Abstract
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.
Highlights
Lung cancer is one of the top three cancers and the leading cause of cancer mortality among men and women worldwide, with about 85% of cases diagnosed as non-small cell lung cancer (NSCLC) [1, 2]
In order to increase the sensitivity of NCI-H460 cells to dihydroberberine and sunitinib, we explored the effect of simultaneous treatment
We evaluated the effects of dihydroberberine on lung cancer cells, including NCI-H460, A549, and NCI-H1299 cells, and confirmed that dihydroberberine treatment resulted in a reduction of cell viability in a dose-dependent manner
Summary
Lung cancer is one of the top three cancers and the leading cause of cancer mortality among men and women worldwide, with about 85% of cases diagnosed as non-small cell lung cancer (NSCLC) [1, 2]. The majority of patients with NSCLC are already in an advanced stage at diagnosis, and surgical treatment is not curative, so chemotherapy remains a mainstay of therapy [3]. Combination therapy, which improves the curative effect and reduces the toxicity of these drugs, has become one of the most important means of improving survival of patients with lung cancer [4]. Agents with anti-inflammatory activities may exert a chemoprotective effect on normal tissues against the toxic insults of chemotherapy. Accumulating evidence has verified that many inflammatory signalling pathways are activated in various cancers; inflammation plays a critical role in multiple stages of tumour development, including initiation, promotion, invasion and metastasis [5, 6].
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