Targeted inhibitors of P-glycoprotein increase chemotherapeutic-induced mortality of multidrug resistant tumor cells

Amila K. Nanayakkara, Courtney A. Follit, Gang Chen, Noelle S. Williams, Pia D. Vogel, John G. Wise

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Overexpression of ATP-binding cassette (ABC) transporters is often linked to multidrug resistance (MDR) in cancer chemotherapies. P-glycoprotein (P-gp) is one of the best studied drug transporters associated with MDR. There are currently no approved drugs available for clinical use in cancer chemotherapies to reverse MDR by inhibiting P-glycoprotein. Using computational studies, we previously identified several compounds that inhibit P-gp by targeting its nucleotide binding domain and avoiding its drug binding domains. Several of these compounds showed successful MDR reversal when tested on a drug resistant prostate cancer cell line. Using conventional two-dimensional cell culture of MDR ovarian and prostate cancer cells and three dimensional prostate cancer microtumor spheroids, we demonstrated here that co-administration with chemotherapeutics significantly decreased cell viability and survival as well as cell motility. The P-gp inhibitors were not observed to be toxic on their own. The inhibitors increased cellular retention of chemotherapeutics and reporter compounds known to be transport substrates of P-gp. We also showed that these compounds are not transport substrates of P-gp and that two of the three inhibit P-gp, but not the closely related ABC transporter, ABCG2/BCRP. The results presented suggest that these P-gp inhibitors may be promising leads for future drug development.

Original languageEnglish (US)
Article number967
JournalScientific Reports
Volume8
Issue number1
DOIs
StatePublished - Dec 1 2018

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P-Glycoprotein
Multiple Drug Resistance
Mortality
Neoplasms
Prostatic Neoplasms
ATP-Binding Cassette Transporters
Pharmaceutical Preparations
Cell Survival
Drug Therapy
Poisons
Ovarian Neoplasms
Cell Movement
Nucleotides
Cell Culture Techniques
Cell Line

ASJC Scopus subject areas

  • General

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Targeted inhibitors of P-glycoprotein increase chemotherapeutic-induced mortality of multidrug resistant tumor cells. / Nanayakkara, Amila K.; Follit, Courtney A.; Chen, Gang; Williams, Noelle S.; Vogel, Pia D.; Wise, John G.

In: Scientific Reports, Vol. 8, No. 1, 967, 01.12.2018.

Research output: Contribution to journalArticle

Nanayakkara, Amila K. ; Follit, Courtney A. ; Chen, Gang ; Williams, Noelle S. ; Vogel, Pia D. ; Wise, John G. / Targeted inhibitors of P-glycoprotein increase chemotherapeutic-induced mortality of multidrug resistant tumor cells. In: Scientific Reports. 2018 ; Vol. 8, No. 1.
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