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
- Authors
- Park, Y.[Park, Y.]; Son, J.-Y.[Son, J.-Y.]; Lee, B.-M.[Lee, B.-M.]; Kim, H.S.[Kim, H.S.]; Yoon, S.[Yoon, S.]
- Issue Date
- Aug-2017
- Publisher
- INT INST ANTICANCER RESEARCH
- Keywords
- Cyclosporine A; Drug-resistance; Elacridar; Halaven; P-gp inhibitors; Verapamil
- Citation
- ANTICANCER RESEARCH, v.37, no.8, pp.4139 - 4146
- Indexed
- SCIE
SCOPUS
- Journal Title
- ANTICANCER RESEARCH
- Volume
- 37
- Number
- 8
- Start Page
- 4139
- End Page
- 4146
- URI
- https://scholarworks.bwise.kr/skku/handle/2021.sw.skku/28022
- DOI
- 10.21873/anticanres.11801
- ISSN
- 0250-7005
- Abstract
- Background/Aim: Eribulin mesylate, also called Halaven (R) (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.
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Collections - Pharmacy > Department of Pharmacy > 1. Journal Articles
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