Abstract
Histone deacetylase inhibitors (HDACi) represent a promising class of epigenetic agents with anticancer properties. Here, we report that (S)-2, a novel hydroxamate-based HDACi, shown previously to be effective against acute myeloid leukemia cells, was also a potent inducer of apoptosis/differentiation in human prostate LNCaP and PC3 cancer cells. In LNCaP cells (S)-2 was capable of triggering H3/H4 histone acetylation, H2AX phosphorylation as a marker of DNA damage and producing G0/G1 cell cycle arrest. Consistently, (S)-2 led to enhanced expression of both the protein and mRNA p21 levels in LNCaP cells but, contrary to SAHA, not in normal non-tumorigenic prostate PNT1A cells. Mechanistic studies demonstrated that (S)-2-induced apoptosis in LNCaP cells developed through the cleavage of pro-caspase 9 and 3 and of poly(ADP-ribose)-polymerase accompanied by the dose-dependent loss of mitochondrial membrane potential. Indeed, the addition of the pan-caspase inhibitor Z-VAD-fmk greatly reduced drug-mediated apoptosis while the antioxidant N-acetyl-cysteine was virtually ineffective. Importantly, preliminary data with nude mice xenografted with LNCaP cells showed that (S)-2 prompted a decrease in the tumor volume and an increase in H2AX phosphorylation within the cancer cells. Moreover, the highly metastatic prostate cancer PC3 cells were also sensitive to (S)-2 that: i) induced growth arrest and moderate apoptosis; ii) steered cells towards differentiation and neutral lipid accumulation; iii) reduced cell invasiveness potential by decreasing the amount of MMP-9 activity and up-regulating TIMP-1 expression; and iv) inhibited cell motility and migration through the Matrigel. Overall, (S)-2 has proven to be a powerful HDACi capable of inducing growth arrest, cell death and/or differentiation of LNCaP and PC3 prostate cancer cells and, due to its low toxicity and efficacy in vivo, might also be of clinical interest to support conventional prostate cancer therapy.
Highlights
Epigenetic changes are reversible chromatin rearrangements capable of modulating gene expression within the cell without modifying DNA sequence
Despite the androgen ablation, virtually all tumors eventually progress with castration-resistant diseases [18,19,20] which need to be treated with conventional cytotoxics or epigenetic agents such as histone deacetylases (HDACs) inhibitors (HDACi)
We have previously reported a new set of potent hydroxamatebased HDACi characterized by a 1,4-benzodiazepine ring (BDZ) used as the cap and linked, through a triple bond connection unit, to a linear alkyl chain carrying a hydroxamic function as the Zn++chelating group [26]
Summary
Epigenetic changes are reversible chromatin rearrangements capable of modulating gene expression within the cell without modifying DNA sequence. Despite the androgen ablation, virtually all tumors eventually progress with castration-resistant diseases [18,19,20] which need to be treated with conventional cytotoxics or epigenetic agents such as HDAC inhibitors (HDACi) The latter have emerged as a new class of powerful anticancer agents capable of inducing tumor cell growth arrest, differentiation and/or apoptosis [16,17] in vitro and acting as radiation sensitizers in cancer cells by down-regulating DNA repair activity [21,22,23]. (S)-2-induced apoptosis in LNCaP cells developed through a caspase-dependent mechanism
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