Abstract 4802: In vitro characterization of TP-2846: a novel tetracycline antileukemia agent

Recently published studies suggest two hypotheses for the mechanism of action (MOA) of tetracyclines’ anticancer activities: a) disruption of mitochondrial translation (Skrtic, Cancer Cell (2011) 20(5): 10.015); b) regulation of the miRNA-199b-5p-HES1-AKT pathway (Yang, Mol Cancer Ther (2016) 15(3): 1535-7163.MCT-15-0709). Upon treatment with TP-2846, suppressed levels of cytochrome oxidase-1 (COX-1) levels were demonstrated in Western blots. The COX-1 mRNA accumulated approximately 1,000-fold over background levels after 48 h incubation. Furthermore, TP-2846 displayed sub-µM inhibitory activities to mitochondrial translation (IC 50 = 0.71 µM) and ribosomal translation both in E. coli and in eukaryotes (IC 50 = 0.56 µM and 3.75 µM, respectively). In addition, TP-2846 led to accumulation of the micro RNA miR-199b in MV4-11 and HL-60 cells after 24 h incubation. TP-2846 had minimal IC 50 shift (Resistance Factor (RF) = 1.53) against K-562/ADR, a leukemia cell line overexpressing P-glycoprotein (Pgp), while daunorubicin displayed an RF value of 3.67 in the same assay. TP-2846 was also studied ex vivo using bone marrow samples from 15 AML patients, including those resistant to AraC, and displayed potent activity in all samples (EC 50 = 150-250 nM), while anthracyclines had similar activity (EC 50 = 100-600 nM) and AraC was 10x less potent (EC 50 = 2.3 µM) in the same ex vivo assay. In summary, TP-2846 exhibits both anticancer MOAs described in the literature for tetracyclines, retains antiproliferation activity in resistant leukemia cell lines, and demonstrates promising ex vivo activity in bone marrow samples from AML patients. This data indicates that further investigations in vitro and in vivo are warranted (see accompanying abstract “ In vivo activities of TP-2846: a novel tetracycline antileukemia agent”). Citation Format: Corey Fyfe, Joseph Newman, Ajay Bhargava, Juan Ballesteros, Alicia Robles, Cuixiang Sun, Xiao-Yi Xiao, Jacques Dumas. In vitro characterization of TP-2846: a novel tetracycline antileukemia agent [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4802.