Synergistic apoptotic effect of Mcl-1 inhibition and doxorubicin on B-cell precursor acute lymphoblastic leukemia cells.

Abstract

BACKGROUND:

Myeloid cell leukemia-1 (MCL-1) is a component of the Bcl-2 anti-apoptotic family that plays a key role in cell proliferation and differentiation. Despite tremendous improvements toward identification of the role of MCL-1 in leukemia progression, the functional significance and molecular mechanism behind the effect of MCL-1 overexpression on the proliferation of B-cell precursor acute lymphoblastic leukemia (BCP-ALL) has not been clarified. In addition, less well appreciated is the effect of MCL-1 inhibition on the potentiation of doxorubicin-induced apoptosis in BCP-ALL cell lines. In the present study, we aimed to shed light on the anti-cancer properties of S63845, a potent Mcl-1 inhibitor, in BCP-ALL cell lines either alone or in combination with a chemotherapeutic drug. METHODS AND RESULTS: Mononuclear cells from patients with Pre-B ALL and BCP-ALL cell lines were treated with S63845 in presence or absence of doxorubicin, induction of apoptosis was evaluated using Annexin-V/PI staining kit. mRNA and protein expression levels were assessed by qRT-PCR and western blot analysis, respectively. Our results declared that inhibition of Mcl-1 impairs cell growth and induces apoptosis in pre-B ALL cells through activation of caspase-3 and up-regulation of a repertoire of pro-apoptotic Bcl-2 family. Additionally, S63845 acts synergically with doxorubicin to induce apoptosis in BCP-ALL cell lines.

CONCLUSIONS:

Our data declared that MCL-1 inhibition alone or in combination with a chemotherapeutic agent is considered an appealing strategy for the induction of apoptosis in BCP-ALL cells.

• Authors: Elham Ebrahimi, Rima Manafi Shabestari, Davood Bashash, Majid Safa
• Journal: Molecular biology reports (Mol Biol Rep) Vol. 49 Issue 3 Pg. 2025-2036 (Mar 2022) ISSN: 1573-4978 [Electronic] Netherlands
• PMID: 35138523 (Publication Type: Journal Article)
• Copyright: © 2022. The Author(s), under exclusive licence to Springer Nature B.V.

Chemical References

• Myeloid Cell Leukemia Sequence 1 Protein
• Proto-Oncogene Proteins c-bcl-2
• Doxorubicin

Topics

• Apoptosis
• Cell Line, Tumor
• Doxorubicin (pharmacology)
• Humans
• Myeloid Cell Leukemia Sequence 1 Protein (genetics, metabolism)
• Precursor Cell Lymphoblastic Leukemia-Lymphoma
• Proto-Oncogene Proteins c-bcl-2 (genetics, metabolism)