Histone acetylation is emerging as a major regulatory mechanism thought to modulate gene expression by altering the accessibility of transcription factors to DNA. In this study, treatment of human tumor cells with the histone deacetylase inhibitor, trapoxin (TPX), resulted in selective changes in genes that control the cell cycle. TPX activated p21waf1 transcription that led to elevated p21 waf1 protein levels in three human tumor cell lines without altering the protein levels of cdk2, cdk4, or cyclin B. In addition, TPX increased cyclin E transcription without increasing the levels of Rb, E2F, dihydrofolate reductase, or glyceraldehyde-3-phosphate dehydrogenase. The elevated levels of p21 waf1 protein led to decreased Rb phosphorylation and cdk2 activity. These effects resulted in G 1 and G 2 cell cycle arrest in H1299 human lung and MDA-MB-435 breast carcinoma cells and apoptosis in A549 lung carcinoma cells. Chromatin immunoprecipitation assays revealed that TPX increased the level of chromatin acetylation associated with histone H3 in the trapoxin-responsive region of the p21 waf1 promoter. This study demonstrates that inhibition of HDAC by TPX increases acetylation of H3-associated chromatin and alters gene expression with marked selectivity.
We have synthesized a histone deacetylase inhibitor, NVP-LAQ824, a cinnamic hydroxamic acid, that inhibited in vitro enzymatic activities and transcriptionally activated the p21 promoter in reporter gene assays. NVP-LAQ824 selectively inhibited growth of cancer cell lines at submicromolar levels after 48 -72 h of exposure, whereas higher concentrations and longer exposure times were required to retard the growth of normal dermal human fibroblasts. Flow cytometry studies revealed that both tumor and normal cells arrested in the G 2 -M phase of the cell cycle after compound treatment. However, an increased sub-G 1 population at 48 h (reminiscent of apoptotic cells) was observed only in the cancer cell line. Annexin V staining data supported our hypothesis that NVP-LAQ824 induced apoptosis in tumor and transformed cells but not in normal cells. Western blotting experiments showed an increased histone H3 and H4 acetylation level in NVP-LAQ824-treated cancer cells, suggesting that the likely in vivo target of NVP-LAQ824 was histone deacetylase(s). Finally, NVP-LAQ824 exhibited antitumor effects in a xenograft animal model. Together, our data indicated that the activity of NVP-LAQ824 was consistent with its intended mechanism of action. This novel histone deacetylase inhibitor is currently in clinical trials as an anticancer agent.
Panobinostat (LBH589) is a highly potent deacetylase inhibitor that has demonstrated clinical efficacy in patients with advanced cutaneous T-cell lymphoma (CTCL). To gain a better understanding of the compound activity in this tumor type, we investigated the cellular and molecular effects of panobinostat using both in vitro and in vivo models of CTCL. All 4 tested CTCL cell lines exhibited very high sensitivity to panobinostat-induced growth inhibition. However, only 2 of 4 lines exhibited significant response to the cytotoxic activity of panobinostat. In a CTCL xenograft mouse tumor model, panobinostat treatment resulted in complete tumor regression. The difference in cell sensitivity to panobinostat-induced death enabled us to further investigate potential mechanisms responsible for tumor sensitivity or resistance. In CTCL cell lines that were insensitive to panobinostat-induced apoptosis, constitutively activated NF-jB and high levels of Bcl-2 were observed. Inhibition of Bcl-2 sensitized cells to the cytotoxic activity of panobinostat. Conversely, knockdown of Bax diminished the CTCL cell sensitivity. Interestingly, panobinostat could induce cytotoxicity in vorinostat-resistant CTCL cells by downregulating phosphorylated STAT3 and STAT5 proteins. These studies suggest distinct mechanisms responsible for resistance to different deacetylase inhibitors. We show that the intrinsic apoptotic signaling plays an essential role in mediating panobinostat anticancer activity. Moreover, cancer cell sensitivity to panobinostat treatment may be further improved by combination with inhibition of anti-apoptotic factors. These data provide preclinical support that panobinostat, as a single agent or in combination with other anticancer agents, is a promising therapy for CTCL.Cutaneous T-cell lymphomas (CTCLs) are lymphoproliferative disorders characterized by clonal expansion and localization of neoplastic T lymphocytes to the skin, resulting in immune dysregulation and tumor growth. 1 The most common form of CTCL is mycosis fungoides (MF), which is typically indolent but may evolve into the leukemic variant, Sézary syndrome (SS) or large-cell lymphoma. Traditionally, a number of skin-directed and systemic therapies are applied to control CTCL progression. Patients with progressed or refractory CTCL generally have a poor prognosis. Subsequent relapses are common in treated MF patients, and few available treatments have impacted overall survival (OS) for CTCL patients, resulting in a serious unmet therapeutic need.Distinct subtypes of CTCL are currently delineated on the basis of clinical or morphological features, and neither underlying pathogenesis of cutaneous lymphomas nor the distinguishing molecular abnormalities have been identified. However, CTCL cells have been shown to have deregulation of apoptotic responses. 2,3 Thus, treatments that can overcome CTCL resistance to apoptosis may provide new therapeutic strategies. To this effect, several novel targeted agents have emerged, which show promise in treating CTCL.Deace...
Inhibitors of histone deacetylase (HDAC) have been shown to induce terminal differentiation of human tumor cell lines and to have antitumor effects in vivo. We have prepared analogues of suberoylanilide hydroxamic acid (SAHA) and trichostatin A and have evaluated them in a human HDAC enzyme inhibition assay, a p21(waf1) (p21) promoter assay, and in monolayer growth inhibition assays. One compound, 4-(dimethylamino)-N-[7-(hydroxyamino)-7-oxoheptyl]-benzamide, was found to affect the growth of a panel of eight human tumor cell lines differentially.
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