Therapeutic Efficacy Of Novel Selenium-Containing Hdaci In Acute Leukemia

Despite tremendous advances in treatment of leukemia that have resulted in increased survival of patients with this disease, therapy for high-risk and relapsed leukemia remains a clinical challenge. This necessitates the development of novel, more potent therapeutic modalities. Epigenetic therapy with various types of inhibitors of histone deacetylases (HDACi), have demonstrated therapeutic efficacy in a range of malignancies, often with minimal side effects. Dr. Shantu Amin9s group recently reported the development of a potent, novel, selenium-containing HDAC inhibitor (SelSA-1), which showed efficacy against Hodgkin9s lymphoma and chronic myelogenous leukemia cells, as well as against lung cancer and melanoma cell lines. Here we expand efficacy studies of selenium-containing HDAC inhibitors to include a broad range of hematopoietic malignancies and begin to address the drug effects on cellular functions. We tested the therapeutic efficacy of two novel HDAC inhibitors - SelSa-1 and SelSa-2 on acute lymphoblastic leukemia, acute myelogenous leukemia and non-Hodgkin9s B cell lymphoma. Cell proliferation assays demonstrated sharp dose-dependent cytotoxic effects in all the above cell lines at 96-hours post-treatment. Quantitative analysis showed that SelSa-1 and SelSa-2 have distinct effects in different types of hematopoietic malignancies. In T-cell acute lymphoblastic leukemia (T-ALL) and in non-Hodgkin9s lymphoma, both SelSa-1 and Selsa-2 have similar therapeutic activity with IC50 = 1uM and 1-2uM, respectively. In B-cell acute lymphoblastic leukemia, SelSa-1 has superior therapeutic activity compared to SelSa-2 with IC50 = 0.2 uM vs. 1.25, respectively. In acute promyelocytic leukemia (APML) without the t:15:17 translocation, SelSa-1 was superior to SelSa-2 (IC50= 0.25uM and 1uM respectively), while APML with the t:15:17 translocation showed similar sensitivity to both compounds with an IC50 of 1-2uM. Cell cycle analysis performed by flow cytometry revealed that these agents induce G1-cell cycle arrest in leukemia cells. Preliminary data suggest that both SelSa-1 and SelSa-2 have a synergistic effect with standard chemotherapeutic agents that induce DNA-damage. In summary, these results demonstrate the effectiveness of two selenium-containing analogs of SAHA, SelSA-1 and 2, on leukemia cells from multiple hematopoietic lineages. Additional studies to identify detailed mechanisms of the effects of these drugs on cellular function are underway. Citation Format: Mansi Sachdev, Dhimant Desai, Sunil Muthusami, Chandrika Gowda, Chunhua Song, Shantu G. Amin, Sinisa Dovat. Therapeutic efficacy of novel selenium-containing HDACi in acute leukemia. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5539. doi:10.1158/1538-7445.AM2014-5539