Salinomycin, a p-glycoprotein inhibitor, sensitizes radiation-treated cancer cells by increasing DNA damage and inducing G2 arrest.

Abstract

Salinomycin (Sal) is potentially useful for the treatment of cancer. The present study examined a novel mechanism of Sal sensitization in cancer cells. Sal sensitized radiation-treated cancer cells by inducing G2 arrest and causing DNA damage. Sal treatment also reduced p21 levels in radiation-treated cells. Considering that Sal sensitizes doxorubicin (DOX)- or etoposide (ETO)-treated cancer cells by causing DNA damage and reducing p21 expression, the results from our study suggest that the mechanism underlying Sal sensitization is conserved in both chemo- and radiation-treated cells. We also tested the ability of Sal to inhibit p-glycoprotein (P-gp), which plays a role in the efflux of anti-cancer drugs to reduce cellular damage. In particular, we compared Sal to verapamil (Ver), a well-known P-gp inhibitor. Sal inhibits P-gp with a different substrate distinct from that of Ver. In addition, Sal sensitized Ver-resistant cells, indicating that this compound is more effective for sensitizing than Ver. Taken together, the results from our study may contribute to the development of Sal-based therapy for cancer patients treated with P-gp-inhibiting drugs or radiation therapy.

• Authors: Won Ki Kim, Ju-Hwa Kim, Kyungsil Yoon, Sunshin Kim, Jungsil Ro, Han Sung Kang, Sungpil Yoon
• Journal: Investigational new drugs (Invest New Drugs) Vol. 30 Issue 4 Pg. 1311-8 (Aug 2012) ISSN: 1573-0646 [Electronic] United States
• PMID: 21573958 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Cyclin-Dependent Kinase Inhibitor p21
• Pyrans
• salinomycin
• Verapamil

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (antagonists & inhibitors, metabolism)
• Cell Line, Tumor
• Combined Modality Therapy
• Cyclin-Dependent Kinase Inhibitor p21 (metabolism)
• DNA Damage
• Drug Screening Assays, Antitumor
• G2 Phase Cell Cycle Checkpoints (drug effects)
• Humans
• Neoplasms (drug therapy, pathology, radiotherapy)
• Pyrans (pharmacology, therapeutic use)
• Substrate Specificity (drug effects)
• Verapamil (pharmacology, therapeutic use)