Antihypertensive calcium channel blockers may promote human cancer cell growth

Abstract

It has been suggested that calcium ion (Ca2+) channel blocking drugs (CCB), commonly employed as antihypertensive agents, may promote growth of pre-existing cancer cells by inhibition of apoptosis. So far, however, there are no experimental data to support this notion, and results from clinical trials and epidemiological studies have been negative or ambiguous, respectively. Therefore, we examined if vascular type (L-type) Ca2+ channels are expressed in human colon cancer cells and if L-type Ca2+ channel activators (CCA) and blockers (CCB) influence Ca2+ influx and subsequent apoptosis in such cells. Both primary (collected at operation) and commercially available human colon cancer cell lines were used. The cells were incubated with three different CCB (verapamil, diltiazem or nifedipine) and one CCA (BayK 8644) at clinically relevant concentrations. RNA was determined by reverse-transcription polymerase chain reaction (RT-PCR SuperScript one-Step). Intracellular Ca2+ levels were measured by fluorometry (Fluo-4-AM). Apoptosis was quantified by flow cytometry (Annexin V binding). Cells from both lines expressed vascular (L-type) Ca2+ channel mRNA but neither N- nor P-type channel mRNA. The L-type Ca2+ channels were composed of a1D and b3- subunits. The selective L-type CCA BayK 8644 markedly increased Ca2+ influx and apoptosis in the cells, and CCB pretreatment abolished BayK 8644-induced Ca2+ influx and apoptosis. Accordingly, while there is no evidence that CCB transformation of normal cells to cancer cells, these drugs may promote growth: of pre-existing cancer cells in humans. As this would become clinically relevant only in subjects who already harbor a critical mass of cancer cells, the negative results in clinical trials and the conflicting results of epidemiological studies are not surprising. Until studies have been conducted in appropriate patient groups to substantiate or refute the notion that CCB treatment poses a real cancer threat, it seems prudent to minimize the use of CCB in hypertensive patients.