Changes in Expression of Genes Encoding Antioxidant Enzymes, Heme Oxygenase-1, Bcl-2, and Bcl-xl and in Level of Reactive Oxygen Species in Tumor Cells Resistant to Doxorubicin

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E. V. Kalinina^1,2*, N. N. Chernov³, A. N. Saprin¹, Ya. N. Kotova¹, Ya. A. Andreev⁴, V. S. Solomka¹, and N. P. Scherbak⁵

¹Center for Theoretical Problems of Physico-Chemical Pharmacology, Russian Academy of Sciences, ul. Kosygina 4, 119991 Moscow, Russia; fax: (495) 938-2533; E-mail: kevsan@orc.ru

²Institute of Cytochemistry and Molecular Pharmacology, ul. 6-ya Radialnaya 24/14, 115404 Moscow, Russia; E-mail: kevsan@orc.ru

³Peoples' Friendship University of Russia, ul. Miklukho-Maklaya 8, 117198 Moscow, Russia; E-mail: chernov@med.pfu.edu.ru

⁴Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, ul. Mikluho-Maklaya 16/10, 117997 Moscow, Russia; E-mail: ay@ok.ru

⁵Institute of Carcinogenesis, Blokhin Russian Cancer Research Center, Russian Academy of Medical Sciences, Kashirskoe Shosse 24, 115478 Moscow, Russia

^* To whom correspondence should be addressed.

Received February 17, 2006; Revision received June 21, 2006

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The relationship between expression of genes encoding key antioxidant enzymes, heme oxygenase-1, Bcl-2, and Bcl-xl and change in production of reactive oxygen species (ROS) resulting from development of resistance of cancer cells K562, MCF-7, and SKOV-3 to the prooxidant chemotherapeutic agent doxorubicin (DOX) has been studied. Significant increase in mRNA level and activity of Mn-superoxide dismutase (Mn-SOD), catalase, and selenium-dependent glutathione peroxidase-1 (GPx-1) and reduced ROS level was found in resistant K562/DOX and SKVLB cells. In contrast, no change in ROS level was observed in MCF-7/DOX cells in parallel with decrease in Mn-SOD and catalase mRNAs and corresponding activities concurrently with high increase in GPx-1 mRNA and activity. As a result of the development of resistance, a similarity was found between the change in ROS level and the change in ho-1 and bcl-2 gene expression, whereas elevation of bcl-xl gene expression was observed in all three types of resistant cells. Particular features of development of adaptive antioxidant response as well as redox-dependent change in bcl-2 gene expression under formation of DOX resistance of cancer cells of different genesis are discussed.

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KEY WORDS: drug resistance of cancer cells, doxorubicin, reactive oxygen species, antioxidant enzymes, heme oxygenase-1, Bcl-2, Bcl-xl

DOI: 10.1134/S0006297906110058

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