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Cytochrome c Release Is Upstream to Activation of Caspase-9, Caspase-8, and Caspase-3 in the Enhanced Apoptosis of Anaplastic Thyroid Cancer Cells Induced by Manumycin and Paclitaxel

Section of Endocrine Neoplasia and Hormonal Disorders, Department of Internal Medicine Specialties (J.P., G.X., S.-C.J.Y.), and Section of General Internal Medicine, Department of Internal Medicine Specialties (S.-C.J.Y.), University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

Address all correspondence and requests for reprints to: S. Jim Yeung, M.D., Ph.D., University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 40, Houston, Texas 77030. E-mail: syeung{at}notes.mdacc.tmc.edu

Abstract

We previously demonstrated that the combination of a farnesyltransferase inhibitor, manumycin A, and paclitaxel had a synergistic antineoplastic effect on anaplastic thyroid cancer. In this study we investigated the apoptosis pathway involved. In ARO and KAT-4 cells, manumycin- plus paclitaxel-induced DNA fragmentation was blocked by the inhibitors of caspase-9, caspase-8, and caspase-3. The drug combination enhanced the activation of caspase-9, caspase-8, and caspase-3 and cytochrome c release into the cytosol. Cytochrome c release was not affected by the inhibitors of caspase-9, caspase-8 and caspase-3. In a cell-free reconstitution assay, DNA fragmentation occurred after incubating nuclei purified from untreated KAT-4 cells with deoxy-ATP, exogenous cytochrome c and S-100 extracts from control KAT-4 cells, and also after incubation of purified KAT-4 nuclei with S-100 extracts from KAT-4 cells treated with manumycin-plus-paclitaxel. In both cases, the DNA fragmentation was blocked by the inhibitors of caspase-9, caspase-8 and caspase-3. We concluded that the cytochrome c release was upstream of the activation of caspase-9, caspase-8, and caspase-3 in the enhanced apoptosis of anaplastic thyroid cancer cells treated with manumycin plus paclitaxel, and that the interaction between manumycin and paclitaxel occurred at or upstream of cytochrome c in the apoptosis regulatory pathway in anaplastic thyroid cancer cells.

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