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Intensification of anti-cancer chemo-therapy effect of cyclophosphamid by using a hybrid anti-inflammatory drug - nitrate salt of diclofenac hydroxamic acid
1 , Konovalova N. P.
1 , Sipjagin A. M.
1 , Bogatyrenko V. R.
1 , Kuropteva Z. V.
2 , Baider L. M.
3 , Sachenkova T. E.
1 , Fedorov B. S.
1 2 Emanuel Institute of biochemical physics, Russian Academy of Sciences, Moscow, Russian Federation
3 Emanuel Institute of biochemical physics, Russian Academy of Sciences, Mosсow, Russian Federation
We investigate hybrid non-steroidal anti-inflammatory drugs (NSAIDs), nitrate salt of diclofenac hydroxamic acid (DHA HNO3), synthesized at the Institute of Problems of Chemical Physics (IPCP), Russian Academy of Sciences. The compound contains a typical anti-inflammatory drug NSAID, an inhibitor of cyclooxygenase (COX) activity, the hydroxaxamic group, an inhibitor of peroxydase (PO) activity, and is a donor of the nitric oxide (NO) formed in the process of HNO3 reduction. In the present study we suggest to investigate a combined action of cytostatic cyclophosphamid (CP) and DHA HNO3 on anti-cancer activity. We show that chemosensibilization effect of combined PC and DHA HNO3, with therapeutic doses of PC, leads to 100 % healing of animals with leukemia P-388. Using ESR technique, we investigate the ESR signal of the active form of cyt P-450 in mouse liver samples after application of DHA HNO3. We find that application of DHA HNO3 leads to formation of nitrosyl cyt P-450-NO complexes, resulting in a decrease in the ESR signal of cyt P-450 within the five hours after application. The formation of P-450-NO complexes is related to nitric oxide formation in the process of HNO3 reduction. We suggest that due to the formation of NO, the prolonged inhibition effect of cyt P-450 results in the enforced chemo-therapeutic activity of CP within the first few hours of application. We conclude that the application of the hybrid nitrate salt of diclofenac hydroxamic acid DHA HNO3 can lead to the enforced chemo-therapeutic effect of CP and 100 % healing of animals
cyclophosphamid, non-steroidal anti-inflammatory drugs, hydroxaxamic acids, nitric oxide, cyt P-450, leukemia P-388, ESR spectroscopy
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