Effect of Nitric Oxide on the Anticancer Activity of the Topoisomerase-Active Drugs Etoposide and Adriamycin in Human Melanoma Cells

Sinha, Birandra K.; Kumar, Ashutosh; Bhattacharjee, Suchandra; Espey, Michael Graham; Mason, Ronald P.

doi:10.1124/jpet.113.207928

Cited by 22 publications

(23 citation statements)

References 47 publications

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“…This is in contrast to our studies with PPNO, an NO-donor, which had no effect on doxorubicin cytotoxicity against human breast MCF-7 and colon HT-29 cell lines in vitro [48]. We also found that * NO did not modulate the toxicity of doxorubicin against human melanoma cells [49]. This suggests that PPNO, which has a short half-life, is not an effective modulator of doxorubicin cytotoxicity.…”

Section: Nitric Oxide In Combination With Antitumor Agentscontrasting

confidence: 99%

Nitric Oxide: Friend or Foe in Cancer Chemotherapy and Drug Resistance: A Perspective

Sinha

2016

J Cancer Sci Ther

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A successful treatment of cancers in the clinic has been difficult to achieve because of the emergence of drug resistant tumor cells. While various approaches have been tried to overcome multi-drug resistance, it has remained a major road block in achieving complete success in the clinic. Extensive research has identified various mechanisms, including overexpression of P-glycoprotein 170, modifications in activating or detoxification enzymes (phase I and II enzymes), and mutation and/or decreases in target enzymes in cancer cells. However, nitric oxide and/or nitric oxide-related species have not been considered an important player in cancer treatment and or drug resistance. Here, we examine the significance of nitric oxide in the treatment and resistance mechanisms of various anticancer drugs. Furthermore, we describe the significance of recently reported effects of nitric oxide on topoisomerases and the development of resistance to topoisomerase-poisons in tumor cells.Nitric oxide is also implicated in cancer cell killing, cancer progression and metastasis and poor survival [13][14][15][16][17]. A poor clinical outcome is believed to result from * NO-induced rapid tumor growth, resulting in hypoxia, nutrient deprivation, poor drug delivery, and selection for drug-resistant tumor cells. In vivo, * NO is formed from L-arginine by nitric oxide synthase (NOS). Three forms of NOS have been identified, including neuronal (nNOS), endothelial (eNOS), and a Ca 2+ -independent inducible isoform (iNOS). High expression of iNOS and increased production of • NO have been described in many human tumors, including breast, prostate and colorectal cancers [17][18][19][20]. Increased and continuous generation of * NO plays a significant role in the regulation of cancer cell progression and carcinogenesis. Hibbs et al. [21,22] and Stuehr and Nathan [23] have shown that co-culturing of leukemia L1210 cells with activated peritoneal macrophages results in the inhibition of L1210 cell proliferation which is correlated with nitrite formation. Inhibitors of NOS (L-NAME) and myoglobin, a scavenger of * NO 2 were effective in inhibiting cell killing actions of the activated macrophages, suggesting that * NO is responsible for the killing actions of activated macrophages towards cancer cells.It is believed that DNA damage and apoptosis induced by * NO in tumor cells cause tumor cell death; studies are needed to explore processes to deliver the highest concentrations of * NO in tumor cells using NO-donors as single chemotherapeutic agents or in combination with other chemotherapeutic agents. While significant progress has been made in the last decade, the role of * NO/ * NO-related species remains poorly understood in chemotherapy and drug resistance. Here, we review the role of * NO/ * NO-related species in cancer chemotherapy

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Section: Nitric Oxide In Combination With Antitumor Agentscontrasting

confidence: 99%

Nitric Oxide: Friend or Foe in Cancer Chemotherapy and Drug Resistance: A Perspective

Sinha

2016

J Cancer Sci Ther

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“…We have previously shown that • NO/ • NO-related species chemically react with VP-16 and produce non-cytotoxic products, resulting in a significant resistance to VP-16 in tumor cells [33, 34]. We have also shown that S-nitrosation resulting from reactions of cysteine residues with • NO/ • NO-related species results in the modification of protein-SH groups of topo I, causing the protein to undergo proteosomal degradation [35] in both the HT-29 and MCF-7 cancer cell lines.…”

Section: 0 Discussionmentioning

confidence: 99%

“…A poor clinical outcome may be related to • NO-induced rapid tumor growth, resulting in hypoxia, nutrient deprivation, poor drug delivery, and selection for drug-resistant tumor cells. Our recent studies have clearly shown that • NO, whether generated intracellularly in human melanoma cells or generated via NO-donors, reacts rapidly with VP-16 rendering it inactive against tumor cells in vitro [33, 34]. More recently, we have shown that generation of • NO via NO-donor induces significant resistance in human breast MCF-7 cancer cells to camptothecin, a topo I-poison [35].…”

