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

Abstract

Melatonin has been reported to attenuate the oxidative damage caused by doxorubicin on kidney, brain, heart and bone marrow, whereas the in vivo antitumor effects of doxorubicin were not attenuated. The effects of melatonin on doxorubicin cytotoxicity have, therefore, been examined on human normal mammary epithelium HBL-100, on mammary adenocarcinoma MCF-7, on colon carcinoma LoVo, and on mouse P388 leukemia cell lines, and on tumor cell sublines pleiotropically resistant to anthracyclines. Melatonin in the concentration 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 significant. Melatonin similarly causes minor effects on doxorubicin cytotoxicity either on the parental human cell lines or on their resistant sublines. On the contrary, 200-1000 pg/mL melatonin cause a significant and dose-dependent partial sensitization to doxorubicin of resistant P388 mouse leukemia (P388/ADR), which occurs also in vivo, as indicated by a significant increase in survival time of the hosts. Doxorubicin intracellular concentrations in P388/ADR cells are increased by melatonin, suggesting that melatonin might inhibit P-glycoprotein-mediated doxorubicin efflux from the cells. These results indicate that the use of melatonin in clinical cancer treatment should not pose the risk of an attenuation of the effectiveness of doxorubicin, and encourage the further examination of the possible reduction by melatonin of the host toxicity of antitumor chemotherapy.

Glutathione depletion-induced apoptosis of Ha-ras-transformed NIH3T3 cells can be prevented by melatonin

“…Third, melatonin has been proven to counteract chemotherapy toxicity by acting as an antioxidant, such as neurotoxicity, cardiotoxicity, stomatitis, and asthenia (Lissoni et al, 1999;Agapito et al, 2001;Xu et al, 2001). Melatonin also increases the efficacy of chemotherapeutic agents (Granzotto et al, 2001;Reiter et al, 2002). Here, we demonstrate that melatonin markedly blocked apoptosis of cells manifesting ras-overexpression and GSH depletion, which suggests that it should be under consideration if coadministration of BSO and melatonin is used to treat ras-related cancer cells.…”

What is known about melatonin, chemotherapy and altered gene expression in breast cancer

“…The present study also reviewed recently published articles associating melatonin with chemotherapeutic agents (135–137,142–149). The results indicate that, for 53 out of the 84 genes evaluated, there are no current data available regarding the effect of melatonin alone or in combination with chemotherapy, either in in vivo or in in vitro studies.…”

“…The resistance of cancer cells to chemotherapy treatments such as doxorubicin usually implicates an upregulation of P-glycoprotein, which is responsible for drug efflux from cells (136). In this context, there is a report describing that melatonin treatment increases doxorubicin intracellular concentrations in cancer cells, suggesting that melatonin may inhibit P-glycoprotein (137). In breast cancer xenografts implanted in animal models (nude mice), treatment with the pineal hormone stopped the tumor progression by reducing tumor size and cell proliferation (Ki-67), as well as by inhibiting angiogenesis (138).…”

“…Recently, the inhibitory effects of melatonin have been described not only for estrogen-dependent breast tumors, but also for numerous different cancers, including gastric cancer, ovarian carcinoma, pancreatic ductal carcinoma, leukemic cell lines, cervical cancer and non-small lung carcinoma cells (25,137–139,142,143,153). The majority of the results are positive, and melatonin has been described as an inhibitor of tumor growth under both in vitro and in vivo experimental conditions (64,81,97).…”

Integrative Physician’s Perspective

“…We agree with his comments that if primary resistance to Adriamycin and Cytoxan were observed, taxane therapy would be appropriate. We would add that melatonin 1 and fish oil 2 have demonstrated in vitro abilities to sensitize multidrug resistant tumor lines to the effects of chemotherapy. While Boasberg is correct that neoadjuvant therapy has not yet shown positive survival benefits in randomized trials, there is growing interest in this strategy due in part to recognized mechanisms of how malignant disease proliferates.…”