Tags

Type your tag names separated by a space and hit enter

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.
Anticancer Res 2017; 37(8):4139-4146AR

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+Show Affiliations

School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea.School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea.School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea.School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea.School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea syoon88@gmail.com.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28739698

Citation

Park, Yujin, et al. "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." Anticancer Research, vol. 37, no. 8, 2017, pp. 4139-4146.
Park Y, Son JY, Lee BM, et al. 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. Anticancer Res. 2017;37(8):4139-4146.
Park, Y., Son, J. Y., Lee, B. M., Kim, H. S., & Yoon, S. (2017). 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. Anticancer Research, 37(8), pp. 4139-4146.
Park Y, et al. 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. Anticancer Res. 2017;37(8):4139-4146. PubMed PMID: 28739698.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Park,Yujin, AU - Son,Ji-Yeon, AU - Lee,Byung-Mu, AU - Kim,Hyung Sik, AU - Yoon,Sungpil, PY - 2017/06/12/received PY - 2017/06/30/revised PY - 2017/07/03/accepted PY - 2017/7/26/entrez PY - 2017/7/26/pubmed PY - 2017/8/11/medline KW - Halaven KW - P-gp inhibitors KW - cyclosporine A KW - drug-resistance KW - elacridar KW - verapamil SP - 4139 EP - 4146 JF - Anticancer research JO - Anticancer Res. VL - 37 IS - 8 N2 - 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. SN - 1791-7530 UR - https://www.unboundmedicine.com/medline/citation/28739698/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_ L2 - http://ar.iiarjournals.org/cgi/pmidlookup?view=long&pmid=28739698 DB - PRIME DP - Unbound Medicine ER -