Activation of Mitochondrial Pathway is Crucial for Tumor Selective Induction of Apoptosis by LAQ824

Abstract

HDAC inhibitors are promising antitumor drugs with several HDAC inhibitors already in clinical trials. LAQ824, a potent pan-HDAC inhibitor, has been shown to induce cell cycle arrest and cell death. However, the mechanism of its antitumor effects and specially its tumor selectivity are still poorly understood. The focus of this study is to elucidate LAQ824 mediated anti-proliferative effects in lung carcinoma cells and the mechanism underlying the different sensitivity of LAQ824 to cancer and normal cells. In this study, LAQ824 mediated apoptosis was found to occur mainly via activation of the mitochondrial death pathway by inducing Apaf1 and caspase 9 and promoting mitochondrial release of key proapoptotic factors in lung cancer cells, but not in normal fibroblast cells. Using chromatin immunoprecipitation assay, we found that RNA Pol II binding and histone H3 acetylation levels at Apaf1 promoter were increased following LAQ824 treatment, explaining LAQ824 induced expression of Apaf1 in lung cancer cells. Furthermore, we showed that LAQ824 only triggered the release of mitochondrial proapoptotic factors such as cytochrome C (Cyto C) and apoptosis inducing factor (AIF) in lung cancer cells but not in normal blast cells. In addition, LAQ824 was found to induce Bax translocation in lung cancer cell, which may play important role in the induction of the release of mitochondrial proapoptotic factors. These data provide insight into the mechanism underlying the selective induction of apoptosis by LAQ824 in cancer cells.

Targeting the Apoptosome for Cancer Therapy

“…For example the ability of the pan -histone deacetylase inhibitor LAQ824 to cause cell death is associated with induction of Apaf-1 and procaspase-9 expression (70).…”

Immunologic pathomechanism of Hodgkin's lymphoma

“…In addition, the therapy can be used before allogenic stem cell transplantation (SCT) [86], before reduced intensity allogeneic SCT [87], in combination with ABVD or AVD in a frontline setting [88], and in transplant-naive patients who refused or were ineligible for transplant [89]. Epigenetic modulation (e.g., acetylation and deacetylation of histones) plays an important role in gene regulation, particularly in those involved in cell proliferation, survival, angiogenesis, and immunity [90][91][92][93]. Therefore, histone deacetylase inhibitors became attractive targets to treat HL.…”

The histone deacetylase inhibitors LAQ824 and LBH589 do not require death receptor signaling or a functional apoptosome to mediate tumor cell death or therapeutic efficacy

“…This results in hyperacetylation of Hsp90 and subsequent polyubiquitylation and proteasomal degradation of client proteins, including Bcr-Abl, AKT, c-Raf, and FLT-3, 9-11 but whether this effect is directly related to the proapoptotic activities of the compounds remains unclear. Other apoptosis-related events, such as activation of the death receptor pathway through transcriptional induction of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors DR4 and DR5, 16 down-regulation and/or degradation of prosurvival proteins (XIAP, Mcl-1, Bcl-2, Bcl-XL), production of reactive oxygen species and the lipid second messenger ceramide, 17 and up-regulation of the apoptosome proteins caspase-9 and Apaf-1, 18 have been reported after treatment of tumor cell lines with LAQ824 and/or LBH589.…”