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P-gp Inhibition by the Anti-psychotic Drug Pimozide Increases Apoptosis, as well as Expression of pRb and pH2AX in Highly Drug-resistant KBV20C Cells.
Anticancer Res 2018; 38(10):5685-5692AR

Abstract

BACKGROUND/AIM

The present study was designed to identify drugs that could sensitize P-glycoprotein (P-gp)-overexpressing resistant KBV20C cancer cells to treatment with Halaven (HAL) or vincristine (VIC).

MATERIALS AND METHODS

Using relatively low doses or IC50 concentrations of drugs to sensitize anti-mitotic drug-resistant KBV20C cells, pimozide (PIM) sensitized HAL-resistant KBV20C cancer cells, with higher P-gp inhibitory activity than another anti-psychotic drug, fluphenazine (FLU).

RESULTS

The first-generation P-gp inhibitor verapamil required a dose that was similar to that of PIM for P-gp inhibition, suggesting that PIM has a similar specificity for binding P-gp to prevent efflux of anti-mitotic drugs. Furthermore, co-treatment with PIM and another anti-mitotic drug, VIC, also increased sensitization of KBV20C cells, suggesting that PIM can be combined with other anti-mitotic drugs to sensitize resistant cancer cells. PIM caused a reduction in cell viability and an increase in the number of cells arresting at the G2 phase of the cell cycle. PIM induced both early and late apoptosis in KBV20C cells in response to HAL treatment. Furthermore, the DNA damage marker pH2AX, the cell-cycle protein pRb, and the pro-apoptotic protein C-PARP levels increased after HAL-PIM co-treatment, indicative of a mechanism involving G2 phase arrest and an increase in the number of cells undergoing apoptosis.

CONCLUSION

PIM may be a promising therapeutic agent for the treatment of cancers that are resistant to anti-mitotic drugs.

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

30275188

Citation

Kim, Ji Yeong, et al. "P-gp Inhibition By the Anti-psychotic Drug Pimozide Increases Apoptosis, as Well as Expression of pRb and pH2AX in Highly Drug-resistant KBV20C Cells." Anticancer Research, vol. 38, no. 10, 2018, pp. 5685-5692.
Kim JY, Park Y, Lee BM, et al. P-gp Inhibition by the Anti-psychotic Drug Pimozide Increases Apoptosis, as well as Expression of pRb and pH2AX in Highly Drug-resistant KBV20C Cells. Anticancer Res. 2018;38(10):5685-5692.
Kim, J. Y., Park, Y., Lee, B. M., Kim, H. S., & Yoon, S. (2018). P-gp Inhibition by the Anti-psychotic Drug Pimozide Increases Apoptosis, as well as Expression of pRb and pH2AX in Highly Drug-resistant KBV20C Cells. Anticancer Research, 38(10), pp. 5685-5692. doi:10.21873/anticanres.12905.
Kim JY, et al. P-gp Inhibition By the Anti-psychotic Drug Pimozide Increases Apoptosis, as Well as Expression of pRb and pH2AX in Highly Drug-resistant KBV20C Cells. Anticancer Res. 2018;38(10):5685-5692. PubMed PMID: 30275188.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - P-gp Inhibition by the Anti-psychotic Drug Pimozide Increases Apoptosis, as well as Expression of pRb and pH2AX in Highly Drug-resistant KBV20C Cells. AU - Kim,Ji Yeong, AU - Park,Yujin, AU - Lee,Byung-Mu, AU - Kim,Hyung Sik, AU - Yoon,Sungpil, PY - 2018/08/27/received PY - 2018/09/12/revised PY - 2018/09/14/accepted PY - 2018/10/3/entrez PY - 2018/10/3/pubmed PY - 2018/10/13/medline KW - P-gp KW - Pimozide KW - cancer KW - drug resistance KW - repositioning drug SP - 5685 EP - 5692 JF - Anticancer research JO - Anticancer Res. VL - 38 IS - 10 N2 - BACKGROUND/AIM: The present study was designed to identify drugs that could sensitize P-glycoprotein (P-gp)-overexpressing resistant KBV20C cancer cells to treatment with Halaven (HAL) or vincristine (VIC). MATERIALS AND METHODS: Using relatively low doses or IC50 concentrations of drugs to sensitize anti-mitotic drug-resistant KBV20C cells, pimozide (PIM) sensitized HAL-resistant KBV20C cancer cells, with higher P-gp inhibitory activity than another anti-psychotic drug, fluphenazine (FLU). RESULTS: The first-generation P-gp inhibitor verapamil required a dose that was similar to that of PIM for P-gp inhibition, suggesting that PIM has a similar specificity for binding P-gp to prevent efflux of anti-mitotic drugs. Furthermore, co-treatment with PIM and another anti-mitotic drug, VIC, also increased sensitization of KBV20C cells, suggesting that PIM can be combined with other anti-mitotic drugs to sensitize resistant cancer cells. PIM caused a reduction in cell viability and an increase in the number of cells arresting at the G2 phase of the cell cycle. PIM induced both early and late apoptosis in KBV20C cells in response to HAL treatment. Furthermore, the DNA damage marker pH2AX, the cell-cycle protein pRb, and the pro-apoptotic protein C-PARP levels increased after HAL-PIM co-treatment, indicative of a mechanism involving G2 phase arrest and an increase in the number of cells undergoing apoptosis. CONCLUSION: PIM may be a promising therapeutic agent for the treatment of cancers that are resistant to anti-mitotic drugs. SN - 1791-7530 UR - https://www.unboundmedicine.com/medline/citation/30275188/P_gp_Inhibition_by_the_Anti_psychotic_Drug_Pimozide_Increases_Apoptosis_as_well_as_Expression_of_pRb_and_pH2AX_in_Highly_Drug_resistant_KBV20C_Cells_ L2 - http://ar.iiarjournals.org/cgi/pmidlookup?view=long&pmid=30275188 DB - PRIME DP - Unbound Medicine ER -