PT  - JOURNAL ARTICLE
AU  - Birandra K Sinha
AU  - Ashutosh Kumar
AU  - Suchandra Bhattacharjee
AU  - Michael G Espey
AU  - Ronald P Mason
TI  - EFFECTS OF NITRIC OXIDE ON ANTICANCER ACTIVITY OF TOPOISOMERSE-ACTIVE DRUGS, ETOPOSIDE AND ADIAMYCIN, IN HUMAN MELONOMA CELLS
AID  - 10.1124/jpet.113.207928
DP  - 2013 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - jpet.113.207928
4099  - http://jpet.aspetjournals.org/content/early/2013/09/18/jpet.113.207928.short
4100  - http://jpet.aspetjournals.org/content/early/2013/09/18/jpet.113.207928.full
AB  - 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 have indicated that ●NO/●NO-derived species react with etoposide (VP-16) in vitro and form products that show significantly reduced activity towards HL60 cells and lipopolysaccharide (LPS)-induced macrophages. Here, we have examined the interactions of ●NO with VP-16 in inducible nitric oxide synthase (iNOS)-expressing human melanoma A375 cells to further confirm the hypothesis that ●NO generation contributes to VP-16 resistance in cancer cells. We also examined the interactions of ●NO with another topoisomerase active drug, adriamycin. Inhibition of iNOS catalysis by N6-(1-iminoethyl)-L-lysine dihydrochloride (L-NIL) in human melanoma A375 cells reversed VP-16 resistance, leading to increased DNA damage and apoptosis. Furthermore, we found that co-culturing A375 melanoma cells with LPS-induced macrophage RAW cells also significantly reduced VP-16 cytotoxicity and DNA damage in A375 cells. In contrast, ●NO caused no significant modulation of cytotoxicity or adriamycin-dependent apoptosis, suggesting that ●NO did not interact with adriamycin. Our studies support the hypothesis that ●NO oxidative chemistry can detoxify VP-16 through direct nitrogen oxide radical attack and provide insights into the pharmacology and anticancer activities of VP-16 that may ultimately contribute to increased resistance, treatment failure, and induction of secondary leukemia in VP-16-treated patients.