Sensitization of multidrug-resistant colon cancer cells to doxorubicin encapsulated in liposomes.
The effectiveness of liposome-encapsulated doxorubicin in overcoming multidrug resistance was studied in various human colon cancer cells. Colon-cancer cell lines SW403, HT29, SW620, and SW620/R overexpressed P-glycoprotein as determined by immunoflow cytometry, thereby confirming the presence of the multidrug-resistant phenotype. Important differences were observed in the cytotoxicity of free doxorubicin as represented by IC50 values of 0.168, 0.058, 0.023, and 9.83 microM for SW403, HT29, SW620, and SW620/R, respectively. Liposomally encapsulated doxorubicin provided an IC50 that was 1.4 times lower than that of the free drug in the doxorubicin-resistant SW 620/R cell line, whereas no difference was evident in the sensitive parental SW620 cells. In addition, liposome-encapsulated doxorubicin exhibited 1.31- and 2.33-fold cytotoxicity to HT-29 and SW403 cells, respectively. The intracellular drug accumulation in SW620/R cells was enhanced by liposomally encapsulated doxorubicin, whereas it was reduced in all other cell lines as compared with that of free drug. The colon-cancer cell lines demonstrated different degrees of doxorubicin-induced DNA strand breakage that correlated with their sensitivities to drug-induced cytotoxicity. However, no difference was observed between DNA breakage caused by the free drug and that induced by liposome-encapsulated doxorubicin in any of the cell lines. The results suggest that the enhanced cytotoxicity of liposomal doxorubicin to colon cancer cells was due to some secondary non-DNA target. However, liposomally encapsulated doxorubicin appears to be effective in diminishing the multidrug-resistant phenotype and may have clinical applications.
Department of Medicine and Pharmacology, Lombardi Cancer Research Center, School of Medicine, Georgetown University, Washington DC 20007.
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Oudard
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Thierry
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Jorgensen
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Rahman
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002277:Carcinoma / Q000188:drug therapy* / Q000378:metabolism; D002460:Cell Line; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D004249:DNA Damage; D004265:DNA Helicases / Q000187:drug effects; D004273:DNA, Neoplasm / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D004337:Drug Carriers; D004351:Drug Resistance; D004354:Drug Screening Assays, Antitumor; D005978:Glutathione / Q000032:analysis / Q000187:drug effects; D006801:Humans; D008081:Liposomes; D008562:Membrane Glycoproteins / Q000032:analysis / Q000187:drug effects; D009363:Neoplasm Proteins / Q000032:analysis / Q000187:drug effects; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004273:DNA, Neoplasm; D004337:Drug Carriers; D008081:Liposomes; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D004317:Doxorubicin; D004265:DNA Helicases; D005978:Glutathione