Delicaflavone Reverses Cisplatin Resistance via Endoplasmic Reticulum Stress Signaling Pathway in Non-Small Cell Lung Cancer Cells

Xuewen Wang; Bing Chen; Danfen Xu; Zhijun Li; Yuxia Sui; Xinhua Lin

doi:10.2147/OTT.S255586

Delicaflavone Reverses Cisplatin Resistance via Endoplasmic Reticulum Stress Signaling Pathway in Non-Small Cell Lung Cancer Cells

Onco Targets Ther. 2020 Oct 13:13:10315-10322. doi: 10.2147/OTT.S255586. eCollection 2020.

Authors

Xuewen Wang^#¹, Bing Chen^#^{1

2

3}, Danfen Xu¹, Zhijun Li⁴, Yuxia Sui^{5

6}, Xinhua Lin^{1

2

3}

Affiliations

¹ Department of Pharmaceutical Analysis, School of Pharmacy, Fujian Medical University, Fuzhou, Fujian, People's Republic of China.
² Nano Medical Technology Research Institute, Fujian Medical University, Fuzhou, Fujian, People's Republic of China.
³ Higher Educational Key Laboratory for Nano Biomedical Technology of Fujian Province, Fujian Medical University, Fuzhou, Fujian, People's Republic of China.
⁴ School of Pharmacy, Fujian Medical University, Fuzhou 350180, Fujian, People's Republic of China.
⁵ Department of Pharmacy, Shengli Clinical Medical College of Fujian Medical University, Fuzhou 350001, People's Republic of China.
⁶ Department of Pharmacy, Fujian Provincial Hospital, Fuzhou 350001, People's Republic of China.

^# Contributed equally.

Abstract

Background: The incidence and mortality of lung cancer continue to increase around the world; in 2018, new lung cancer cases accounted for 11.6% of all cancer cases, and lung cancer deaths accounted for 18.4% of cancer deaths. Cisplatin (DDP) is a first-line chemotherapy drug for lung cancer; however, DDP resistance can lead to a poor prognosis in patients with lung cancer. Therefore, reversing DDP resistance is a treatment goal.

Materials and methods: Cell counting kit-8 (CCK8) assays, wound healing analyses, Transwell assays, in vitro tumor xenografts, and flow cytometry were used to detect the proliferation, migration, invasion, and apoptosis of multidrug resistant A549/DDP and PC9/DDP cells, respectively. Western blot was performed to detect protein levels of cleaved caspase-3, CHOP, and GRP78.

Results: Delicaflavone inhibited DDP resistance of lung cancer cells and decreased proliferation in a dose- and time-dependent manner. It also decreased migration and invasion and enhanced apoptosis. Western blots showed that delicaflavone overcame DDP resistance by increasing the expression of GRP78 and CHOP and the apoptosis-related protein cleaved caspase-3.

Conclusion: Delicaflavone can reverse DDP resistance in A549/DDP and PC9/DDP cells by inhibiting cell proliferation and migration and enhancing apoptosis and cleaved caspase-3 levels by increasing the expression of CHOP and GRP78 protein via the endoplasmic reticular stress pathway. It could be a useful therapeutic adjunct to treat DDP-resistant lung cancer.

Keywords: Cisplatin; DDP; delicaflavone; endoplasmic reticulum stress; lung cancer.

Grants and funding

The authors gratefully acknowledge the financial supports of the National Natural Science Foundation of China (21775023), Joint Funds for the innovation of science and Technology of Fujian province (2017Y9123, 2017Y9124 and 2018Y9076), Health and Youth Research Project of Fujian province (2019-1-60), Funds for scientific research start-up of high-level talents of Fujian Medical University (XRCZX2018020), Guiding Project of Science and Technology Plan of Fujian Province (Grant number 2018Y0011), The Young and Middle-aged Talents Training Project of Fujian Provincial Health Commission (Grant number 2018-ZQN-3), and Sailing Funds of Fujian Medical University (2018QH2013and 2018QH1016).