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Bax, Bcl-2, and Bax/Bcl-2 as prognostic markers in acute myeloid leukemia: are we ready for Bcl-2-directed therapy?

Authors Kulsoom B, Shamsi TS, Afsar NA, Memon Z, Ahmed N, Hasnain SN

Received 19 October 2017

Accepted for publication 4 January 2018

Published 2 March 2018 Volume 2018:10 Pages 403—416

DOI https://doi.org/10.2147/CMAR.S154608

Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 2

Editor who approved publication: Professor Nakshatri


Bibi Kulsoom,1 Tahir Sultan Shamsi,1 Nasir Ali Afsar,2,3 Zahida Memon,4 Nikhat Ahmed,4 Syed Nazrul Hasnain5

1National Institute of Blood Diseases and Bone Marrow Transplantation, Karachi, Pakistan; 2Jinnah Medical and Dental College, Karachi, Pakistan; 3College of Medicine, Alfaisal University, Riyadh, Saudi Arabia; 4Ziauddin University, Karachi, Pakistan; 5Dow International Medical College, Karachi, Pakistan

Purpose:
Many anticancer drugs induce apoptosis in malignant cells, and resistance to apoptosis could lead to suboptimal or no therapeutic benefit. Two cytoplasmic proteins, B-cell lymphoma protein 2 (Bcl-2)-associated X (Bax) and Bcl-2, act as a promoter and an inhibitor of apoptosis, respectively. Both Bax and Bcl-2 as well as their ratio have been regarded as prognostic markers in various cancers. However, conflicting results have been reported. A clear understanding of apoptosis has also become crucial due to reports about anti-Bcl-2 chemotherapy. We explored the relationship of Bax and Bcl-2 gene expression and their ratio with the therapeutic response in acute myeloid leukemia (AML) patients.
Patients and methods: Bone marrow and/or blood samples from 90 AML patients treated with cytarabine and daunorubicin were included. Expression of Bax and Bcl-2 was determined through real-time polymerase chain reaction by using ΔΔCt method of relative expression.
Results: Bax and Bcl-2 expression among marrow and blood samples correlated with each other (rs=0.5, p<0.01). Although bone marrow expression of Bax and Bcl-2 tended to remain higher among responders (median 1.01 and 0.29, respectively) as compared to non-responders (median 0.66 and 0.24, respectively), the difference failed to reach statistical significance (U=784.5 and 733; p=0.68 and 0.28, respectively). Conversely, Bax/Bcl-2 ratio was higher among poor responders (median 3.07 vs 1.78), though again failed to reach statistical significance (U=698.5, p=0.07).
Conclusion: Expression of Bax and Bcl-2 does not differ significantly among AML patients treated with cytarabine and daunorubicin in terms of remission, relapse, resistance, overall survival, and disease-free survival, thus questioning the utility of emerging anti-Bcl-2 therapy.

Keywords: anthracyclines, cytarabine, Bcl-2, Bax Bcl-2 ratio, anti Bcl-2 therapy, BH3 mimetic inhibitors

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