Abstract 2532: Influence of survivin-targeted therapy on chemosensitivity in the treatment of acute myeloid leukemia

Abstract

Abstract Background: Survivin is a dual functional protein. It acts as a critical inhibitor of apoptosis and a key cell cycle regulator. In general, survivin expresses in embryonic tissues during development and is undetectable in most terminally differentiated tissues. It plays a pivotal role in normal hematopoiesis; however, overexpression of survivin has been reported in various hematological malignancies, including acute myeloid leukemia (AML). Studies with AML patients indicate that elevated expression of survivin correlates with a worse clinical outcome. To date, no study initiated to test the efficacy of survivin-targeted therapy in AML patients; and it remains unclear whether downregulation/inactivation of survivin may alter chemosensitivity against AML. Thus, we evaluate the effects of specific knockdown of survivin expression on AML cells and the AML cells’ responsiveness to chemotherapy. We have also investigated the therapeutic potential of the survivin inhibitor YM155, which is under clinical trials in a variety of human cancers, either alone or in combination with the commonly used chemotherapeutic agents in the treatment of AML. Material and Methods: Traditional PCR and real-time PCR were used to measure mRNA levels in AML cell lines. Western blot analyses were performed to determine protein expression and activation. Cell death was quantified by a specific apoptotic ELISA (enzyme linked immunosorbent assay). Flow cytometric analyses were used to explore cell cycle progression. Cell Titer AQueous Non-Radioactive Cell Proliferation Assays (MTS) were carried out to evaluate changes of cell proliferation. Results: Kasumi-1 and HL-60 cells showed relatively higher expression levels of survivin among all AML cell lines tested. Specific knockdown of survivin expression in Kasumi-1 and HL-60 cells resulted in: inhibition of cell proliferation; cell cycle G2/M arrest; upregulation of DNA damage response and apoptotic-related proteins; and increased histone-associated DNA fragmentation. Downregulation of survivin enhanced AML cells’ sensitivity to etoposide- or doxorubicin-induced anti-proliferative/anti-survival activity. The small inhibitor YM155 trigged dose- and time-dependent reduction of survivin and apoptosis in both Kasumi-1 and HL-60 cells. The combinatorial effects of YM155 and chemotherapeutics were either synergetic or antagonistic, depending on the drugs used for combination and the type of cells being treated. Conclusions: These data demonstrate that survivin is important for the maintenance and proliferation of AML cells. Downregulation of survivin in AML cells enhances chemosensitivity. The combinatorial effects of YM155 and chemotherapeutics can be synergetic or antagonistic, depending on the drugs and the AML cell types. Our findings provide a rationale for further evaluation of survivin-targeted therapy in the treatment of patients with AML. Citation Format: Jingcao Huang, Hui Lyu, Ying Wu, Bolin Liu. Influence of survivin-targeted therapy on chemosensitivity in the treatment of acute myeloid leukemia. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2532. doi:10.1158/1538-7445.AM2015-2532