Nifedipine Synergizes With Calcium in Activating the Calcium Sensing Receptor, Suppressing the Expression of Thymidylate Synthase and Survivin and Promoting Sensitivity to Fluorouracil in Human Colon Carcinoma Cells

We have previously reported that activation of the G protein coupled calcium-sensing receptor (CaSR) by extracellular Ca2+ down-modulates the expression of thymidylate synthase (TS) and survivin and promotes sensitivity to fluorouracil in human colon carcinoma cells. Here, we report for the first time that the cardiac drug nifedipine acted synergistically with Ca2+ in CaSR activation and in the induction of intracellular Ca2+. Nifedipine in combination with Ca2+ significantly down-modulated the expression of TS and survivin and promoted sensitivity to 5-FU above and beyond the level achievable with Ca2+ alone. Nifedipine by itself, however, had no effect on the suppression of TS or survivin or sensitivity to 5-FU. The action of Ca2+ or in combination with nifedipine was entirely CaSR dependent as the aforementioned effects did not occur in CaSR knocked down cells. siRNAs targeting TS or survivin or both could mimic the effect of CaSR activation in promoting sensitivity to 5-FU. We conclude that nifedipine acts in synergy with Ca2+ in activating CaSR and in promoting sensitivity to 5-FU by down modulating the expression of TS and survivin. G-protein coupled CaSR has the potential of serving as a target for improving therapeutic outcome in colon cancer. (C) 2011 Wiley Periodicals, Inc.