Effects of melatonin on doxorubicin cytotoxicity in sensitive and pleiotropically resistant tumor cells

Melatonin has been reported to attenuate the oxidative damage caused by dox orubicin on kidney, brain, heart and bone marrow, whereas the in vivo antit umor effects of doxorubicin were not attenuated. The effects of melatonin o n doxorubicin cytotoxicity have, therefore, been examined on human normal m ammary epithelium HBL-100, on mammary adenocarcinoma MCF-7, on colon carcin oma LoVo, and on mouse P388 leukemia cell lines, and on tumor cell sublines pleiotropically resistant to anthracyclines. Melatonin in the concentratio n range 10-2000 pg/mL causes an inhibition of the growth of the human cell lines examined which is not clearly dose-dependent and less than 25% when s ignificant. Melatonin similarly causes minor effects on doxorubicin cytotox icity either on the parental human cell lines or on their resistant subline s. On the contrary, 200-1000 pg/mL melatonin cause a significant and dose-d ependent partial sensitization to doxorubicin of resistant P388 mouse leuke mia (P388/ADR), which occurs also in vivo, as indicated by a significant in crease in survival time of the hosts. Doxorubicin intracellular concentrati ons in P388/ADR cells are increased by melatonin, suggesting that melatonin might inhibit P-glycoprotein-mediated doxorubicin efflux from the cells. T hese results indicate that the use of melatonin in clinical cancer treatmen t should not pose the risk of an attenuation of the effectiveness of doxoru bicin, and encourage the further examination of the possible reduction by m elatonin of the host toxicity of antitumor chemotherapy.