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Cytoskeleton Inhibitors Combined with TRAIL Induce Apoptosis in HeLa Carcinoma Cells Overexpressing Antiapoptotic Protein Bcl-2

M. E. Gasparian1, L. V. Domnina2, O. Yu. Ivanova2, D. S. Izyumov2, A. Yu. Lomakin2, E. N. Popova2, A. V. Yagolovich1, O. Yu. Pletjushkina2, D. A. Dolgikh1, and B. V. Chernyak2*

1Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, ul. Miklukho-Maklaya 16/10, 117997 Moscow, Russia; fax: (495) 335-0100; E-mail: office@ibch.ru

2Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119899 Moscow, Russia; fax: (495) 939-3181; E-mail: bchernyak@yahoo.com

* To whom correspondence should be addressed.

Received September 13, 2007; Revision received November 9, 2007
TRAIL (Apo2L), a cytokine from the family of tumor necrosis factors (TNF), causes apoptosis in various types of tumor cells but is not toxic for normal cells. Recombinant TRAIL obtained using an original method stimulates the release of cytochrome c from mitochondria into the cytoplasm and apoptosis in HeLa carcinoma cells. Expression of oncoprotein Bcl-2 in these cells blocks both processes. The microtubule inhibitors taxol, nocodazole, and colcemid, as well as an inhibitor of actin microfilaments cytochalasin D, enhance the action of TRAIL and allow it to overcome protection caused by overexpression of Bcl-2. This effect is not associated with enhancement of early steps of TRAIL-dependent apoptosis leading to activation of caspase-8 and Bid protein. The inactivation of Bcl-2 also does not define the effect of cytoskeleton inhibitors. It is supposed that destruction of cytoskeleton alters the mechanism of the TRAIL- (or TNF)-dependent cytochrome c release from mitochondria by making it resistant to Bcl-2. The combined use of cytoskeleton inhibitors, which are antitumor drugs, with the recombinant TRAIL preparations may be efficient in therapy of tumors resistant to traditional chemotherapy.
KEY WORDS: apoptosis, cytokines, mitochondria, cytoskeleton, Bcl-2

DOI: 10.1134/S000629790803019X