RT Journal Article
SR Electronic
T1 Effect of Nitric Oxide on the Anticancer Activity of the Topoisomerase-Active Drugs Etoposide and Adriamycin in Human Melanoma Cells
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 607
OP 614
DO 10.1124/jpet.113.207928
VO 347
IS 3
A1 Birandra K. Sinha
A1 Ashutosh Kumar
A1 Suchandra Bhattacharjee
A1 Michael G. Espey
A1 Ronald P. Mason
YR 2013
UL http://jpet.aspetjournals.org/content/347/3/607.abstract
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 indicated that ⋅NO/⋅NO-derived species react with etoposide (VP-16) in vitro and form products that show significantly reduced activity toward HL60 cells and lipopolysaccharide (LPS)-induced macrophages. Here, we further confirm the hypothesis that ÷NO generation contributes to VP-16 resistance by examining interactions of ⋅NO with VP-16 in inducible nitric-oxide synthase (iNOS)–expressing human melanoma A375 cells. 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 coculturing A375 melanoma cells with LPS-induced macrophage RAW cells also significantly reduced VP-16 cytotoxicity and DNA damage in A375 cells. We also examined the interactions of ⋅NO with another topoisomerase active drug, Adriamycin, in A375 cells. In contrast, to VP-16, ⋅NO caused no significant modulation of cytotoxicity or Adriamycin-dependent apoptosis, suggesting that ⋅NO does not interact with Adriamycin. Our studies support the hypothesis that ⋅NO oxidative chemistry can detoxify VP-16 through direct nitrogen oxide radical attack. Our results provide insights into the pharmacology and anticancer mechanisms of VP-16 that may ultimately contribute to increased resistance, treatment failure, and induction of secondary leukemia in VP-16–treated patients.