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Research ArticleExperimental Studies

A Low Dose of Aripiprazole Has the Strongest Sensitization Effect Among 19 Repositioned Bipolar Drugs in P-gp-overexpressing Drug-resistant Cancer Cells

CHUNXUE JIANG, SU HYUN LEE, JAE HYEON PARK, JIN-SOL LEE, JI WON PARK, JU RI KIM, SONG HEE LEE, HYUNG SIK KIM and SUNGPIL YOON
Anticancer Research February 2021, 41 (2) 687-697; DOI: https://doi.org/10.21873/anticanres.14820
CHUNXUE JIANG
School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea
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SU HYUN LEE
School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea
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JAE HYEON PARK
School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea
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JIN-SOL LEE
School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea
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JI WON PARK
School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea
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JU RI KIM
School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea
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SONG HEE LEE
School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea
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HYUNG SIK KIM
School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea
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  • For correspondence: syoon88@gmail.com hkims@skku.edu
SUNGPIL YOON
School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea
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  • For correspondence: syoon88@gmail.com hkims@skku.edu
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Abstract

Background/Aim: We investigated drugs that could sensitize P-glycoprotein (P-gp)-overexpressing drug-resistant cancer cells to vincristine (VIC) or eribulin treatment and assessed their associated mechanisms of action. Materials and Methods: We investigated 15 bipolar drugs (quetiapine, risperidone, clozapine, asenapine, iloperidone, paliperidone, ziprasidone, trifluoperazine, loxapine succinate, pilocarpine, valproic acid, carbamazepine, levetiracetam, topiramate, and felbamate) to identify drugs with a sensitizing effect on VIC-resistant KBV20C cells at relatively low doses. Fluorescence-activated cell sorting (FACS), annexin V analyses, and rhodamine uptake tests were performed to further investigate the mechanism of action. Results: We found that co-treatment with half the tested drugs (quetiapine, iloperidone, trifluoperazine, loxapine, risperidone, ziprasidone, or felbamate) at low doses could highly sensitize VIC-resistant KBV20C cells. With lower amounts of the bipolar drugs or VIC, we found that among the 15 bipolar drugs tested, 2 combinations (VIC-quetiapine and VIC-trifluoperazine) had much higher sensitization effects, suggesting that lower effective doses were sufficient for sensitizing P-gp-overexpressing resistant cells compared to those required with the other drugs. Furthermore, when we compared quetiapine and trifluoperazine to previously known bipolar drugs (fluphenazine, thioridazine, pimozide, or aripiprazole), we found that aripiprazole, administered at lower doses, had a much higher sensitization effect. We also demonstrated that co-treatment with another anti-mitotic drug (eribulin) increased the sensitization of KBV20C cells similar to VIC. We also found that aripiprazole had higher P-gp-inhibitory activity than the other bipolar drugs, indicating that this activity was involved in the higher level of VIC-aripiprazole sensitization. Conclusion: Co-treatment of anti-mitotic drug-resistant cancer cells with a low dose of aripiprazole had the strongest sensitization effect and is highly dependent on P-gp-inhibitory activity.

Key Words:
  • Aripiprazole
  • quetiapine
  • trifluoperazine
  • bipolar drugs
  • repositioning drug
  • resistant cancer
  • P-gp
  • Received December 3, 2020.
  • Revision received December 22, 2020.
  • Accepted January 14, 2021.
  • Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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Anticancer Research: 41 (2)
Anticancer Research
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February 2021
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A Low Dose of Aripiprazole Has the Strongest Sensitization Effect Among 19 Repositioned Bipolar Drugs in P-gp-overexpressing Drug-resistant Cancer Cells
CHUNXUE JIANG, SU HYUN LEE, JAE HYEON PARK, JIN-SOL LEE, JI WON PARK, JU RI KIM, SONG HEE LEE, HYUNG SIK KIM, SUNGPIL YOON
Anticancer Research Feb 2021, 41 (2) 687-697; DOI: 10.21873/anticanres.14820

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A Low Dose of Aripiprazole Has the Strongest Sensitization Effect Among 19 Repositioned Bipolar Drugs in P-gp-overexpressing Drug-resistant Cancer Cells
CHUNXUE JIANG, SU HYUN LEE, JAE HYEON PARK, JIN-SOL LEE, JI WON PARK, JU RI KIM, SONG HEE LEE, HYUNG SIK KIM, SUNGPIL YOON
Anticancer Research Feb 2021, 41 (2) 687-697; DOI: 10.21873/anticanres.14820
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Keywords

  • Aripiprazole
  • quetiapine
  • trifluoperazine
  • bipolar drugs
  • repositioning drug
  • resistant cancer
  • P-gp
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