Research Summary

In collaboration with Abdul-Kader Souid, Karen A. Galvan and Kirk A. Tacka, Department of Pediatrics, State University of New York, Upstate Medical Center, Syracuse, New York.

Dr. Penefsky and his collaborators are seeking to determine the effect of anticancer drugs on oxygen consumption by normal and cancerous cells. While the purpose of administering anticancer drugs to patients is to kill the cancer, it is well known that many anticancer drugs in use today damage normal cells as well. They are studying how this damage occurs. Much of the damage results from interaction of the drugs with cell DNA, resulting in inhibition of protein synthesis and consequent cell death. Recently however, they found that anticancer drugs can inhibit cellular oxygen consumption both directly and indirectly.

Their study has focused on the effects of anticancer drugs on oxygen consumption by mitochondria. Mitochondria are tiny organelles, found within almost all cells in the body, that oxidize ingested foodstuffs and capture the energy released in a form that can be used to support life processes. Inhibition of mitochondrial oxygen consumption would deprive the cells of their critical energy supply and lead to cell death. They have found that cisplatin, a much-used anticancer agent containing platinum, indirectly inhibits mitochondrial oxidations by promoting the release from mitochondria of a critical component, cytochrome c. The effect of cisplatin on mitochondrial oxidations is delayed until significant amounts of cytochrome c are released. On the other hand, cyclophosphamide and anthracycline antibiotics, two other frequently-used anticancer agents, directly and immediately inhibit oxygen consumption in a dose-dependent manner.

Dr. Penefsky and his collaborators have concluded that mitochondria are a common target for many anticancer drugs and that these effects on mitochondria are related to frequently observed adverse clinical responses.




Recent Articles

Tacka KA, Dabrowiak JC, Goodisman J, Penefsky HS, Souid AK. (2004).
Effects of Cisplatin on Mitochondrial Function in Jurkat Cells.
Chem Res Toxicol. 2004 Aug 16;17(8):1102-1111
PMID: 15310242
Abstract

Sadowitz, P.D., Penefsky, H.S. and Souid, A-K. (2004 submitted).
Cellular Toxicities of Doxorubicin and Modulation by Caspase Inhibition, Dexrazoxane and WR-1065.
Submitted, 2004

Souid AK, Tacka KA, Galvan KA, Penefsky HS. (2003).
Immediate effects of anticancer drugs on mitochondrial oxygen consumption.
Biochem Pharmacol. 2003 Sep 15;66(6):977-87
PMID: 12963484
Abstract  |  Full Article

Knowles AF, Penefsky HS. (1997).
Reconstitution of beef heart mitochondrial F0F1 in reverse phase evaporation vesicles.
Biochim Biophys Acta. 1997 Oct 23;1329(2):311-20
PMID: 9371423
Abstract

Souid, A.K., and Penefsky, H.S. (1995).
Energetics of ATP dissociation from the mitochondrial ATPase during oxidative phosphorylation.
J. Biol. Chem., 270:9074-9082.

Martins, I.S., and Penefsky, H.S. (1994).
Covalent modification of catalytic sites on membrane-bound beef heart mitochondrial ATPase by 2-azido-adenine nucleotides.
Eur. J. Biochem., 224:1057-1065.

Ziegler, M., Xiao, R., and Penefsky, H.S. (1994).
Close proximity of Cys64 and Cys140 in the delta subunit of Escherichia coli F1-ATPase.
J. Biol. Chem., 269:4233-4239.

Xiao, R., and Penefsky, H.S., (1994).
Unisite catalysis of the delta subunit of F1-ATPase in Escherichia coli.
J. Biol. Chem., 269:19232-19237.

Souid, A.K., and Penefsky, H.S., (1994).
Mechanism of ATP synthesis by mitochondrial ATP synthase from beef heart.
Bioenergetics and Biomembranes, 26:627-630.

PubMed Lisitings>




C.V.

Ph.D., University of Chicago, Ph.B., 1948; New York University, B.A., 1956; New York University, Ph.D., 1960; University of Amsterdam, Post-doc., 1960-1962; PHRI, 1956-1988; State University of New York, Syracuse, 1988-1995; PHRI, 1996-present.