Novel plant triterpenoid drug amooranin overcomes multidrug resistance in human leukemia and colon carcinoma cell lines.
Amooranin (AMR), a plant terpenoid, isolated from Amoora rohituka, was investigated for its ability to overcome multidrug resistance in human leukemia and colon carcinoma cell lines. AMR IC(50) values of multidrug-resistant leukemia (CEM/VLB) and colon carcinoma (SW620/Ad-300) cell lines were higher (1.9- and 6-fold) than parental sensitive cell lines (CEM and SW620). AMR induced G(2)+M phase-arrest during cell cycle traverse in leukemia and colon carcinoma cell lines and the percentage of cells in G(2)+M phase increased in a dose-dependent manner. Coincubation of tumor cells with both DOX and AMR reversed DOX resistance in 104-fold DOX-resistant CEM/VLB and 111-fold DOX-resistant SW620/Ad-300 cell lines with a dose modification factor of 50.9 and 99.6, respectively. Flow cytometric assay showed that AMR causes enhanced cellular DOX accumulation in a dose-dependent manner. AMR inhibits photolabeling of P-glycoprotein (P-gp) with [(3)H]-azidopine and the blocking effect enhanced with increasing concentrations of AMR. Our results show that AMR competitively inhibits P-gp-mediated DOX efflux, suggestive of a mechanism underlying the enhanced DOX accumulation and reversal of multidrug resistance by AMR.
Ramachandran
Cheppail
C
Research Institute, Miami Children's Hospital, Miami, FL 33155, USA. cheppail.ramachandran@mch.com
Rabi
Thangaiyan
T
Fonseca
Hugo B
HB
Melnick
Steven J
SJ
Escalon
Enrique A
EA
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000032:analysis; D000345:Affinity Labels; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000633:toxicity*; D001386:Azides; D002277:Carcinoma / Q000188:drug therapy* / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D004095:Dihydropyridines; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000378:metabolism / Q000633:toxicity; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007938:Leukemia / Q000188:drug therapy* / Q000378:metabolism; D014315:Triterpenes / Q000737:chemistry / Q000633:toxicity*; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000345:Affinity Labels; D000972:Antineoplastic Agents, Phytogenic; D001386:Azides; D004095:Dihydropyridines; D014315:Triterpenes; C453733:amooranin; C041130:azidopine; D004317:Doxorubicin