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Terconazole, an Azole Antifungal Drug, Increases Cytotoxicity in Antimitotic Drug-Treated Resistant Cancer Cells with

Ji Sun Lee1, Yunmoon Oh1, Jae Hyeon Park1

  • 1School of Pharmacy, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon 16419, Korea.

International Journal of Molecular Sciences
|November 26, 2022
PubMed

Insights

Azole antifungal drugs, like terconazole, can enhance chemotherapy effectiveness against drug-resistant cancers by inhibiting P-glycoprotein (P-gp). This repositioning offers a rapid treatment option for patients with resistant tumors.

Area of Science:

  • Oncology
  • Pharmacology
  • Drug Discovery

Background:

  • P-glycoprotein (P-gp) overexpression confers multidrug resistance in cancer, limiting chemotherapy efficacy.
  • Azole antifungal drugs are known to modulate P-gp activity, but their potential in combination cancer therapy is underexplored.

Purpose of the Study:

  • To investigate the efficacy of azole antifungal drugs, specifically terconazole (TCZ) and butoconazole (BTZ), in combination with the antimitotic drug vincristine (VIC) against P-gp-overexpressing resistant cancer cells.
  • To explore the potential of repositioning existing azole antifungal drugs for cancer treatment.

Main Methods:

  • Assessed the cytotoxicity of TCZ and BTZ in combination with VIC in P-gp-overexpressing KBV20C cancer cells.
  • Analyzed the effects of VIC + TCZ on apoptosis and cell cycle progression (G2 arrest).
  • Screened 12 azole antifungal drugs for their ability to enhance VIC cytotoxicity in resistant cancer cell lines (KBV20C and MCF-7/ADR).

Main Results:

  • Both TCZ and BTZ demonstrated increased cytotoxicity when combined with VIC in resistant cancer cells.
  • Low-dose VIC + TCZ exhibited superior cytotoxicity compared to VIC + BTZ.
  • VIC + TCZ treatment led to increased apoptosis and G2 cell cycle arrest.
  • VIC + TCZ, VIC + itraconazole, and VIC + posaconazole showed the strongest cytotoxicity against P-gp-overexpressing resistant cells.
  • TCZ demonstrated significant P-gp inhibitory activity, contributing to drug sensitization.

Conclusions:

  • Low-dose azole antifungal drugs, particularly terconazole, can be effectively combined with antimitotic agents to overcome P-gp-mediated drug resistance in cancer.
  • The P-gp inhibitory activity of azole antifungals is a key mechanism for sensitizing resistant cancer cells.
  • Repositioning of approved azole antifungal drugs presents a promising and rapid strategy for treating patients with P-gp-overexpressing resistant cancers.
Keywords:
P-gpazole antifungal drugscancerco-treatmentdrug resistanceterconazole

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