Abstract 315: Cell Death of AML Blasts Induced by Cytarabine and Enhanced by the Vitamin D2/Carnosic Acid Cell Differentiating Combination Involves Apoptosis Signal-Regulating Kinase 1 (ASK1) Activation

Abstract Acute Myeloid Leukemia (AML) is a disease with a grim prognosis and limited curative treatment options. The principal agent used to induce disease remissions is Cytarabine (AraC), typically combined with an anthracycline, though multiple other combinations have been explored. We have previously reported that the exposure of AML blasts, in which the DNA is already damaged by AraC, to the Vitamin D2 analog Doxercalciferol combined with Carnosic Acid (D2/CA) enhances AraC cytotoxicity, resulting in an increased cell kill of the blasts. To obtain an understanding of the underlying mechanisms, and thus facilitate the translation of this finding to the clinic, we conducted in vitro studies on HL60, U937 cell lines and on AML blasts in primary culture. The initial findings were that the kinases BRAF and JNK1 and the pro-apoptotic protein BIM participate in the enhancement of AraC action. We now report that the kinase activity of ASK1 (MAP3K5) is upregulated by both AraC and D2/CA, and this appears to be additive thus increasing the apoptosis by this sequential combination regimen. Interestingly, we also noted that BRAF directly binds to ASK1, and since it is a kinase, this raises the possibility that it activates ASK1 in this experimental system. This possibility is strengthened by the report that JNK activation which leads to apoptosis is dependent on BRAF. The ongoing investigation of additional details of the molecular events responsible for enhanced cell death may provide clues for the improvement of the therapy of AML. (Supported by NIH grant R01CA044722-26 from NCI). Citation Format: Xuening Wang, Jonathan S. Harrison, George P. Studzinski. Cell death of AML blasts induced by cytarabine and enhanced by the Vitamin D2/Carnosic acid cell differentiating combination involves apoptosis signal-regulating kinase 1 (ASK1) activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 315.