Anti-proliferative effect of Jesridonin on paclitaxel-resistant EC109 human esophageal carcinoma cells

Abstract

Chemoresistance to anticancer drugs is a major obstacle in the efforts to develop a successful treatment strategy for esophageal squamous carcinoma (ESCC). Thus, the exploration of new drugs and treatment strategies for combating resistance are of utmost importance. In this study, we investigated the antitumor drug resistance activity of Jesridonin, a new ent-kaurene diterpenoid, and its possible mechanisms of action using the resistant cancer cell line, EC109/Taxol. MTT assay revealed that Jesridonin had similar IC50 values against EC109 paclitaxel-sensitive cells and drug-resistant EC109/Taxol cells in vitro. In mice, Jesridonin effectively prevented the growth of EC109/Taxol tumor xenografts without exerting any significant toxicity. In addition, Jesridonin significantly inhibited the proliferation of EC109/Taxol cells, induced apoptosis and arrested the cell cycle at the G2/M phase. Furthermore, western blot analysis revealed that Jesridonin upregulated the expression of p53, p53 upregulated modulator of apoptosis (PUMA), cleaved-caspase-9 and cleaved-caspase-3 in EC109/Taxol cells, and downregulated the expression of procaspase-3, procaspase-9 and Bcl-2 in the EC109/Taxol cells in a concentration-dependent manner. Overall, our results demonstrate that Jesridonin may have potential for use in the treatment of paclitaxel-resistant ESCC. The data of the present study may lead to the development of novel treatment strategies for paclitaxel-resistant tumors.

Advances and challenges in the treatment of esophageal cancer

“…The combination of heavy carbon ion beam irradiation and docetaxel posess a synergistic effect on EC, thereby representing a promising treatment option for locally advanced ESCC 58 . Docetaxel toxicity and the development of drug resistance limit the extensive clinical application of this agent; resistance is attributed to overexpression of the P-gp efflux pump and resistance to apoptosis 59 . In paclitaxel-resistant EC109 cells (EC109/Taxol cells), jesridonin (JD) has an anti-MDR effect, through upregulating P53, cleaved-caspase-9, and cleaved-caspase-3 and downregulating procaspase-3 and procaspase-9.…”

“…In paclitaxel-resistant EC109 cells (EC109/Taxol cells), jesridonin (JD) has an anti-MDR effect, through upregulating P53, cleaved-caspase-9, and cleaved-caspase-3 and downregulating procaspase-3 and procaspase-9. JD activates the mitochondrial-mediated intrinsic apoptosis pathway, thereby inducing EC109/Taxol cell apoptosis and effectively suppressing the growth of tumor xenografts with no obvious toxicity 59 . Thus, combination therapy is likely to overcome drug toxicity and resistance during ESCC treatment.…”