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Suppression of human tumor cell proliferation through mitochondrial targeting

Division of Cardiovascular Diseases, Departments of Medicine, Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Mayo Foundation, Rochester, Minnesota, USA; and
^* Section of Clinical Pharmacology, Department of Medicine, Dartmouth Medical School and Dartmouth Hitchkock Medical Center, Lebanon, New Hampshire, USA

¹Correspondence: Guggenheim 7, Mayo Clinic, Rochester, MN, 55905, USA. E-mail: terzic.andre{at}mayo.edu

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.—Holmuhamedov, E., Lewis, L., Bienengraeber, M., Holmuhamedova, M., Jahangir, A., Terzic, A. Suppression of human tumor cell proliferation through mitochondrial targeting.

Key Words: mitochondrial DNA • calcium release-activated calcium channels • diazoxide • cancer

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