Contents lists available at ScienceDirect International Journal of Biochemistry and Cell Biology journal homepage: www.elsevier.com/locate/biocel Small molecule inhibitor of c-Myc 10058-F4 inhibits proliferation and induces apoptosis in acute leukemia cells, irrespective of PTEN status Davood Bashash a, ⁎ , Mohamad Sayyadi b , Ava Safaroghli-Azar b , Negar Sheikh-Zeineddini b , Niknam Riyahi b , Majid Momeny c a Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran b Student Research Committee, Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran c Cancer Cell Signaling, Turku Center for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland ARTICLE INFO Keywords: Acute leukemia c-Myc inhibition 10058-F4 PI3K pathway p53 PTEN ABSTRACT Based on the frequent over-expression of c-Myc in hematologic malignancies and its crucial role in the regulation of diverse oncogenic pathways involved in leukomogenesis, intense interest has recently focused on this factor as an appealing therapeutically target in leukemia. In the present study, we aimed to investigate the anti-leukemic property of small molecule inhibitor of c-Myc 10058-F4 in two distinct acute leukemia cell lines consist of acute promyelocytic leukemia (APL)-derived NB4 cells (with wild-type PTEN) and acute lymphoblastic leukemia (ALL)-derived Nalm-6 cells (with down-regulated PTEN). 10058-F4 effectively reduced survival of leukemic cells; however, we found a different cell sensitivity pattern in the tested cell lines. To the best of our knowledge, no study has addressed the underlying mechanisms responsible for leukemic cell resistance to 10058-F4, and we propose for the first time that the effectiveness of c-Myc inhibition might be attenuated through over-activated phosphoinositide 3-kinase (PI3K) in less sensitive Nalm-6 cells. Notably, we failed to find an obvious correlation between PTEN status and cell sensitivity to the inhibitor in a panel of hematologic malignant cells. Beyond 10058-F4 cytotoxicity as a single agent, synergistic experiments also delineated that pharmaceutical targeting of c-Myc could potentiate the anti-cancer effect of both vincristine and Arsenic trioxide in ALL and APL cells, respectively. In conclusion, this study sheds light on the potent anti-leukemic characteristics of 10058-F4 and provide an interesting evidence to the application of this agent in combination with PI3K inhibitors especially in acute leukemia with over-activated PI3K, irrespective of PTEN status. 1. Introduction The intensive molecular and genetic investigations have recently disclosed a unique as well as a strong role for c-Myc oncogene in the regulation of cell growth and differentiation in the hematopoietic system (Wilson et al., 2004). As the knowledge about the intercellular function of c-Myc grows, more association between the aberrant ex- pression of this oncogene and leukomogenesis are discovered (Hoffman et al., 2002). It has been demonstrated that the amplification of c-Myc and its chromosome translocation are frequently involved in the in- itiation and progression of both myeloid and lymphoid acute leukemia (Delgado and León, 2010). The importance of this oncoprotein in acute leukemia has also loaned from the recent large-scale expression data reflecting that c-Myc acts as a bridge between various signaling pathways, foremost p53, nuclear factor (NF)-κB, and PI3K (Schlee et al., 2007; Sachdeva et al., 2009; Tsai et al., 2012). Notably, the prominence of c-Myc in acute leukemia is not restricted only to the maintenance of leukemic cell survival and recently, tremendous attention to this mo- lecule is due to its fundamental role in inducing chemo-resistant phe- notype (Xia et al., 2015). Given these, it is not surprising that c-Myc is considered as an appealing druggable factor and exploitation of small molecule inhibitors of this protein turns to be intensively debatable in future therapeutic approaches. Among different mechanisms to halt c-Myc on the path of cancer formation, 10058-F4 perturbs the ability of c-Myc to form productive DNA-binding heterodimers (Fletcher and Prochownik, 2015). The fa- vorable anti-cancer property of this inhibitor has been described in several studies, either in the context of in vitro or in vivo investigations https://doi.org/10.1016/j.biocel.2019.01.005 Received 30 September 2018; Received in revised form 15 December 2018; Accepted 8 January 2019 ⁎ Corresponding author at: Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran. E-mail address: d.bashash@sbmu.ac.ir (D. Bashash). International Journal of Biochemistry and Cell Biology 108 (2019) 7–16 Available online 09 January 2019 1357-2725/ © 2019 Elsevier Ltd. All rights reserved. T