Aqueous extract of Cordyceps sinensis potentiates the antitumor effect of DDP and attenuates therapy-associated toxicity in non-small cell lung cancer via IκBα/NFκB and AKT/MMP2/MMP9 pathways

Abstract

Cordyceps sinensis is reported as an invigorant with pleiotropic biological effects that has potential for tumor therapy. Here, we focused on a combined therapy using aqueous extract of C. sinensis (AECS) along with cis-diamminedichloroplatinum(II) (DDP) to potentiate the inhibitory effect of DDP and, meanwhile, reduce therapy-associated toxicity on NSCLC. We initially examined the in vitro antitumor effect of AECS, in vivo antitumor and toxicity-reduced effects of the combined treatment in a Lewis xenograft mice model, and further evaluated the potential mechanisms of action of the combined treatment. The synergistic antitumor activity and toxicity-attenuated effect of the combined treatment were further evaluated in zebrafish models. We found that AECS exhibited significant antitumor effects against various cancer cells in vitro. AECS, particularly AECS1, substantially potentiated the antitumor effect of DDP, as evidenced by a significant decrease in tumor growth, a prolongation of the survival time, and also alleviated toxicity in the Lewis xenograft mice model, accompanied by attenuated NFκB and AKT/MMP2/MMP9 pathways. Moreover, a remarkable increase of tumor inhibition in an A549 xenograft zebrafish model was observed with the combined therapy when compared to DDP treatment alone, and alleviated toxicity in zebrafish was also observed when treated with the combined therapy. Collectively, our results indicate that the combination of AECS1 and DDP should be a novel therapeutic modality to improve the efficacy of DDP-based chemotherapy and reduce therapy-associated toxicity, possibly by inhibiting IκBα/NFκB and AKT/MMP2/MMP9 pathways.