Abstract
Histone deacetylase (HDAC) inhibitor has been a promising therapeutic option in cancer therapy due to its ability to induce growth arrest, differentiation, and apoptosis. In this study, we demonstrated that MPT0E028, a novel HDAC inhibitor, reduces the viability of B-cell lymphomas by inducing apoptosis and shows a more potent HDAC inhibitory effect compared to SAHA, the first HDAC inhibitor approved by the FDA. In addition to HDACs inhibition, MPT0E028 also possesses potent direct Akt targeting ability as measured by the kinome diversity screening assay. Also, MPT0E028 reduces Akt phosphorylation in B-cell lymphoma with an IC50 value lower than SAHA. Transient transfection assay revealed that both targeting HDACs and Akt contribute to the apoptosis induced by MPT0E028, with both mechanisms functioning independently. Microarray analysis also shows that MPT0E028 may regulate many oncogenes expression (e.g., TP53, MYC, STAT family). Furthermore, in vivo animal model experiments demonstrated that MPT0E028 (50-200 mg/kg, po, qd) prolongs the survival rate of mice bearing human B-cell lymphoma Ramos cells and inhibits tumor growth in BJAB xenograft model. In summary, MPT0E028 possesses strong in vitro and in vivo activity against malignant cells, representing a potential therapeutic approach for cancer therapy.
Highlights
According to the American Cancer Society, B-cell lymphomas make up approximately 85 percent of nonHodgkin lymphomas (NHLs) in the United States [1]
We show that MPT0E028 possesses a more potent inhibitory effect against Histone deacetylase (HDAC) and greater ability in targeting Akt compared with the HDAC inhibitor vorinostat (SAHA) in human B-cell lymphoma cells
We previously demonstrated that MPT0E028, a novel HDAC inhibitor, exhibited potent anticancer ability toward various cell lines, including hematological malignances and solid tumors
Summary
According to the American Cancer Society, B-cell lymphomas make up approximately 85 percent of nonHodgkin lymphomas (NHLs) in the United States [1]. Class III HDACs, known as sirtuins (sirtuins 1–7), requires NAD+ as a cofactor for enzymatic activity; HDAC11 is the sole member of HDAC11. Class I, II, and IV are classical HDACs which need Zn2+ for enzymatic activity and are inhibited by HDAC inhibitors that chelate Zn2+ ion in their catalytic sites. HDAC inhibitors have multiple mechanisms of inducing cell cycle arrest, cell differentiation, and cell death through apoptosis, autophagy, or necrosis in many cancer cells. They have shown to inhibit angiogenesis, migration, and metastasis [3, 4]. HDAC inhibitors, proven to be effective against hematological malignancies in clinical trials, are increasingly perceived as promising anticancer agents [5]. Vorinostat [6] and Romidepsin [7] are two HDAC inhibitors recently approved by the U.S Food and Drug Administration (FDA) for cutaneous T-cell lymphoma (CTCL)
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