Calcium channel blockers lercanidipine and amlodipine inhibit YY1/ERK/TGF-ß mediated transcription and sensitize the gastric cancer cells to doxorubicin.

Elevated expression of YY1 is known to confer anti-apoptotic phenotype and hence is an attractive target for cancer therapeutics. In a repurpose screening, towards the identification of the inhibitors of YY1 regulated transcription in gastric cancer cells, the calcium channel blockers lercanidipine and amlodipine have been identified to inhibit YY1 more efficiently. We further probed these calcium channel blockers for their potential feature of alleviating the drug resistance in gastric cancer cells. Lercanidipine and amlodipine were found to show an enhanced effect with doxorubicin in inhibiting the growth of gastric cancer cells. While doxorubicin was identified to activate the pathways TGF-ß and ERK/MAPK, lercanidipine was found to inhibit these pathways. This being the molecular mechanism behind the identified advantage of lercanidipine and amlodipine in sensitizing gastric cancer cells to doxorubicin. In multiple cellular models from different lineages, the cells with less sensitivity to doxorubicin were found to have the inherent activation of ERK/MAPK and TGF-ß pathways. Also, we have identified that doxorubicin, in combination with any of the calcium channel blockers, could inhibit the potential of cellular proliferation and spheroid formation in gastric cancer cells. The current study shows the usefulness of lercanidipine and amlodipine for the targeted and combinatorial therapeutics of gastric cancer and specifically to improve the efficiency of doxorubicin.

Stratification and delineation of gastric cancer signaling by in vitro transcription factor activity profiling and integrative genomics.

Integrative functional genomic approaches are helpful in delineating the complex dysregulations in cancers. In the present study, in vitro activity profiling of 45 signaling pathway driven transcription factors in eight gastric cancer cell lines and direct comparison with genome-wide profiles of gastric tumors were performed and the integration resulted in the identification of three categories of factors/pathways: i) highly activated signaling pathways that stem from mutations are the critical oncogenic drivers, ii) constitutively activated stress responsive pathways which are activated not due to genetic alterations, and iii) consistently down-regulated nuclear receptor responsive factors. This functional profiling helps in discriminating therapeutic targets and signaling interactions.