A semisynthetic taxane Yg-3-46a effectively evades P-glycoprotein and β-III tubulin mediated tumor drug resistance in vitro.
Tumor resistance, especially that mediated by P-glycoprotein (P-gp) and β-III tubulin, is a major obstacle to the efficacy of most microtubule-targeting anticancer drugs in clinics. A novel semisynthetic taxane, 2-debenzoyl-2-(3-azidobenzyl)-10-propionyldocetaxel (Yg-3-46a) was shown to be highly cytotoxic to breast cancer cell lines MCF-7 and MCF/ADR which overexpressed P-gp via long term culture with doxorubicin, and cervical cancer cell lines Hela and Hela/βIII which overexpressed βIII-tubulin via stable transfection with TUBB3 gene. siRNA transfection experiments also confirmed that Yg-3-46a can circumvent P-gp and β-III tubulin mediated drug resistance. In addition, its cytotoxicity was lower than that of paclitaxel in the human mammary cell line HBL-100 and the human telomerase-immortalized retinal pigment epithelium cell line (hTERT-RPE1), suggesting a better safety margin for this compound in vivo. It exhibited more potent microtubule polymerization ability than paclitaxel in vitro, and also induced G2/M phase arrest in MCF-7/ADR cells. Moreover, it was found to induce apoptosis in MCF-7/ADR cells through the caspase-dependent death-receptor pathway by enhancing levels of Fas and FasL, and activating caspase-8 and 3. Yg-3-46a was found to be a poorer substrate of P-gp compared to paclitaxel, in both binding and ATPase experiments, which is likely responsible for its ability to circumvent P-gp mediated multidrug resistance (MDR). All of these results indicate that Yg-3-46a is a novel microtubule-stabilizing agent that has the potential to evade drug resistance mediated by P-gp and β-III tubulin overexpression.
State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, 2A Nan Wei Road, Beijing 100050, China.
Pei
P
Cai
Peihua
P
Lu
Frances J
FJ
Sharom
Wei-Shuo
WS
Fang
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001952:Bridged-Ring Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D053181:Caspase 8 / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D053222:Fas Ligand Protein / Q000378:metabolism; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D061986:MCF-7 Cells; D008856:Microscopy, Fluorescence; D015394:Molecular Structure; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D058105:Polymerization / Q000187:drug effects; D034622:RNA Interference; D043823:Taxoids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014404:Tubulin / Q000235:genetics / Q000378:metabolism*; D019014:fas Receptor / Q000378:metabolism
C585584:2-debenzoyl-2-(3-azidobenzyl)-10-propionyldocetaxel; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D001952:Bridged-Ring Compounds; D053222:Fas Ligand Protein; C498585:TUBB3 protein, human; D043823:Taxoids; D014404:Tubulin; D019014:fas Receptor; C080625:taxane; D053181:Caspase 8; D017239:Paclitaxel
Apoptosis; Microtubule; Multidrug resistance (MDR); P-glycoprotein; Taxane; β-III Tubulin