Epigenetic Priming with Decitabine Augments the Therapeutic Effect of Cisplatin on Triple-Negative Breast Cancer Cells through Induction of Proapoptotic Factor NOXA

Abstract

Epigenetic alterations caused by aberrant DNA methylation have a crucial role in cancer development, and the DNA-demethylating agent decitabine, is used to treat hematopoietic malignancy. Triple-negative breast cancers (TNBCs) have shown sensitivity to decitabine; however, the underlying mechanism of its anticancer effect and its effectiveness in treating TNBCs are not fully understood. We analyzed the effects of decitabine on nine TNBC cell lines and examined genes associated with its cytotoxic effects. According to the effect of decitabine, we classified the cell lines into cell death (D)-type, growth inhibition (G)-type, and resistant (R)-type. In D-type cells, decitabine induced the expression of apoptotic regulators and, among them, NOXA was functionally involved in decitabine-induced apoptosis. In G-type cells, induction of the cyclin-dependent kinase inhibitor, p21, and cell cycle arrest were observed. Furthermore, decitabine enhanced the cytotoxic effect of cisplatin mediated by NOXA in D-type and G-type cells. In contrast, the sensitivity to cisplatin was high in R-type cells, and no enhancing effect by decitabine was observed. These results indicate that decitabine enhances the proapoptotic effect of cisplatin on TNBC cell lines that are less sensitive to cisplatin, indicating the potential for combination therapy in TNBC.

Epigenetics: Mechanisms, potential roles, and therapeutic strategies in cancer progression

“…Decitabine increased cisplatin's NOXA-mediated pro-apoptotic effect on breast cancer cell lines, demonstrating decitabine's good clinical potential in combination with cisplatin for the treatment of triple-negative breast cancers. 84 It has been shown that mitochondrial DNA depletion and low mitochondrial membrane potential can induce DNA methylation via DNMT and that zebularine inhibits epithelial–mesenchymal transition and improves chemotherapy sensitivity in mitochondrial DNA-depleted esophageal cancer cells. As a result, therapeutic strategies that increase the copy number of mitochondrial DNA and DNMT inhibitors may be useful in preventing epithelial–mesenchymal transition and chemotherapy resistance.…”

Venetoclax and Hypomethylating Agent Combination in Myeloid Malignancies: Mechanisms of Synergy and Challenges of Resistance

“…MCL-1 overexpression is one of the putative mechanisms of resistance to Venetoclax-based therapies in AML cells; hence, the Pev/5-Aza/Ven combination could be used as a novel therapeutic approach to overcome such Ven resistance. Notably, NOXA induction has been observed with decitabine in triple-negative breast cancer cells [ 44 ], enhancing the cytotoxic potential of cisplatin therapy in such cells.…”

Estudo do receptor Frizzled classe 9 (FZD9), um potencial biomarcador prognóstico e alvo terapêutico

“…Em linhagem MDA-MB-231, negativa para ER, o tratamento com 5-aza foi capaz de restaurar a expressão de receptores de estrógeno (SALAHUDDIN et al, 2022). Interessantemente, efeitos pró-apoptóticos mediados por cisplatina foram aumentados após tratamento em linhagens TNBC com decitabina (NAKAJIMA et al, 2022). Apesar desses significativos avanços, nem todas as linhagens de cânceres de mama respondem de modo similar, seja no tratamento com decitabina ou com a TSA.…”