Birandra K Sinha1, Carl D Bortner2, Ronald P Mason3, Ronald E Cannon2. 1. Immunity, Inflammation and Disease Laboratory, USA. Electronic address: sinha1@niehs.nih.gov. 2. Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA. 3. Immunity, Inflammation and Disease Laboratory, USA.
Abstract
BACKGROUND: Development of resistance to chemotherapy drugs is a significant problem in treating human malignancies in the clinic. Overexpression of drug efflux proteins, including P-170 glycoprotein (P-gp), an ATP-dependent efflux protein, is one of the main mechanisms responsible for multi-drug resistance (MDR). Because our previous studies have shown that nitric oxide (˙NO) or its related species inhibit the ATPase activities of topoisomerase II, we hypothesized that ˙NO should also inhibit the ATPase activity of P-gp and increase drug accumulation in MDR cells, causing a reversal of drug resistance. RESULTS: Cytotoxicity and cellular accumulation studies showed that ˙NO significantly inhibited the ATPase activity of P-gp in isolated membranes and in NCI/ADR-RES tumor cells, causing an increase in drug accumulation and reversals of adriamycin and taxol resistance in the MDR cells. While ˙NO had no effects on topoisomerase II-induced, adriamycin-dependent DNA cleavage complex formation, it significantly inhibited adriamycin-induced DNA double-strand breaks. Electron spin resonance studies showed an increase in adriamycin-dependent hydroxyl radical formation in the presence of an NO-donor. CONCLUSIONS: The reversal of drug resistance is due to inhibition of the ATPase activity by ˙NO, resulting in enhancement of the drug accumulation in the MDR cells. Furthermore, DNA damage was not responsible for this reversal of adriamycin resistance. However, formation of adriamycin-dependent toxic free radical species and subsequent cellular damage may be responsible for the increased cytotoxicity of adriamycin by ˙NO in NCI/ADR-RES cells. GENERAL SIGNIFICANCE: Appropriately designed NO donors would be ideal for the treatment of P-gp-overexpressing tumors in the clinic. Published by Elsevier B.V.
BACKGROUND: Development of resistance to chemotherapy drugs is a significant problem in treating human malignancies in the clinic. Overexpression of drug efflux proteins, including P-170 glycoprotein (P-gp), an ATP-dependent efflux protein, is one of the main mechanisms responsible for multi-drug resistance (MDR). Because our previous studies have shown that nitric oxide (˙NO) or its related species inhibit the ATPase activities of topoisomerase II, we hypothesized that ˙NO should also inhibit the ATPase activity of P-gp and increase drug accumulation in MDR cells, causing a reversal of drug resistance. RESULTS: Cytotoxicity and cellular accumulation studies showed that ˙NO significantly inhibited the ATPase activity of P-gp in isolated membranes and in NCI/ADR-RES tumor cells, causing an increase in drug accumulation and reversals of adriamycin and taxol resistance in the MDR cells. While ˙NO had no effects on topoisomerase II-induced, adriamycin-dependent DNA cleavage complex formation, it significantly inhibited adriamycin-induced DNA double-strand breaks. Electron spin resonance studies showed an increase in adriamycin-dependent hydroxyl radical formation in the presence of an NO-donor. CONCLUSIONS: The reversal of drug resistance is due to inhibition of the ATPase activity by ˙NO, resulting in enhancement of the drug accumulation in the MDR cells. Furthermore, DNA damage was not responsible for this reversal of adriamycin resistance. However, formation of adriamycin-dependent toxic free radical species and subsequent cellular damage may be responsible for the increased cytotoxicity of adriamycin by ˙NO in NCI/ADR-RES cells. GENERAL SIGNIFICANCE: Appropriately designed NO donors would be ideal for the treatment of P-gp-overexpressing tumors in the clinic. Published by Elsevier B.V.
Authors: Krzysztof J Reszka; Michael L McCormick; Garry R Buettner; C Michael Hart; Bradley E Britigan Journal: Nitric Oxide Date: 2006-05-02 Impact factor: 4.427
Authors: Fei Shen; Shaoyou Chu; Aimee K Bence; Barbara Bailey; Xinjian Xue; Priscilla A Erickson; Marshall H Montrose; William T Beck; Leonard C Erickson Journal: J Pharmacol Exp Ther Date: 2007-10-18 Impact factor: 4.030