A semisynthetic taxane Yg-3-46a effectively evades P-glycoprotein and β-III tubulin mediated tumor drug resistance in vitro

• Published in: Cancer letters 2013-12, Vol.341 (2), p.214-223
• Main Authors: Cai, Pei, Lu, Peihua, Sharom, Frances J, Fang, Wei-Shuo
• Format: Article
• Language: English
• Subjects: adenosinetriphosphatase; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; ATP-Binding Cassette, Sub-Family B, Member 1 - genetics; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Blotting, Western; breast neoplasms; Bridged-Ring Compounds - chemical synthesis; Bridged-Ring Compounds - chemistry; Bridged-Ring Compounds - pharmacology; Caspase 8 - metabolism; caspase-8; Cell Line; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; cytotoxicity; doxorubicin; Drug Resistance, Neoplasm - drug effects; epithelium; Fas Ligand Protein - metabolism; fas Receptor - metabolism; G2 Phase Cell Cycle Checkpoints - drug effects; gene overexpression; genes; HeLa Cells; Hematology, Oncology and Palliative Medicine; Humans; margin of safety; MCF-7 Cells; Microscopy, Fluorescence; Microtubule; Molecular Structure; Multidrug resistance (MDR); multiple drug resistance; Neoplasms - genetics; Neoplasms - metabolism; Neoplasms - pathology; P-glycoprotein; paclitaxel; Paclitaxel - analogs & derivatives; Paclitaxel - chemistry; Paclitaxel - pharmacology; polymerization; Polymerization - drug effects; RNA Interference; Taxane; taxanes; Taxoids - chemical synthesis; Taxoids - chemistry; Taxoids - pharmacology; transfection; tubulin; Tubulin - genetics; Tubulin - metabolism; uterine cervical neoplasms; β-III Tubulin
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2013.08.010

Abstract 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.