The Vinca alkaloid, vincristine (VINC) and anthracycline antitumor agent, doxorubicin (DOX) are among the most effective drugs currently available for the treatment of various human neoplastic diseases. However, their antitumour activity is drastically reduced towards tumour cells developing the multidrug resistance (MDR) against a wide range of drugs, structurally dissimilar and having different intracellular targets. MDR phenomenon is associated with the presence of the membrane transporters (e.g. P-glycoprotein, MRP1, BCRP), responsible for the ATP-dependent export of drugs out of resistant cells.

Therefore, many efforts are focused on the search for agents able to increase the activity of anthracycline and Vinca alkaloid drugs. Recently, some interest is paid to biological activities of 1-methyl pyridinium salts capable of shifting NAD(P)H/ NAD(P)⁺ equilibrium in non-enzymatic and enzyme-mediated process. The changes in NAD(P)H and NAD(P)⁺ concentrations can disturb the cellular metabolism by affecting the rates of NAD(P)H- and NAD(P)⁺-dependent reactions. Consequently, the cells with impaired metabolism should be more sensitive to cytotoxic agents. In our previous study it was evidenced that selected pyridinium salts increased the cytotoxicity of VINC towards human promyelocytic leukaemia HL60 cells and its resistant sublines HL60/VINC and HL60/DOX. However, they were unable to increase the cytotoxic activity of bioreductive drug, DOX.

The aim of this study was to examine the influence of VINC and DOX on reductive properties of pyridinium salts related to their biological properties. The effect of these drugs on non-enzymatic and enzymatic NADPH oxidation stimulated by selected 1-methyl pyridinium salts: MNP⁺ (1-methyl-3-nitropyridinium) and MDION⁺ (3,3,6,6,10-pentamethyl-3,4,6,7-tetrahydro-[1,8(2H,5H)-dion]acridine) salts was examined using spectrophotometric methods. It was found that VINC had no effect on non-enzymatic as well as NADPH-cytochrome P450 reductase (CPR)-dependent NADPH oxidation stimulated by examined pyridinium salts. DOX had no influence on non-enzymatic NADPH oxidation stimulated by MNP⁺ and MDION⁺ salts but drastically inhibited enzymatic (CPR-dependent) NADPH oxidation stimulated by MDION⁺ salt.

In conclusion: presented data suggest that the bioreductive drug DOX, in contrast to VINC, affect the ability of pyridinium salts to interact with NADPH-dependent oxidoreductases. It could explain the inefficiency of these salts to increase the cytotoxic activity of DOX against examined leukaemic HL60 cell lines.

This study was supported by the State Committee for Scientific Research, Warsaw, Poland (Grant no. PBZ-KBN-101/T09/2003).

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