Novel naphthoquinone-coumarin hybrids as inhibitors of BCR-ABL-STAT5 signaling pathway in chronic myelogenous leukemia

Abstract

NPQ and coumarin represent promising scaffolds in medicinal chemistry for finding novel inhibitors of carcinogenic pathways. This is exemplified by the discovery of NPQ-coumarin hybrids as inhibitors of topoisomerase II [1]. BCR-ABL-STAT5 is an oncogenic signaling pathway in Human Chronic Myelogenous Leukemia (CML) and it represents a valid target for anti-CML drug design [2]. In this study, the effects of a novel naphthoquinone-coumarin conjugate NPQ-C6 were evaluated on human CML-derived K562 cells. Live-Cell Imaging analysis revealed that NPQ-C6 inhibited 2D (IC50AUC = 1.4 ± 0.6 µM) growth of K562 cells. NPQ-C6 caused a dose- and time-dependent cell cycle arrest which was associated with increased levels of apoptotic markers (apoptotic nuclei, cleavage of caspase-3, -9, PARP and annexin V-positive cells) and increased γH2AX expression protein, a double-strand DNA break marker. NPQ-C6 showed multikinase modulatory effects through an early increased phosphorylation of JNK, P38-MAPK and AKT, and decreased phosphorylation of ERK1/2, BCR-ABL and STAT5 and inhibited expression of oncoprotein c-MYC. Molecular modeling suggested to BCR-ABL and JAK2 proteins as potential targets for NPQ-C6. In summary, NPQ-C6 is a novel multikinase modulator that might be effective on BCR-ABL-STAT5 oncogenic pathway in BCR-ABL-STAT5 related malignancies.