Histone deacetylase inhibitors induced caspase-independent apoptosis in human pancreatic adenocarcinoma cell lines

Abstract

The antitumor activity of the histone deacetylase inhibitors was tested in three well-characterized pancreatic adenocarcinoma cell lines, IMIM-PC-1, IMIM-PC-2, and RWP-1. These cell lines have been previously characterized in terms of their origin, the status of relevant molecular markers for this kind of tumor, resistance to other antineoplastic drugs, and expression of differentiation markers. In this study, we report that histone deacetylase inhibitors induce apoptosis in pancreatic cancer cell lines, independently of their intrinsic resistance to conventional antineoplastic agents. The histone deacetylase inhibitorinduced apoptosis is due to a serine protease -dependent and caspase-independent mechanism. Initially, histone deacetylase inhibitors increase Bax protein levels without affecting Bcl-2 levels. Consequently, the apoptosisinducing factor (AIF) and Omi/HtrA2 are released from the mitochondria, with the subsequent induction of the apoptotic program. These phenomena require AIF relocalization into the nuclei to induce DNA fragmentation and a serine protease activity of Omi/HtrA2. These data, together with previous results from other cellular models bearing the multidrug resistance phenotype, suggest a possible role of the histone deacetylase inhibitors as antineoplastic agents for the treatment of human pancreatic adenocarcinoma. [Mol Cancer Ther 2005; 4(8);1222 -30]

CPTH6, a Thiazole Derivative, Induces Histone Hypoacetylation and Apoptosis in Human Leukemia Cells

“…Together, these data suggest that cell death induced by CPTH6 may proceed independently from caspases activation. Our results are in agreement with previous reports showing that caspase-independent pathways may play essential roles in apoptosis induced by histone acetylation-targeted drugs (36,37). It is possible that proapoptotic mitochondrial factors such as calpain, apoptosis-inducing factor, endonuclease G or Omi/HtrA2, which have been reported to participate in caspase-independent apoptosis (38,39), may play a role in CPTH6-induced apoptosis.…”

Histone Deacetylase Inhibition Attenuates Cell Growth with Associated Telomerase Inhibition in High-Grade Childhood Brain Tumor Cells

“…For example, PFSK-1 and DAOY cells show a marked reduction in cell viability at 0.5 μmol/L TSA, whereas caspase-3 activation occurs only at >2.0 μmol/L TSA. This paradox may at least be partially explained by the activation of caspase-independent apoptosis, as reported by similar studies using HDACi including TSA (42)(43)(44). It is plausible that in PFSK-1 and DAOY cells, cell viability is reduced due to caspase-3-independent phenomena at low TSA doses, whereas at high TSA doses, this reduction in cell viability is reinforced by canonical caspase-3-dependnet apoptosis.…”

Serine Proteases in Histone Deacetylase Inhibitor–Induced Apoptosis – Letter

“…In particular, the significance of caspases and other proteases in the apoptotic pathway mediated by HDACi has not yet been conclusively resolved. In a recent article, the hydroxamic acid HDACi trichostatin A (TSA) and vorinostat [also called suberoylanilide hydroxamic acid (SAHA)] have been reported to induce caspaseindependent, but serine protease-dependent, apoptosis in pancreatic cancer cells (2). It was shown that the serine protease inhibitor 4-(2-aminoethyl)-benzenesulfonylfluoride (AEBSF; also called Pefabloc; and called ISP in ref.…”