Small molecule inhibitor of c-Myc 10058-F4 inhibits proliferation and induces apoptosis in acute leukemia cells, irrespective of PTEN status.

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.

• Authors: Davood Bashash, Mohamad Sayyadi, Ava Safaroghli-Azar, Negar Sheikh-Zeineddini, Niknam Riyahi, Majid Momeny
• Journal: The international journal of biochemistry & cell biology (Int J Biochem Cell Biol) Vol. 108 Pg. 7-16 (03 2019) ISSN: 1878-5875 [Electronic] Netherlands
• PMID: 30639430 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents
• MYC protein, human
• Proto-Oncogene Proteins c-myc
• Small Molecule Libraries
• PTEN Phosphohydrolase

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Drug Synergism
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Leukemia, Promyelocytic, Acute (pathology)
• PTEN Phosphohydrolase (metabolism)
• Proto-Oncogene Proteins c-myc (antagonists & inhibitors)
• Small Molecule Libraries (pharmacology)