Suppression of c‐Myc using 10058‐F4 exerts caspase‐3‐dependent apoptosis and intensifies the antileukemic effect of vincristine in pre‐B acute lymphoblastic leukemia cells

• Published in: Journal of cellular biochemistry Vol. 120; no. 8; pp. 14004 - 14016
• Main Authors: Sheikh‐Zeineddini, Negar, Bashash, Davood, Safaroghli‐Azar, Ava, Riyahi, Niknam, Shabestari, Rima Manafi, Janzamin, Ehsan, Safa, Majid
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.08.2019
• Subjects: 1-Phosphatidylinositol 3-kinase; 10058‐F4; Acute lymphoblastic leukemia; Anticancer properties; Apoptosis; Autophagy; Cancer; Caspase; Chloroquine; c‐Myc; G1 phase; Gene expression; Genes; Inhibitors; Leukemia; Leukemogenesis; Lymphatic leukemia; Lymphocytes B; Myc protein; Phagocytosis; PI3K signaling pathway; RNA-directed DNA polymerase; Road construction; Synergistic effect; Telomerase; Telomerase reverse transcriptase; Vincristine; autophagy; PI3K signaling pathway; 10058-F4; acute lymphoblastic leukemia; c-Myc
• ISSN: 0730-2312; 1097-4644
• DOI: 10.1002/jcb.28675

Despite an old history behind the identification of the leading role of c‐Myc in leukemogenesis, the road to constructing a therapeutic perspective for this molecule in acute lymphoblastic leukemia (ALL) is yet mesmerizing. This study was designed to provide a better outlook for the anticancer property of 10058‐F4, an appealing inhibitor of c‐Myc, in pre‐B ALL cell lines either in the context of monotherapy or in combination with chemotherapeutic drugs. Our results declared that abrogation of c‐Myc decreased the proliferative capacity of pre‐B ALL‐derived cells through halting the transition of the cells from G1 phase, and reducing the replicative potential of both REH and Nalm‐6 cells, at least partly, through c‐Myc‐mediated suppression of human telomerase reverse transcriptase. Moreover, 10058‐F4 potently induced a caspase‐3‐dependent apoptosis in pre‐B ALL cells via shifting the balance between pro‐ and anti‐apoptotic target genes. Although the inhibition of PI3Kδ using Idelalisib upregulated the messenger RNA expression of autophagy‐related genes in 10058‐F4‐treated cells, treatment with autophagy inhibitor chloroquine decreased viability of the cells, either as a single agent or in combination with Idelalisib and/or 10058‐F4; suggesting that the activation of autophagy in pre‐B ALL cells could blunt apoptotic events and attenuate anticancer effect of both c‐Myc and PI3K inhibitors. Finally, the results of our synergistic experiments delineated that 10058‐F4 produced a synergistic effect with vincristine and provided an enhanced therapeutic efficacy in ALL cells, highlighting that c‐Myc oncoprotein could be a bona fide target for the treatment of ALL. Abrogation of c‐Myc decreased the proliferative capacity of pre‐B ALL‐derived cells through G1 cell cycle arrest and induction of caspase‐3‐dependent apoptosis. Moreover, while c‐Myc inhibition only merely altered the expression of autophagy‐related genes, suppression of PI3K signaling potentiated the antileukemic effect of 10058‐F4 through stimulation of autophagy; proposing that the concomitant suppression of PI3K and c‐Myc could augment cytotoxicity in ALL through induction of both apoptosis and autophagy.