Polyaromatic alkaloids from marine invertebrates as cytotoxic compounds and inhibitors of multidrug resistance caused by P-glycoprotein.
The effects of several members of the family of lamellarins, polyaromatic alkaloids isolated from tunicates belonging to the genus Didemnum, on the growth of several tumour cell lines and on P-glycoprotein (P-gp)-mediated multidrug resistance (MDR), were investigated. Cytotoxicity experiments of lamellarins were performed on a panel of tumour cell lines, including two multidrug-resistant cell lines. Some lamellarins showed good anti-tumour activity, with similar levels of cytotoxicity against both the resistant and their corresponding parental cell lines. Two lamellarins displayed a high potency against lung carcinoma cells. Studies of the resistance modifier activity of the different lamellarins at non-toxic concentrations were also carried out in cells exhibiting MDR, and lamellarin I was selected for the highest chemosensitising activity. At non-toxic doses, verapamil and lamellarin I effectively increased the cytotoxicity of doxorubicin, vinblastine and daunorubicin in a concentration-dependent manner in multidrug-resistant cells, but the potency of lamellarin I as a MDR modulator was 9- to 16-fold higher than that of verapamil. In vitro measurements of rhodamine 123 accumulation in the multidrug-resistant Lo Vo/Dx cells suggest that lamellarin I reverses MDR by directly inhibiting the P-gp-mediated drug efflux. This work underscores the possibility of using these marine-derived compounds as a potential new source of anti-tumoral drugs active on resistant cells as well as of non-toxic modulators of the MDR phenotype.
Quesada
A R
AR
Facultad de Ciencias, Universidad de Málaga, Spain.
García Grávalos
M D
MD
Fernández Puentes
J L
JL
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology; D000230:Adenocarcinoma / Q000188:drug therapy; D000470:Alkaloids / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000378:metabolism; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy*; D006224:Cricetinae; D003630:Daunorubicin / Q000008:administration & dosage; D004317:Doxorubicin / Q000008:administration & dosage; D018432:Drug Resistance, Multiple / Q000502:physiology*; D019008:Drug Resistance, Neoplasm / Q000502:physiology; D006801:Humans; D007941:Leukemia P388 / Q000188:drug therapy*; D008175:Lung Neoplasms / Q000188:drug therapy*; D051379:Mice; D020112:Rhodamine 123; D012235:Rhodamines / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000008:administration & dosage; D014747:Vinblastine / Q000008:administration & dosage
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000470:Alkaloids; D000964:Antimetabolites, Antineoplastic; D012235:Rhodamines; D020112:Rhodamine 123; D014747:Vinblastine; D004317:Doxorubicin; D014700:Verapamil; D003630:Daunorubicin