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

Abstract

BackgroundCisplatin 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.MethodsCaspase-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.ResultsOur 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 Ser317/345 but an increase for cisplatin-induced ATM phosphorylation at Ser1981 in both HTB182 and A549 cells.ConclusionThe 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.

Cisplatin Resistance in Osteosarcoma: In vitro Validation of Candidate DNA Repair-Related Therapeutic Targets and Drugs for Tailored Treatments

“…This ability to block DNA repair has important implications for the anticancer activity of CDDP, which effectiveness has been shown to be enhanced by the combined treatment with triptolide (26). In agreement with that, experimental studies confirmed that low concentrations of triptolide were able to potentiate the CDDP activity in human lung cancer (27) and human bladder CDDP-resistant cells (28).…”

Naturally occurring anti-cancer compounds: shining from Chinese herbal medicine

“…The combined therapy of triptolide and 5-fluorouracil further promotes apoptosis and inhibits tumor growth through down-regulating vimentin in human pancreatic cancer AsPC-1 cells and AsPC-1 xenograft mice [453]. Besides, low concentration of triptolide potentiates cisplatin-induced apoptosis in human lung cancer HTB-182, A549 and CRL-5810 and CRL-5922 cells [454], and triptolide with cisplatin synergistically enhances apoptosis and induces cell cycle arrest in human bladder cancer cisplatin-resistant cells [409].…”

Downregulation of RIF1 Enhances Sensitivity to Platinum-Based Chemotherapy in Epithelial Ovarian Cancer (EOC) by Regulating Nucleotide Excision Repair (NER) Pathway

“…Platinum analogues induce DNA damage by binding to DNA in target cells, promoting apoptosis and leading to the anti-neoplastic activity [5-9]. One of the main mechanisms of platinum resistance is DNA repair [10].…”