Nitric oxide enhancement of melphalan-induced cytotoxicity

ABSTRACT The effects of the diatomic radical, nitric oxide (NO), on melphalan-induced cytotoxicity in Chinese hamster V79 and human MCF-7 breast cancer cells were studied using clonogenic

assays. NO delivered by the NO-releasing agent (C2H5)2N[N(O)NO]- Na+ (DEA/NO; 1 mM) resulted in enhancement of melphalan-mediated toxicity in Chinese hamster V79 lung fibroblasts and human

breast cancer (MCF-7) cells by 3.6- and 4.3-fold, respectively, at the IC50 level. Nitrite/nitrate and diethylamine, the ultimate end products of DEA/NO decomposition, had little effect on

melphalan cytotoxicity, which suggests that NO was responsible for the sensitization. Whereas maximal sensitization of melphalan cytotoxicity by DEA/NO was observed for simultaneous exposure

of DEA/NO and melphalan, cells pretreated with DEA/NO were sensitized to melphalan for several hours after NO exposure. Reversing the order of treatment also resulted in a time-dependent

enhancement in melphalan cytotoxicity. To explore possible mechanisms of NO enhancement of melphalan cytotoxicity, the effects of DEA/NO on three factors that might influence melphalan

toxicity were examined, namely NO-mediated cell cycle perturbations, intracellular glutathione (GSH) levels and melphalan uptake. NO pretreatment resulted in a delayed entry into S phase and

a G2/M block for both V79 and MCF-7 cells; however, cell cycle redistribution for V79 cells occurred after the cells returned to a level of cell survival, consistent with treatment with

melphalan alone. After 15 min exposure of V79 cells to DEA/NO (1 mM), GSH levels were reduced to 40% of control values; however, GSH levels recovered fully after 1 h and were elevated 2 h

after DEA/NO incubation. In contrast, DEA/NO (1 mM) incubation did not reduce GSH levels significantly in MCF-7 cells (approximately 10%). Melphalan uptake was increased by 33% after DEA/NO

exposure in V79 cells. From these results enhancement of melphalan cytotoxicity mediated by NO appears to be complex and may involve several pathways, including possibly alteration of the

repair of melphalan-induced lesions. Our observations may give insights for improving tumour kill with melphalan using either exogenous or possibly endogenous sources of NO. Access through

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TO REDUCE THE RISK OF RADIATION THERAPY Article Open access 29 April 2025 AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Radiation Biology Branch, National Cancer Institute, Bethesda, 20892,

MD, USA JA Cook Authors * JA Cook View author publications You can also search for this author inPubMed Google Scholar * MC Krishna View author publications You can also search for this

author inPubMed Google Scholar * R Pacelli View author publications You can also search for this author inPubMed Google Scholar * W DeGraff View author publications You can also search for

this author inPubMed Google Scholar * J Liebmann View author publications You can also search for this author inPubMed Google Scholar * JB Mitchell View author publications You can also

search for this author inPubMed Google Scholar * A Russo View author publications You can also search for this author inPubMed Google Scholar * DA Wink View author publications You can also

search for this author inPubMed Google Scholar RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Cook, J., Krishna, M., Pacelli, R. _et al._ Nitric oxide

enhancement of melphalan-induced cytotoxicity. _Br J Cancer_ 76, 325–334 (1997). https://doi.org/10.1038/bjc.1997.386 Download citation * Issue Date: 01 August 1997 * DOI:

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