Possible involvement of NO in the stimulating effect of pifithrins on survival of hemopoietic clonogenic cells.
Pifithrin alpha (PFTalpha), 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 PFTalpha was administered either before or after irradiation. Increase in CFU-C8 was also observed after administration of two PFTalpha 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 PFTalpha, 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 PFTalpha and its structural analogs increase survival of hemopoietic clonogenic cells in vivo, and NO may play a role in the mechanism of this effect.
Proskuryakov
S Ya
SY
Medical Radiological Research Center, Russian Academy of Medical Sciences, Obninsk, Kaluga Region, Russia. pros@mrrc.obninsk.ru
Konoplyannikov
A G
AG
Konoplyannikova
O A
OA
Shevchenko
L I
LI
Verkhovskii
Yu G
YG
Tsyb
A F
AF
D000818:Animals; D052160:Benzothiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000528:radiation effects; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D009569:Nitric Oxide / Q000096:biosynthesis / Q000502:physiology*; D011837:Radiation-Protective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects; D013329:Structure-Activity Relationship; D014050:Toluene / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors*
C540568:2-(4-methylphenyl)imidazo(2,1-b)-5,6,7,8-tetrahydrobenzothiazole; C540567:2-amino-4,5,6,7-tetrahydrobenzothiazole; D052160:Benzothiazoles; D007093:Imidazoles; D011837:Radiation-Protective Agents; D016159:Tumor Suppressor Protein p53; D009569:Nitric Oxide; D014050:Toluene; C121565:pifithrin