Highly Eribulin-resistant KBV20C Oral Cancer Cells Can Be Sensitized by Co-treatment with the Third-generation P-Glycoprotein Inhibitor, Elacridar, at a Low Dose.

Abstract

BACKGROUND/AIM:

Eribulin mesylate, also called Halaven® (HAL), was recently developed as a microtubule-targeting drug and is used in the clinic for resistant or metastatic cancer. Previously, we showed that P-glycoprotein (P-gp)-overexpressing KBV20C oral cancer cells are highly resistant to HAL compared to sensitive KB cells. This qualitative study was designed to identify specific P-gp inhibitors that increase the sensitivity of highly resistant cancer cells to HAL.

MATERIALS AND METHODS:

In order to identify functional P-gp inhibitors, HAL-treated KBV20C cells were co-treated with P-gp inhibitors, verapamil, elacridar, cyclosporine A, mitotane, piperine, fumagillin, curcumin, indomethacin, probenecid, sulindac, tesmilifene, and C-4. We then evaluated which P-gp inhibitors required a low dose to sensitize KBV20C cells to HAL. We also determined whether a low dose of a P-gp inhibitor could inhibit P-gp efflux pumping.

RESULTS:

We found that cyclosporine A sensitized HAL-treated KBV20C cells at a low dose, whereas verapamil, another first-generation P-gp inhibitor, required a dose that was nearly 10-fold higher. We also found that the natural products, piperine and mitotane, sensitized KBV20C cells to HAL co-treatment. Interestingly, we found that elacridar, a third-generation P-gp inhibitor, sensitized HAL-treated cells at a low dose. Elacridar required approximately a 500-fold lower dose than that of verapamil to exert a similar effect. All inhibitors showed P-gp inhibitory activity that correlated with sensitivity to HAL.

CONCLUSION:

These results suggest that highly HAL-resistant cancer cells can be sensitized with cyclosporine A or elacridar, specific P-gp inhibitors that exert their effects at a low dose. These findings provide important information regarding the sensitization of highly HAL-resistant cells with selective P-gp inhibitors and indicate that elacridar may be used to treat such highly HAL-resistant cancer cells.

• Authors: Yujin Park, Ji-Yeon Son, Byung-Mu Lee, Hyung Sik Kim, Sungpil Yoon
• Journal: Anticancer research (Anticancer Res) Vol. 37 Issue 8 Pg. 4139-4146 (08 2017) ISSN: 1791-7530 [Electronic] Greece
• PMID: 28739698 (Publication Type: Journal Article)
• Copyright: Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Acridines
• Furans
• Ketones
• Tetrahydroisoquinolines
• eribulin
• Elacridar

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (antagonists & inhibitors)
• Acridines (administration & dosage)
• Cell Line, Tumor
• Dose-Response Relationship, Drug
• Drug Resistance, Neoplasm (drug effects, genetics)
• Drug Synergism
• Furans (administration & dosage)
• Humans
• Ketones (administration & dosage)
• Mouth Neoplasms (drug therapy, genetics, pathology)
• Tetrahydroisoquinolines (administration & dosage)