A new 2α,5α,10β,14β-tetraacetoxy-4(20),11-taxadiene (SIA) derivative overcomes paclitaxel resistance by inhibiting MAPK signaling and increasing paclitaxel accumulation in breast cancer cells.

Abstract

Tumor resistance due to multiple mechanisms seriously hinders the efficacy of chemotherapy drugs such as paclitaxel. The most widely studied P-glycoprotein inhibitors still have limited ability to reverse resistance in the clinic. In this study, NPB304, a novel Sinenxan A (SIA) derivative, was found to significantly sensitize resistant breast cancer cells to paclitaxel in vitro and in vivo. Treatment with NPB304 increased paclitaxel-induced apoptosis in a p53-dependent manner through PARP cleavage. Importantly, NPB304 enhanced the antitumor effect of paclitaxel in resistant breast tumor xenografts in nude mice without significantly affecting weight loss. NPB304 regulated cell resistance through inhibition of MAPK pathway components, including p-ERK and p-p38. Moreover, NPB304 increased paclitaxel accumulation by affecting P-gp function. In addition to increasing Rhodamine 123 accumulation, NPB304 promoted bidirectional permeability but decreased the efflux ratio of paclitaxel in a Caco-2 monolayer model, thereby increasing the intracellular concentration of paclitaxel. Similarly, NPB304 increased the concentration of paclitaxel in the resistant tumor tissue. Hence, NPB304 is a novel compound that promotes the sensitization of resistant cells to paclitaxel through multiple mechanisms and has the potential for use in combination therapies to treat resistant breast cancer.

• Authors: Mei Mei, Dan Xie, Yi Zhang, Jing Jin, Feng You, Yan Li, Jungui Dai, Xiaoguang Chen
• Journal: PloS one (PLoS One) Vol. 9 Issue 8 Pg. e104317 ( 2014) ISSN: 1932-6203 [Electronic] United States
• PMID: 25093335 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Acetates
• Antineoplastic Agents
• Diterpenes
• sinenxan A
• Paclitaxel

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (genetics, metabolism)
• Acetates (chemical synthesis, chemistry, pharmacology)
• Animals
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Apoptosis (drug effects)
• Breast Neoplasms (genetics, metabolism)
• Cell Line, Tumor
• Disease Models, Animal
• Diterpenes (chemical synthesis, chemistry, pharmacology)
• Drug Resistance, Neoplasm (genetics)
• Drug Synergism
• Female
• Humans
• MAP Kinase Signaling System (drug effects)
• Paclitaxel (pharmacology)
• Xenograft Model Antitumor Assays