A small compound spindlactone A sensitizes human endometrial cancer cells to TRAIL-induced apoptosis via the inhibition of NAD(P)H dehydrogenase quinone 1

作者：Zhao, Xiang-Zhai; Wu, Xiao-Hua^*

来源：OncoTargets and Therapy, 2018, 11: 3609-3617.

DOI：10.2147/OTT.S165723

• dicoumarol derivative
• SPL-A
• endometrial carcinoma
• TRAIL
• Bcl-2
• apoptosis
• NQO1

Introduction: Spindlactonc A (SPL-A) is a novel small molecule inhibitor of TACC3 that selectively inhibits the nucleation of centnnome microtubules and induces mitotic arrest in ovarian cancer cells. SPL-A is derived from dicoumarol which inhibits the activity of NAD(P)H dehydrogenase quinone oxidoreductase 1 (NQO1). This study aimed to investigate the mechanism by which SPL-A enhances TRAIL-induced apoptosis in endometrial carcinoma cells.
Materials and methods: Endometrial carcinoma cells were treated with SPL-A and/or TRAIL, and the apoptosis and protein expression in the treated cells were examined.
Results: Combined treatment with SPL-A and TRAIL significantly induced apoptosis in various human endometrial carcinoma cells, but not in normal human endometrial strom al cells and endometrial epithelial cells. Notably, both NQOI inhibitor ES936 and NQO1 siRNA enhanced TRAIL-induced apoptosis of endometrial carcinoma cells. Furthermore, SPL-A downregulated the expression of c-FLIP, Bcl-2, Bcl-xl, and Mcl-1, while increasing p53 expression.
Conclusion: In particular, luciferase assay showed that SPL-A inhibited Bc1-2 promoter activity, and p53 inhibitor PFT-alpha could reverse the effect of SPL-A on Bcl-2 expression. Moreover, Bcl-2 overexpression inhibited the apoptosis induced by SPL-A and TRAIL. Taken together, our results suggest that SPL-A sensitizes endometrial cancer cells to TRAIL-induced apoptosis via the regulation of apoptosis-related proteins and the inhibition of NQO1 activity.

• 出版日期2018
• 单位河北医科大学