Melanin inhibits cytotoxic effects of doxorubicin and daunorubicin in MOLT 4 cells.
In the present study we have developed a simple method to elucidate the melanin binding ability of different chemotherapeutic agents. The anthracyclines, doxorubicin and daunorubicin, or the alkylating agent cisplatin were preincubated with melanin (Sepia). Melanin and free drug was then separated through centrifugation and the cytotoxic effects of corresponding drug were evaluated in a MTT (3-(4,5-dimetyltiazol-2-yl)-2,5-difenyl-tetrazoliumbromide) assay using MOLT-4 cells. Our results show that melanin pretreatment shifted the IC50 value for doxorubicin from 0.06 to 0.97 microM and for daunorubicin from 0.04 to 0.80 microM. In contrast, the IC50 values of cisplatin was not influenced by melanin pre-treatment indicating that cisplatin does not bind to melanin. By comparing equi-active concentrations from concentration-response curves with or without melanin pretreatment an approximate binding capacity of melanin could be estimated. Our results show that melanin binds about 900 nmol/mg doxorubicin and 760 nmol/mg daunorubicin. Chloroquine, which is known to bind to melanin with high affinity, was found to inhibit melanin binding of both daunorubicin and doxorubicin, thereby leading to an increased sensitivity of the anthracyclines. The clinical implications of melanin binding regarding unwanted accumulation of anthracyclines in the skin as well as chemoprotective effects against chemotherapy are discussed.
Svensson
Samuel P S
SP
Department of Pharmacology, Faculty of Health Sciences, University of Linköping, Linköping, Sweden. samuel.svensson@imv.liu.se
Lindgren
Sofi
S
Powell
Wendy
W
Green
Henrik
H
D000970:Antineoplastic Agents / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000633:toxicity; D045744:Cell Line, Tumor; D002738:Chloroquine / Q000378:metabolism; D003630:Daunorubicin / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000633:toxicity; D006801:Humans; D008543:Melanins / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding
D000970:Antineoplastic Agents; D008543:Melanins; D004317:Doxorubicin; D002738:Chloroquine; D003630:Daunorubicin