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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 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.
PMID
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Authors

Mayor MeshTerms
Keywords

Halaven

P-gp inhibitors

cyclosporine A

drug-resistance

elacridar

verapamil

Journal Title anticancer research
Publication Year Start




PMID- 28739698
OWN - NLM
STAT- In-Process
DA  - 20170725
LR  - 20170725
IS  - 1791-7530 (Electronic)
IS  - 0250-7005 (Linking)
VI  - 37
IP  - 8
DP  - 2017 Aug
TI  - 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.
PG  - 4139-4146
AB  - 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.
CI  - Copyright(c) 2017, International Institute of Anticancer Research (Dr. George J. 
      Delinasios), All rights reserved.
FAU - Park, Yujin
AU  - Park Y
AD  - School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea.
FAU - Son, Ji-Yeon
AU  - Son JY
AD  - School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea.
FAU - Lee, Byung-Mu
AU  - Lee BM
AD  - School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea.
FAU - Kim, Hyung Sik
AU  - Kim HS
AD  - School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea.
FAU - Yoon, Sungpil
AU  - Yoon S
AD  - School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea
      [email protected]
LA  - eng
PT  - Journal Article
PL  - Greece
TA  - Anticancer Res
JT  - Anticancer research
JID - 8102988
OTO - NOTNLM
OT  - Halaven
OT  - P-gp inhibitors
OT  - cyclosporine A
OT  - drug-resistance
OT  - elacridar
OT  - verapamil
EDAT- 2017/07/26 06:00
MHDA- 2017/07/26 06:00
CRDT- 2017/07/26 06:00
PHST- 2017/06/12 [received]
PHST- 2017/06/30 [revised]
PHST- 2017/07/03 [accepted]
AID - 37/8/4139 [pii]
PST - ppublish
SO  - Anticancer Res. 2017 Aug;37(8):4139-4146.