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Possible Involvement of NO in the Stimulating Effect of Pifithrins on Survival of Hemopoietic Clonogenic Cells

S. Ya. Proskuryakov*, A. G. Konoplyannikov, O. A. Konoplyannikova, L. I. Shevchenko, Yu. G. Verkhovskii, and A. F. Tsyb

Medical Radiological Research Center, Russian Academy of Medical Sciences, 249036 Obninsk, Kaluga Region, Russia; fax: (495) 956-1440; E-mail: pros@mrrc.obninsk.ru

* To whom correspondence should be addressed.

Received November 4, 2007; Revision received September 22, 2008
Pifithrin α (PFTα), one of the first known low molecular weight modulators of activity of tumor suppressor p53, increases survival of hemopoietic clonogenic cells (evaluated by the criterion of formation of endogenous spleen CFU-C8 colonies in irradiated animals). This effect appeared when PFTα was administered either before or after irradiation. Increase in CFU-C8 was also observed after administration of two PFTα analogs, derivatives of 2-amino-4,5,6,7-tetrahydrobenzothiazole. These included a parent compound, 2-ATBT (2-amino-4,5,6,7-tetrahydrobenzothiazole), which is used for synthesis of PFTα, and a product of its intramolecular cyclization under physiological conditions, cyclo-PFT (2-(4-methylphenyl)imidazo[2,1-b]-5,6,7,8-tetrahydrobenzothiazole). Earlier we found that many low molecular weight compounds increasing number of CFU-C8 (e.g. isothiourea derivatives) demonstrate NO inhibitory activity. Such activity was also found in 2-ATBT and cyclo-PFT by means of EPR spectroscopy of NO. These compounds caused more than twofold inhibition of NO production in vivo. Thus, it has been demonstrated that PFTα and its structural analogs increase survival of hemopoietic clonogenic cells in vivo, and NO may play a role in the mechanism of this effect.
KEY WORDS: pifithrin α, cyclo-pifithrin, hemopoietic clonogenic cells, endogenous spleen colonies, nitric oxide production, EPR spectroscopy of NO spin trap

DOI: 10.1134/S0006297909020023