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Low Doses of the Anti-psychotic Drug Aripiprazole Have Strong P-gp-inhibitory Activity and Sensitize Anti-mitotic Drug-resistant Cancer Cells.
Anticancer Res 2018; 38(9):5101-5108AR

Abstract

BACKGROUND/AIM

The present study was designed to identify conditions that would increase the sensitivity of resistant cancer cells to anti-mitotic drugs.

MATERIALS AND METHODS

Previously, we showed that KBV20C cancer cells highly resistant to Halaven® (HAL) were sensitized by co-treatment with fluphenazine (FLU). In this study, we found that low doses of aripiprazole (ARI), another antipsychotic drug, sensitized HAL-resistant KBV20C cancer cells. We then investigated the mechanisms and roles of ARI in the sensitization of HAL-treated KBV20C cancer cells.

RESULTS

First-generation P-glycoprotein (P-gp) inhibitor verapamil required a dose that was nearly four-fold higher than that of ARI for P-gp inhibition, which suggested that ARI had a high specificity for P-gp binding to prevent efflux of anti-mitotic drugs. ARI was also found to sensitize HAL-treated KBV20C cells at a low dose, approximately 4-fold lower than that of verapamil. Co-treatment of ARI with another anti-mitotic drug, vincristine, also increased the sensitization of KBV20C cells. ARI caused a reduction in cell viability, increased G2 arrest, and up-regulated expression of the DNA damage protein, pH2AX, when co-treated with HAL. Moreover, G2 phase arrest and apoptosis in HAL-ARI co-treated cells resulted from the up-regulation of retinoblastoma protein, reduced extracellular signal-regulated kinase pathway activity, and down-regulation of cell division cyclin protein.

CONCLUSION

Cancer cells that are highly resistant to HAL can be sensitized with the antipsychotic drug, ARI, which exerts specific P-gp inhibitory effects at a low dose.

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

30194155

Citation

Kim, Ji Yeong, et al. "Low Doses of the Anti-psychotic Drug Aripiprazole Have Strong P-gp-inhibitory Activity and Sensitize Anti-mitotic Drug-resistant Cancer Cells." Anticancer Research, vol. 38, no. 9, 2018, pp. 5101-5108.
Kim JY, Tae IH, Lee BM, et al. Low Doses of the Anti-psychotic Drug Aripiprazole Have Strong P-gp-inhibitory Activity and Sensitize Anti-mitotic Drug-resistant Cancer Cells. Anticancer Res. 2018;38(9):5101-5108.
Kim, J. Y., Tae, I. H., Lee, B. M., Kim, H. S., & Yoon, S. (2018). Low Doses of the Anti-psychotic Drug Aripiprazole Have Strong P-gp-inhibitory Activity and Sensitize Anti-mitotic Drug-resistant Cancer Cells. Anticancer Research, 38(9), pp. 5101-5108. doi:10.21873/anticanres.12830.
Kim JY, et al. Low Doses of the Anti-psychotic Drug Aripiprazole Have Strong P-gp-inhibitory Activity and Sensitize Anti-mitotic Drug-resistant Cancer Cells. Anticancer Res. 2018;38(9):5101-5108. PubMed PMID: 30194155.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Low Doses of the Anti-psychotic Drug Aripiprazole Have Strong P-gp-inhibitory Activity and Sensitize Anti-mitotic Drug-resistant Cancer Cells. AU - Kim,Ji Yeong, AU - Tae,In Hwan, AU - Lee,Byung-Mu, AU - Kim,Hyung Sik, AU - Yoon,Sungpil, PY - 2018/07/27/received PY - 2018/08/06/revised PY - 2018/08/07/accepted PY - 2018/9/9/entrez PY - 2018/9/9/pubmed PY - 2018/9/15/medline KW - Aripiprazole KW - P-gp KW - anti-psychotic drug KW - cancer KW - drug resistance SP - 5101 EP - 5108 JF - Anticancer research JO - Anticancer Res. VL - 38 IS - 9 N2 - BACKGROUND/AIM: The present study was designed to identify conditions that would increase the sensitivity of resistant cancer cells to anti-mitotic drugs. MATERIALS AND METHODS: Previously, we showed that KBV20C cancer cells highly resistant to Halaven® (HAL) were sensitized by co-treatment with fluphenazine (FLU). In this study, we found that low doses of aripiprazole (ARI), another antipsychotic drug, sensitized HAL-resistant KBV20C cancer cells. We then investigated the mechanisms and roles of ARI in the sensitization of HAL-treated KBV20C cancer cells. RESULTS: First-generation P-glycoprotein (P-gp) inhibitor verapamil required a dose that was nearly four-fold higher than that of ARI for P-gp inhibition, which suggested that ARI had a high specificity for P-gp binding to prevent efflux of anti-mitotic drugs. ARI was also found to sensitize HAL-treated KBV20C cells at a low dose, approximately 4-fold lower than that of verapamil. Co-treatment of ARI with another anti-mitotic drug, vincristine, also increased the sensitization of KBV20C cells. ARI caused a reduction in cell viability, increased G2 arrest, and up-regulated expression of the DNA damage protein, pH2AX, when co-treated with HAL. Moreover, G2 phase arrest and apoptosis in HAL-ARI co-treated cells resulted from the up-regulation of retinoblastoma protein, reduced extracellular signal-regulated kinase pathway activity, and down-regulation of cell division cyclin protein. CONCLUSION: Cancer cells that are highly resistant to HAL can be sensitized with the antipsychotic drug, ARI, which exerts specific P-gp inhibitory effects at a low dose. SN - 1791-7530 UR - https://www.unboundmedicine.com/medline/citation/30194155/Low_Doses_of_the_Anti_psychotic_Drug_Aripiprazole_Have_Strong_P_gp_inhibitory_Activity_and_Sensitize_Anti_mitotic_Drug_resistant_Cancer_Cells_ L2 - http://ar.iiarjournals.org/cgi/pmidlookup?view=long&pmid=30194155 DB - PRIME DP - Unbound Medicine ER -