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

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.

• Authors: Pei Cai, Peihua Lu, Frances J Sharom, Wei-Shuo Fang
• Journal: Cancer letters (Cancer Lett) Vol. 341 Issue 2 Pg. 214-23 (Dec 01 2013) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 23941826 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• 2-debenzoyl-2-(3-azidobenzyl)-10-propionyldocetaxel
• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Antineoplastic Agents
• Bridged-Ring Compounds
• Fas Ligand Protein
• TUBB3 protein, human
• Taxoids
• Tubulin
• fas Receptor
• taxane
• Caspase 8
• Paclitaxel

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (genetics, metabolism)
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Apoptosis (drug effects)
• Blotting, Western
• Bridged-Ring Compounds (chemical synthesis, chemistry, pharmacology)
• Caspase 8 (metabolism)
• Cell Line
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Drug Resistance, Neoplasm (drug effects)
• Fas Ligand Protein (metabolism)
• G2 Phase Cell Cycle Checkpoints (drug effects)
• HeLa Cells
• Humans
• MCF-7 Cells
• Microscopy, Fluorescence
• Molecular Structure
• Neoplasms (genetics, metabolism, pathology)
• Paclitaxel (analogs & derivatives, chemistry, pharmacology)
• Polymerization (drug effects)
• RNA Interference
• Taxoids (chemical synthesis, chemistry, pharmacology)
• Tubulin (genetics, metabolism)
• fas Receptor (metabolism)