Triptolide potentiates lung cancer cells to cisplatin-induced apoptosis by selectively inhibiting the NER activity

Biomarker Research

Gan Wang¹  Xing Wang²  Xiaoxin Xu¹ 

[1] Institute of Environmental Health Sciences, Wayne State University, 259 Mack Avenue, Detroit 48201, MI, USA

[2] Array Bridge Inc., St. Louis, MO, USA

关键词: Potentiation of lung cancer cells;    Inhibition of NER;    NER;    Apoptosis;    Lung cancer cells;    Triptolide;    Cisplatin;   

Others  :  1219054
DOI  :  10.1186/s40364-015-0043-2

 received in 2015-05-19, accepted in 2015-06-27,  发布年份 2015

【 摘 要 】

Background

Cisplatin and many other platinum-based compounds are important anticancer drugs that are used in treating many cancer types. The development of cisplatin-resistant cancer cells, however, quickly diminishes the effectiveness of these drugs and causes treatment failure. New strategies that reverse cancer cell drug resistance phenotype or sensitize cancer cells to these drugs, therefore, need to be explored in order to improve platinum drug-based cancer treatment. Triptolide is a bioactive ingredient isolated from Tripterygium wilfordii, a Chinese herbal medicine. Triptolide binds to the TFIIH basal transcription factor and is required for both transcription and nucleotide excision repair (NER), a DNA repair pathway involved in repairing DNA damage generated by the platinum-based anticancer drugs.

Methods

Caspase-3 activation and cell growth inhibition assays were used to determine the effect of triptolide on cisplatin-induced apoptosis and cell growth in lung cancer cells. Real time PCR, immunoblotting, and expression of reef coral red protein were used to determine a mechanism through which the presence of triptolide increased cisplatin-induced apoptosis of the lung cancer cells.

Results

Our caspase-3 activation studies demonstrated that the presence of low-levels of triptolide greatly increased the cisplatin-induced apoptosis of HTB182, A549, CRL5810, and CRL5922 lung cancer cells. The results of our cell growth inhibition studies revealed that the presence of low-levels triptolide itself had little effect on cell growth but greatly enhanced cisplatin-induced cell growth inhibition in both A549 and HTB182 cells. The results of our reef coral-red protein reporter expression studies indicated that the presence of low-levels triptolide did not affect expression of the reef coral-red protein from pDsRed2-C1 plasmid but greatly inhibited expression of the reef coral-red protein from cisplatin-damaged pDsRed2-C1 plasmid DNA in A549 cells. In addition, the results of our protein phosphorylation studies indicated that the presence of low-levels triptolide caused a decrease for cisplatin-induced CHK1 phosphorylation at Ser ^317/345but an increase for cisplatin-induced ATM phosphorylation at Ser ¹⁹⁸¹in both HTB182 and A549 cells.

Conclusion

The results of our studies suggest that the presence of low-levels of triptolide potentiates lung cancer cells to cisplatin treatment by selectively inhibiting NER activity, resulting in an increase in apoptosis of the lung cancer cells.

【 授权许可】

   
2015 Wang et al.

【 图 表 】

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