TY - JOUR
T1 - Suppression of human tumor cell proliferation through mitochondrial targeting
AU - Holmuhamedov, Ekhson
AU - Lewis, Lionel
AU - Bienengraeber, Martin
AU - Holmuhamedova, Madina
AU - Jahangir, Arshad
AU - Terzic, Andre
PY - 2002
Y1 - 2002
N2 - 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 (ICRAC) perpetuating progression through the cell cycle. Although ICRAC 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 ICRAC 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 ICRAC inhibitor. Deletion of the mitochondrial genome, which encodes essential respiratory chain enzyme subunits, attenuated the inhibitory effect of diazoxide on ICRAC-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.
AB - 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 (ICRAC) perpetuating progression through the cell cycle. Although ICRAC 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 ICRAC 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 ICRAC inhibitor. Deletion of the mitochondrial genome, which encodes essential respiratory chain enzyme subunits, attenuated the inhibitory effect of diazoxide on ICRAC-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.
KW - Calcium release-activated calcium channels
KW - Cancer
KW - Diazoxide
KW - Mitochondrial DNA
UR - http://www.scopus.com/inward/record.url?scp=0036313863&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0036313863&partnerID=8YFLogxK
U2 - 10.1096/fj.01-0996com
DO - 10.1096/fj.01-0996com
M3 - Article
C2 - 12087062
AN - SCOPUS:0036313863
SN - 0892-6638
VL - 16
SP - 1010
EP - 1016
JO - FASEB Journal
JF - FASEB Journal
IS - 9
ER -