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

Negar Sheikh-Zeineddini, Davood Bashash, Ava Safaroghli-Azar, Niknam Riyahi, Rima Manafi Shabestari, Ehsan Janzamin, Majid Safa

J Cell Biochem. 2019 Aug;120(8):14004-14016.

PMID: 30957273

Abstract:

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP403811552-A	10058-F4		403811-55-2	Price

Catalog Number

Product Name

Structure

CAS Number

Price

AP403811552-A

10058-F4

403811-55-2

Price

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