Low Doses of the Anti-psychotic Drug Aripiprazole Have Strong P-gp-inhibitory Activity and Sensitize Anti-mitotic Drug-resistant Cancer Cells.

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: Ji Yeong Kim, In Hwan Tae, Byung-Mu Lee, Hyung Sik Kim, Sungpil Yoon
• Journal: Anticancer research (Anticancer Res) Vol. 38 Issue 9 Pg. 5101-5108 (Sep 2018) ISSN: 1791-7530 [Electronic] Greece
• PMID: 30194155 (Publication Type: Journal Article)
• Copyright: Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Chemical References

• ABCB1 protein, human
• ATP Binding Cassette Transporter, Subfamily B
• Antimitotic Agents
• Furans
• Ketones
• Vincristine
• Aripiprazole
• eribulin

Topics

• ATP Binding Cassette Transporter, Subfamily B (metabolism)
• Antimitotic Agents (pharmacology)
• Aripiprazole (pharmacology)
• Cell Line, Tumor
• Cell Survival (drug effects)
• DNA Damage
• Down-Regulation
• Drug Resistance, Neoplasm (drug effects)
• Drug Synergism
• Furans (pharmacology)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Ketones (pharmacology)
• Neoplasms (drug therapy, genetics, metabolism)
• Vincristine (pharmacology)