Section: Introductionmentioning

confidence: 99%

Nitric oxide inhibits topoisomerase II activity and induces resistance to topoisomerase II-poisons in human tumor cells

Kumar¹,

Ehrenshaft²,

Tokar

et al. 2016

Biochimica et Biophysica Acta (BBA) - General Subjects

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Background Etoposide and doxorubicin, topoisomerase II poisons, are important drugs for the treatment of tumors in the clinic. Topoisomerases contain several free sulfhydryl groups which are important for their activity and are also potential targets for nitric oxide (•NO)-induced nitrosation. •NO, a physiological signaling molecule nitrosates many cellular proteins, causing altered protein and cellular functions. Methods Here, we have evaluated the roles of •NO/•NO-derived species in the activity stability of topo II both in vitro and in human tumor cells, and in the cytotoxicity of topo II-poisons, etoposide and doxorubicin. Results Treatment of purified topo IIα with propylamine propylamine nonoate (PPNO), an •NO donor, resulted in inhibition of both the catalytic and relaxation activity in vitro, and decreased etoposide-dependent cleavable complex formation in both human HT-29 colon and MCF-7 breast cancer cells. PPNO treatment also induced significant nitrosation of topo IIα protein in these human tumor cells. These events, taken together, caused a significant resistance to etoposide in both cell lines. However, PPNO had no effect on doxorubicin-induced cleavable complex formation, or doxorubicin cytotoxicity in these cell lines. Conclusion Inhibition of topo II function by •NO/•NO-derived species induces significant resistance to etoposide, without affecting doxorubicin cytotoxicity in human tumor cells. General Significance As tumors express inducible nitric oxide synthase and generate significant amounts of •NO, modulation of topo II functions by •NO/•NO-derived species could render tumors resistant to certain topo II-poisons in the clinic.

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“…5 Iminoxyls were found to be the intermediate product of the reaction between nitrogen oxide and the anticancer drug etoposide (VP-16) diminishing its cytotoxic activity toward cancer cells. 6 These radicals were also identified in lichens thalli collected from atmospherically polluted environments and also generated in laboratory conditions as a result of the nitrogen dioxide action on these composite organisms. 7 Moreover, iminoxyl radicals derived from unsaturated ketoximes are the starting reagents in organic synthesis.…”

Section: Introductionmentioning

confidence: 91%

Toward an Understanding of the Ambiguous Electron Paramagnetic Resonance Spectra of the Iminoxy Radical from o-Fluorobenzaldehyde Oxime: Density Functional Theory and ab Initio Studies

Witwicki

Jezierska

2015

J. Phys. Chem. A

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Iminoxy radicals (R1R2C═N—O•) possess an inherent ability to exist as E and Z isomers. Although isotropic hyperfine couplings for the species with R1 = H allow one to distinguish between E and Z, unequivocal assignment of the parameters observed in the EPR spectra of the radicals without the hydrogen atom at the azomethine carbon to the right isomer is not a simple task. The iminoxyl derived from o-fluoroacetophenone oxime (R1 = CH3 and R2 = o-FC6H5) appears to be a case in point. Moreover, for its two isomers the rotation of the o-FC6H5 group brings into existence the syn and anti conformers, depending on the mutual orientation of the F atom and C═N—O• group, making a description of hyperfine couplings to structure even more challenging. To accomplish this, a vast array of theoretical methods (DFT, OO-SCS-MP2, QCISD) was used to calculate the isotropic hyperfine couplings. The comparison between experimental and theoretical values revealed that the E isomer is the dominant radical form, for which a fast interconversion between anti and syn conformers is expected. In addition, the origin of the significant AF increase with solvent polarity was analyzed.

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Effect of Nitric Oxide on the Anticancer Activity of the Topoisomerase-Active Drugs Etoposide and Adriamycin in Human Melanoma Cells

Abstract: Nitric oxide (× NO) was originally identified as an innate cytotoxin. However, in tumors it can enhance resistance to chemotherapy and exacerbate cancer progression. Our previous studies indicated that

Cited by 22 publications

References 47 publications

Nitric Oxide: Friend or Foe in Cancer Chemotherapy and Drug Resistance: A Perspective

Nitric Oxide: Friend or Foe in Cancer Chemotherapy and Drug Resistance: A Perspective

Nitric oxide inhibits topoisomerase II activity and induces resistance to topoisomerase II-poisons in human tumor cells

Toward an Understanding of the Ambiguous Electron Paramagnetic Resonance Spectra of the Iminoxy Radical from o-Fluorobenzaldehyde Oxime: Density Functional Theory and ab Initio Studies

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