The cytotoxic effects of indoleamine 2, 3-dioxygenase inhibitors on triple negative breast cancer cells upon tumor necrosis factor α stimulation

Bilir C., Eskiler G. G., Bilir F.

Journal of Cancer Research and Therapeutics, vol.19, no.8, pp.74-80, 2023 (SCI-Expanded) identifier identifier

  • Publication Type: Article / Article
  • Volume: 19 Issue: 8
  • Publication Date: 2023
  • Doi Number: 10.4103/jcrt.jcrt_2365_21
  • Journal Name: Journal of Cancer Research and Therapeutics
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, CAB Abstracts, CINAHL, EMBASE, MEDLINE, Veterinary Science Database
  • Page Numbers: pp.74-80
  • Keywords: 3-dioxygenase, 3-dioxygenase inhibitors, Epacadostat, indoleamine 2, indoleamine 2, triple-negative breast cancer, tumor necrosis factor-α
  • Kocaeli University Affiliated: Yes

Abstract

Context: Overexpressed indoleamine 2,3-dioxygenase (IDO) has been observed in many types of cancer and plays an essential role in the tumor microenvironment through immune cells function. Aims: In our study, the therapeutic potentials of two different IDO inhibitors (Epacadostat [EPA] and 1-methyl-L-tryptophan [L-1MT]) in triple-negative breast cancer (TNBC) cells were assessed with and without tumor necrosis factor-α (TNF-α) stimulation. Materials and Methods: The anticancer activity of EPA and L-1MT alone and in combination with TNF-α was analyzed by WST-1, annexin V, cell cycle analysis, and acridine orange/ethidium bromide staining. In addition, the relationship between IDO1 and programmed death-ligand 1 (PD-L1) expressions in TNBC cells upon treatment with IDO inhibitors was evaluated by reverse transcription-polymerase chain reaction analysis. Statistical Analysis Used: SPSS 22.0 was conducted for statistical analysis. The one-way analysis of variance with Tukey's multiple comparison test was performed for multiple groups. Independent (unpaired) t -test was used for the comparison of two groups. Results: EPA and L-1MT alone significantly suppressed the TNBC cell viability through the induction of apoptotic cell death and G0/G1 arrest (P < 0.05). TNF-α alone induced the overexpression of IDO1 and PD-L1 in TNBC cells compared with MCF-10A control cells. However, IDO inhibitors significantly inhibited overexpressed IDO1 mRNA levels. Furthermore, EPA alone and co-treated with TNF-α suppressed the mRNA level of PD-L1 in TNBC cells. Therefore, TNF-α stimulation enhanced the therapeutic effects of IDO inhibitors on TNBC. Conclusions: Our findings showed that the efficacy of IDO inhibitors was mediated by pro-inflammatory cytokine. However, different molecular signaling pathways are associated with pro-inflammatory cytokines production, and the expression of IDO1 and PD-L1 calls for further investigations.