Dihydroberberine exhibits synergistic effects with sunitinib on NSCLC NCI-H460 cells by repressing MAP kinase pathways and inflammatory mediators

Highly effective and attenuated dose schedules are good regimens for drug research and development. Combination chemotherapy is a good strategy in cancer therapy. We evaluated the antitumour effects of dihydroberberine combined with sunitinib (DCS) on the human non-small cell lung cancer cell lines (NSCLC), A549, NCI-H460, and NCI-H1299 in vitro and in vivo. DCS showed synergic effects on NCI-H460 cell proliferation, colony formation and transplantable tumour growth, which suggested dihydroberberine increases the sensitivity of lung carcinoma to sunitinib. Further studies indicated that DCS down-regulated phosphorylation of JNK, p38, and NF-κB in NCI-H460 cells and tumours and suppressed the IκB and COX-2 expression. In addition, DCS reduced the secretion of the pro-inflammatory cytokine, interleukin-1 (IL-1), in tumours. Inhibition of p38 activation by DCS was a likely contributing factor in IL-1 and COX-2 down-regulation. Consistent with these results, a genomewide microarray analysis found that DCS induced the expression of cell cycle signal molecules that are known to be affected by JNK and p38. The change of cell cycle, in turn, led to down-regulation of JNK and p38, and further reduced IL-1 secretion. Collectively, these findings highlight potential molecular mechanisms of DCS chemotherapeutic activity and suggest that DCS is an efficacious strategy in NSCLC therapy.