Suppression of human tumor cell proliferation through mitochondrial targeting.

Intracellular calcium signaling plays a central role in cell proliferation. In leukemic cells, the calcium release-activated calcium channels provide a major pathway for calcium entry (I(CRAC)) perpetuating progression through the cell cycle. Although I(CRAC) is under mitochondrial regulation, targeting mitochondrial function has not been exploited to control malignant cell growth. The benzothiadiazine diazoxide, which depolarized respiration-dependent mitochondrial membrane potential, reduced the rate of proliferation and arrested human acute leukemic T cells in the G0/G1 phase. Diazoxide did not alter cellular energetics, but rather inhibited the mitochondria-controlled I(CRAC) and reduced calcium influx into tumor cells. The antiproliferative action of diazoxide was mimicked by removal of extracellular calcium or by the tyrphostin A9, an I(CRAC) inhibitor. Deletion of the mitochondrial genome, which encodes essential respiratory chain enzyme subunits, attenuated the inhibitory effect of diazoxide on I(CRAC)-mediated calcium influx and cell proliferation. Thus, manipulation of mitochondrial function and associated calcium signaling provides a basis for a novel anticancer strategy.