Inhibition of HDAC increases the senescence induced by natural polyphenols in glioma cells

Abstract

Cellular senescence is an irreversible block of cellular division, and induction of senescence is being considered for treatment of many cancer types, mainly those resistant to classical pro-apoptotic therapies. Resveratrol (Rsv) and quercetin (Quer), two natural polyphenols, are able to induce senescence in different cancer models, including gliomas, the most common and aggressive primary brain tumor. These polyphenols modulate the activity of several proteins involved in cell growth and death in cancer cells, including histone deacetylases (HDAC), but the role of HDAC in senescence induced by Rsv and Quer is unclear. The HDAC inhibitor sodium butyrate (NaB) potentiated the pro-senescent effect of Rsv and Quer in human and rat glioma cell lines but not in normal rat astrocytes. Furthermore, the increment of Quer-induced senescence by NaB was accompanied by an increase of reactive oxygen species levels and an increment of the number of cells with nuclear abnormalities. Altogether, these data support a positive role of HDAC inhibition on the senescence induced by these polyphenols, and therefore co-treatment of HDAC inhibitors and polyphenols emerges as a potential alternative for gliomas.

Silencing NKG2D ligand-targeting miRNAs enhances natural killer cell-mediated cytotoxicity in breast cancer

“…The basis for normal breast cell resistance to HDACis is not fully understood, although cancer cells with multiple defects cannot reverse the critical effects of HDACis similar to normal cells. 44, 45 This resistance of normal breast cells presumably functions to avoid the autoimmunity caused by treatment with HDACis. Taken together, our study indicates that BC patients who receive HDACi treatment might show increased immune activation in addition to tumor cell inhibition.…”

From molecular promise to preclinical results: HDAC inhibitors in the race for healthy aging drugs

“…Inducing senescence—a quiescent, non‐dividing cell state—in cancerous cells is a desired outcome for cancer therapy, and a number of studies have shown HDAC inhibitors to cause various cancer cells to senesce (Lorenz et al , ; Vargas et al , ; Venkatesh et al , ). In the context of aging however, senescent cell reduction , rather than promotion , is desired, since senescent cells contribute to age‐related diseases (De Keizer, ).…”

“…In the context of aging however, senescent cell reduction , rather than promotion , is desired, since senescent cells contribute to age‐related diseases (De Keizer, ). Importantly, the ability of HDAC inhibitors to cause cell senescence may be cancer specific; sodium butyrate was shown to potentiate senescence in human and rat glioma cell lines but not in normal astrocytes (Vargas et al , ). Furthermore, as the senescent cell state is reinforced by the chromatin state at the epigenetic level (Narita et al , ; Funayama & Ishikawa, ), there is high potential for HDAC inhibitor involvement in the phenotype.…”

Phytochemicals based chemopreventive and chemotherapeutic strategies and modern technologies to overcome limitations for better clinical applications

“…Quercetin inhibits the growth of multiple human cancer cell lines (colon, breast, lung, etc.) through demethylation, induction of HAT, inhibition of HDAC, and alteration in miRNA expression of tumor suppressor and oncogenic miRNAs (Guo et al, 2015;Lam et al, 2012;Lee, Chen, & Tseng, 2011;Tan et al, 2009;Vargas et al, 2014).…”