G-Quadruplex Binders Induce Immunogenic Cell Death Markers in Aggressive Breast Cancer Cells

Abstract

Background: DNA G-quadruplex (G4) structures represent potential anti-cancer targets. In this study, we compared the effect of two G4-targeting compounds, C066-3108 and the gold standard BRACO-19. Methods: In breast and prostate cancer cells, cytotoxicity induced by both molecules was measured by a sulforhodamine B assay. In breast cancer cells, cycle, apoptosis, the formation of G4 structures, calreticulin and high mobility group box 1 (HMGB1), as well as T cell activation, were analyzed by flow cytometry and adenosine triphosphate (ATP) by luminescence. Results: Both ligands inhibited cell survival and induced DNA damage. In MCF-7 cells, G4 ligands increased the subG0/G1 phase of the cell cycle inducing apoptosis and reduced intracellular ATP. In untreated MCF-7 cells, we observed a slight presence of G4 structures associated with the G2/M phase. In MDA-MB231 cells, G4 ligands decreased the G1 and enhanced the G2/M phase. We observed a decrease of intracellular ATP, calreticulin cell surface exposure and an increase of HMGB1, accompanied by T cell activation. Both compounds induced G4 structure formation in the subG0/G1 phase. Conclusions: Our data report similar effects for both compounds and the first evidence that G4 ligands induce the release of danger signals associated with immunogenic cell death and induction of T cell activation.

Insights into P-Glycoprotein Inhibitors: New Inducers of Immunogenic Cell Death

“…On the other hand, breast cancer patients with high CD8 + CTL infiltration, which correlated with a higher intratumor expression of CRT, have a better survival [46]. Increasing the ICD of triple-negative breast cancer cells with compounds other than conventional chemotherapeutic drugs [47] has been explored in this resistant cancer type. Our data indicate that specific Pgp inhibitors may be useful for this purpose.…”

Antitumor Effect of a Novel Spiro-Acridine Compound is Associated with Up-Regulation of Th1-Type Responses and Antiangiogenic Action

“…On cell cycle analysis, AMTAC-17 induced an increase in the sub-G1 peak to 41.48% (p < 0.05), associated with a decrease in the G0/G1 phase to 31.30% (p < 0.05), when compared to a control group (26.16 and 43.98%, respectively) ( Figure 2). Literature have shown that the increase in the sub-G1 peak is indicative of the apoptosis process [14,15]. In addition, previous studies suggested that acridine derivatives could induce cell cycle arrest and apoptosis [16].…”

Targeting HMGB1: An available Therapeutic Strategy for Breast Cancer Therapy

“…For instance, oleandrin, a cardiac glycoside, can induce ER stress in breast cancer cells and trigger ICD-mediated immune responses via the PERK/elF2α/ATF4/CHOP pathway 18 . In addition, Somma et al found that G-quadruplex binders induced ICD in MDA-MB-231 breast cancer cells, accompanied by T-cell activation 140 . Furthermore, Huang et al indicated that the antioxidant N-acetylcysteine (NAC) enhanced not only the antitumor activity of polyglycolylated arginine deiminase (ADI-PEG20), but also the features of ICD, including HMGB1 and ATP secretion 19 .…”