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Research ArticleExperimental Studies

Co-treatment With HIV Protease Inhibitor Nelfinavir Greatly Increases Late-phase Apoptosis of Drug-resistant KBV20C Cancer Cells Independently of P-Glycoprotein Inhibition

JI YEONG KIM, YOO JUNG PARK, BYUNG-MU LEE and SUNGPIL YOON
Anticancer Research July 2019, 39 (7) 3757-3765; DOI: https://doi.org/10.21873/anticanres.13524
JI YEONG KIM
School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea
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YOO JUNG PARK
School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea
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BYUNG-MU LEE
School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea
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SUNGPIL YOON
School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea
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  • For correspondence: syoon88@gmail.com
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Abstract

Background/Aim: The study focused on identifying the mechanisms or drugs that might sensitize resistant KBV20C human oral squamous carcinoma cells overexpressing P-glycoprotein (P-gp) to antimitotic drug treatment. Materials and Methods: Five HIV protease inhibitors (atazanavir, nelfinavir, darunavir, lopinavir, and ritonavir) were tested to identify drugs that could be used at a relatively low dose for sensitizing antimitotic drug-resistant KBV20C cells. Fluorescence-activated cell sorting, annexin V analyses, and rhodamine uptake tests were performed to further investigate the mechanism of action. Results: Co-treatment with nelfinavir or lopinavir had a high sensitizing effect on vincristine-treated KBV20C cells. Nelfinavir and lopinavir reduced cell viability, increased G2 phase arrest, and up-regulated apoptosis when used as a co-treatment with vincristine. We also demonstrated that eribulin co-treatment with nelfinavir and lopinavir similarly increased sensitization of KBV20C cells. Only lopinavir was found to have a high P-gp-inhibitory activity (similar to verapamil). Interestingly, nelfinavir had very low P-gp-inhibitory activity, suggesting that vincristine–nelfinavir sensitization is independent of the P-gp-inhibitory effect of nelfinavir. We also demonstrated this same combination mainly caused sensitization due to late apoptosis in P-gp-overexpressing drug-resistant KBV20C cells. Conclusion: Highly antimitotic drug-resistant KBV20C cells can be sensitized by co-treatment with the repositioned HIV protease inhibitors nelfinavir and lopinavir. In particular, the sensitizing effect of co-treatment with nelfinavir on antimitotic drug-resistant cancer cells was found to be strong and independent of P-gp-inhibitory activity. As P-gp inhibition can be toxic to normal cells, selecting nelfinavir may be safer for normal cells in patients with drug-resistant cancer.

  • Nelfinavir
  • lopinavir
  • HIV protease inhibitors
  • repositioning drug
  • cancer
  • P-gp
  • drug resistance
  • Received April 5, 2019.
  • Revision received May 7, 2019.
  • Accepted May 8, 2019.
  • Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
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Anticancer Research: 39 (7)
Anticancer Research
Vol. 39, Issue 7
July 2019
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Co-treatment With HIV Protease Inhibitor Nelfinavir Greatly Increases Late-phase Apoptosis of Drug-resistant KBV20C Cancer Cells Independently of P-Glycoprotein Inhibition
JI YEONG KIM, YOO JUNG PARK, BYUNG-MU LEE, SUNGPIL YOON
Anticancer Research Jul 2019, 39 (7) 3757-3765; DOI: 10.21873/anticanres.13524

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Co-treatment With HIV Protease Inhibitor Nelfinavir Greatly Increases Late-phase Apoptosis of Drug-resistant KBV20C Cancer Cells Independently of P-Glycoprotein Inhibition
JI YEONG KIM, YOO JUNG PARK, BYUNG-MU LEE, SUNGPIL YOON
Anticancer Research Jul 2019, 39 (7) 3757-3765; DOI: 10.21873/anticanres.13524
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Keywords

  • nelfinavir
  • Lopinavir
  • HIV protease inhibitors
  • repositioning drug
  • cancer
  • P-gp
  • Drug resistance
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