Schisandrin B reverses doxorubicin resistance through inhibiting P-glycoprotein and promoting proteasome-mediated degradation of survivin.

Abstract

Acquired drug resistance poses a great challenge in cancer therapy. Drug efflux and anti-apoptotic processes are the most two common mechanisms that confer cancer drug resistance. In this study, we found that Schisandrin B (Sch B), one of the major dibenzocyclooctadiene derivatives extracted from Chinese herbal medicine Schisandrae Chinensis Fructus, could significantly enhance the sensitivity of doxorubicin (DOX)-resistant breast cancer and ovarian cancer cells to DOX. Our results showed that Sch B increased the intracellular accumulation of DOX through inhibiting expression and activity of P-glycoprotein (P-gp). Meanwhile, Sch B could markedly downregulate the expression of anti-apoptotic protein survivin. Overexpression of survivin attenuated the sensitizing effects of Sch B, while silencing of survivin enhanced Sch B-mediated sensitizing effects. Furthermore, Sch B preferentially promoted chymotryptic activity of the proteasome in a concentration-dependent manner, and the proteasome inhibitor MG-132 prevented Sch B-induced survivin downregulation. Taken together, our findings suggest that Sch B could be a potential candidate for combating drug resistant cancer via modulating two key factors that responsible for cancer resistance.

• Authors: Shengpeng Wang, Anqi Wang, Min Shao, Ligen Lin, Peng Li, Yitao Wang
• Journal: Scientific reports (Sci Rep) Vol. 7 Issue 1 Pg. 8419 (08 21 2017) ISSN: 2045-2322 [Electronic] England
• PMID: 28827665 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Anti-Inflammatory Agents
• Antineoplastic Agents
• Cyclooctanes
• Lignans
• Polycyclic Compounds
• Survivin
• schizandrin B
• Doxorubicin
• Proteasome Endopeptidase Complex

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (antagonists & inhibitors)
• Anti-Inflammatory Agents
• Antineoplastic Agents (pharmacology)
• Cell Line, Tumor
• Cyclooctanes (pharmacology)
• Doxorubicin (pharmacology)
• Drug Resistance (drug effects)
• Humans
• Lignans (pharmacology)
• Polycyclic Compounds (pharmacology)
• Proteasome Endopeptidase Complex (metabolism)
• Survivin (metabolism)