α-Mangostin and Doxorubicin Combination Synergistically Inhibited Cell Growth, Induced Cell Apoptosis with Increased Bak Protein and Decreased FLT3-ITD Phosphorylation in AML MOLM-13 Cell Line

Osemeke, Cynthia, Wen, Xuesong ORCID: https://orcid.org/0000-0001-6518-8962, Garelick, Hemda ORCID: https://orcid.org/0000-0003-4568-2300 and Appiah, Sandra S. ORCID: https://orcid.org/0000-0002-7497-3388 (2021) α-Mangostin and Doxorubicin Combination Synergistically Inhibited Cell Growth, Induced Cell Apoptosis with Increased Bak Protein and Decreased FLT3-ITD Phosphorylation in AML MOLM-13 Cell Line. Clinical Oncology and Research, 4 (8) . pp. 1-10. ISSN 2613-4942 [Article] (doi:10.31487/j.COR.2021.08.12)

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Abstract

Acute myeloid leukemia (AML) is associated with numerous mutations, with the Feline McDonough Sarcoma (FMS) like tyrosine kinase 3 (FLT3) mutation resulting in with poor prognosis and outcome. Therapies have been developed using FLT3 inhibitors, however, drug resistance often leads to disease relapse. In this study, α-Mangostin and doxorubicin (Dox) were evaluated, singly and in combination, for their anti-leukemic effect on MOLM-13, an AML cell line with FLT3-ITD mutation. Cell viability and apoptosis were determined using CyQUANTGR and TUNEL assay, respectively. Cell cycle analysis was conducted on propidium iodide-stained cells using flow cytometry. Cellular proteins were quantified using Western blot technique, with additional study by ELISA for FLT3 kinase activity. The results revealed that cell treatment by the combined drug, Dox (1 µM) and α-Mangostin (20 µM), compared to Dox (1 µM) alone, caused a significant inhibitory effect (P<0.001) and indicated synergistic cell growth inhibition. The combined drug also showed increased TUNEL positive apoptotic cells and increased expression of the pro-apoptotic protein Bak compared to Dox alone (P<0.05). Dox treated cells, as well as the combined drug induced cell cycle arrest at G2/M phase compared to untreated cells (P<0.05 and P<0.001, respectively). There was also statistically significant (P<0.05) reduction of cdc25 phosphatases (enzymes which play an important role in G2/M transition) by the combination drug compared to sole cell treatment by Dox. Furthermore, phosphorylated FLT3 protein expression was reduced when the combined treatment was compared to Dox only after 2 h (P<0.05) and after 24 h (P<0.001). Thus, Dox and α-Mangostin combined treatment inhibited FLT3 phosphorylation in MOLM-13 cells which could have contributed to G2M cell arrest and apoptosis via cdc25s and Bak proteins respectively. Further studies are warranted to further evaluate the potential of Dox and α-Mangostin combined drug as inhibitors of FLT3-ITD phosphorylation and its potential clinical relevance in AML treatment.

Item Type: Article
Research Areas: A. > School of Science and Technology > Natural Sciences > Biomarkers for Cancer group
Item ID: 33841
Notes on copyright: © 2021 Sandra Appiah. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Hosting by Science Repository. All rights reserved. http://dx.doi.org/10.31487/j.COR.2021.08.12
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Depositing User: Sandra Appiah
Date Deposited: 14 Sep 2021 15:17
Last Modified: 15 Nov 2021 11:40
URI: https://eprints.mdx.ac.uk/id/eprint/33841

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