Abstract B122: 3,3′-bis(2-aminoethanol)-2,2′-binaphthoquinone promotes killing of acute myeloid leukemia cells by augmenting oxidative stress and inhibiting indoleamine dioxygenase

Abstract

Abstract Introduction: Acute myeloid leukemia (AML) is a genetically heterogeneous neoplasm with poor clinical outcome after treatment with current conventional chemotherapy. New treatments are therefore needed to combat this aggressive cancer. One of the hallmarks of AML blasts is disrupted cellular oxidative state resulting from elevated level of reactive oxygen species (ROS) and overexpressed antioxidant proteins. Another characteristic of AML blasts is escaping host immune surveillance mediated in part by overexpression of the tryptophan-metabolizing enzyme, indoleamine 2,3-dioxygenase (IDO). We have designed and synthesized a novel hydroxylamine dimeric naphthoquinone (MCD-66), which can kill leukemia cells by dual mechanisms: 1) negatively perturbing cellular oxidative balance, and 2) effectively inhibiting IDO-1. Results: Two AML cell lines (MV4-11 and MOLM14) were treated with increasing doses of the clinically used naphthoquinones, atovaquone, and vitamin K, as well as with MCD-66, and IC50 curves were generated. With nanomolar range IC50s, MCD-66 was 25-30 fold more potent than other naphthoquinones against AML cells. MCD-66 effectively inhibited clonogenicity of AML cells in a dose-dependent manner. When MV4-11 cells were treated with MCD-66 at IC50 concentration, ROS levels significantly peaked after 2 hours and returned to baseline within 24 hours. The augmented production of ROS led to concomitant increase in DNA damage, evidenced by γH2AX foci in treated AML blasts. Additionally, MCD-66 inhibited IDO-1 activity at 1 µM (37%) and 10 µM (79%), but not its isozymes IDO-2 or tryptophan-2,3-dioxygenase (TDO). Conclusion: The novel amino-alcohol dimeric naphthoquinone MCD-66 has shown promising activity against AML blast in vitro with dual mechanisms of action. The in vivo studies focusing on tolerability and efficacy, including modulating immune surveillance in xenograft models of AML, are ongoing. Citation Format: Elizabeth Tsuying Chang, Brandon A. Carter-Cooper, Smaraki Dash, Dana Ferraris, Ashkan Emadi, Rena G. Lapidus. 3,3′-bis(2-aminoethanol)-2,2′-binaphthoquinone promotes killing of acute myeloid leukemia cells by augmenting oxidative stress and inhibiting indoleamine dioxygenase [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B122.