicals are candidates for overcoming cisplatin resistance. Our previous studies found that PLB has a significant inhibitory effect on the proliferation of TSCC in vitro

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