Selective Growth Inhibition of Tumor Cells by a Novel Histone Deacetylase Inhibitor, NVP-LAQ824

Abstract

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.

Sodium butyrate sensitizes human glioma cells to TRAIL-mediated apoptosis through inhibition of Cdc2 and the subsequent downregulation of survivin and XIAP

“…Inhibition of HDACs may contribute to the induction of cell cycle arrest during the G 1 and/or G 2 phase, differentiation, and/or apoptosis in various cancer cells (Marks et al, 2001). Several HDAC inhibitors can halt tumor growth in animal models with little toxicity, while the inhibition of HDAC is normally not sufficient to cause cell death in nontumor cells (Vigushin et al, 2001;Atadja et al, 2004). This selectivity for tumor cells makes these compounds particularly attractive for cancer therapy, and several newly developed HDAC inhibitors have been tested on cancer patients in clinical trials (Piekarz and Bates, 2004).…”

Antibody response to a non‐conserved C‐terminal part of human histone deacetylase 3 in colon cancer patients

“…22 Other inhibitors, such as Scriptaid, NVP-LAQ824 and others, were recently proposed for clinical use for colon cancer and other malignancies, including lymphomas. 23,24 Confirmation of HDAC role in gene regulation in human colorectal cancer was provided recently by a study in which inhibition of histone deacetylases (with or without demethylation of DNA) led to increased expression of substantial number of genes that are epigenetically silenced in this type of malignancy. 5 Despite significant similarities to other Class I HDAC (especially to HDAC1 and HDAC2), HDAC3 possesses several unique features.…”

Histone deacetylase inhibitor NVP-LAQ824 has significant activity against myeloid leukemia cells in vitro and in vivo

“…69,70 NVP-LAQ824 is a hydroxamic acid-derived HDAC inhibitor, which differs from other clinically active compounds in this class in its ability to induce apoptosis and cause cell cycle arrest in myeloid cell lines and primary patient samples with an IC 50 in the nanomolar range. [26][27][28][29][30] Normal bone marrow CFU-GM were approximately two-fold less sensitive to NVP-LAQ824 in terms of induction of apoptosis, as compared to AML patient cells, and, in vivo, the agent was generally well-tolerated and prolonged survival in a mouse model. It has previously been shown that NVP-LAQ824 kills multiple myeloma cells resistant to conventional chemotherapy at nanomolar concentrations, and shows efficacy in a murine myeloma model.…”

“…12,[23][24][25] The combination of phenylbutyrate and ATRA has induced a complete clinical remission in a patient with APL resistant to ATRA alone. 24 We now report the effects of the cinnamic acid hydroxamate NVP-LAQ824, a novel HDAC inhibitor with activity in nanomolar concentrations, [26][27][28][29][30] on leukemia cells. We show that this agent induces cell cycle arrest and programmed cell death in both acute and chronic myeloid leukemia cells in vitro.…”