Degradation of P-glycoprotein by pristimerin contributes to overcoming ABCB1-mediated chemotherapeutic drug resistance in vitro.

Abstract

ABCB1 (P-glycoprotein, ABCB1/MDR1) is one of the major members of the ABC transporters linked to MDR in cancer cells. In this study, we observed that pristimerin, a natural triterpenoid, potently decreased P-gp in a dose-dependent manner in both drug-resistant KBv200 and stable transfected HEK293/ABCB1 cell lines. Moreover, pristimerin also inhibited cell proliferation and induced apoptosis in both cell lines. Intriguingly, reverse transcription-PCR, real-time PCR and protein turn-over assay revealed that the decrease of P-gp was independent of mRNA level but primarily owing to its protein stability. Furthermore, immunofluorescence study with anti-P-gp antibody showed that pristimerin disturbed the subcellular distribution of P-gp with decreased location in the plasma membrane. Taken together, these data suggest that subcellular distribution of P-gp and subsequent downregulation by pristimerin contribute to overcoming ABCB1-mediated chemotherapeutic drug resistance. Our findings suggested inducing the decrease of P-gp membrane protein could be a new promising alternative therapeutic strategy in ABCB1-mediated MDR.

• Authors: Yan-Yan Yan, Fang Wang, Xiao-Qin Zhao, Xiao-Kun Wang, Yi-Fan Chen, Hong Liu, Yong Xie, Li-Wu Fu
• Journal: Oncology reports (Oncol Rep) Vol. 37 Issue 1 Pg. 31-40 (Jan 2017) ISSN: 1791-2431 [Electronic] Greece
• PMID: 27840996 (Publication Type: Journal Article)

Chemical References

• ABCB1 protein, human
• ATP Binding Cassette Transporter, Subfamily B
• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Pentacyclic Triterpenes
• Triterpenes
• Doxorubicin
• celastrol

Topics

• ATP Binding Cassette Transporter, Subfamily B (genetics, metabolism)
• ATP Binding Cassette Transporter, Subfamily B, Member 1 (metabolism)
• Cell Line, Tumor
• Cells, Cultured
• Doxorubicin (pharmacology)
• Drug Resistance, Multiple (drug effects, genetics)
• Drug Resistance, Neoplasm (drug effects, genetics)
• HEK293 Cells
• Humans
• Pentacyclic Triterpenes
• Proteolysis (drug effects)
• Triterpenes (pharmacology)