Obatoclax reduces cell viability of acute myeloid leukemia cell lines independently of their sensitivity to venetoclax

Lima, Keli; Vicari, Hugo Passos; Hirakata, C.; Carlos, Jorge Antonio Elias Godoy; Silva, J.C.L.; Traina, Fabı́ola; Pontes, Lorena Lobo Figueiredo; Costa-Lotufo, L. V.; Rego, Eduardo Magalhães; Machado-Neto, João Agostinho

doi:10.1016/j.htct.2021.01.004

Cited by 2 publications

(1 citation statement)

References 18 publications

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“…Furthermore, multiple Bcl-2 inhibitors are being tested in clinical studies against various cancer types [9,10], and activity has been widely reported in pre-clinical models such as human breast cancer cells MCF-7 [11,12] and MDA-MB-231 [13] and human lung cancer cell A549 [14,15]. These trials are assessing their safety, efficacy, and potential synergistic benefits when combined with existing medicines, offering the promise of improved cancer treatment outcomes [16].…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Potent Anticancer Activity of Novel Indole-Based Bcl-2 Inhibitors

Almehdi,

Soliman,

El-Shorbagi

et al. 2023

IJMS

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The Bcl-2 family plays a crucial role in regulating cell apoptosis, making it an attractive target for cancer therapy. In this study, a series of indole-based compounds, U1–6, were designed, synthesized, and evaluated for their anticancer activity against Bcl-2-expressing cancer cell lines. The binding affinity, safety profile, cell cycle arrest, and apoptosis effects of the compounds were tested. The designed compounds exhibited potent inhibitory activity at sub-micromolar IC50 concentrations against MCF-7, MDA-MB-231, and A549 cell lines. Notably, U2 and U3 demonstrated the highest activity, particularly against MCF-7 cells. Respectively, both U2 and U3 showed potential BCL-2 inhibition activity with IC50 values of 1.2 ± 0.02 and 11.10 ± 0.07 µM using an ELISA binding assay compared with 0.62 ± 0.01 µM for gossypol, employed as a positive control. Molecular docking analysis suggested stable interactions of compound U2 at the Bcl-2 binding site through hydrogen bonding, pi-pi stacking, and hydrophobic interactions. Furthermore, U2 demonstrated significant induction of apoptosis and cell cycle arrest at the G1/S phase. Importantly, U2 displayed a favourable safety profile on HDF human dermal normal fibroblast cells at 10-fold greater IC50 values compared with MDA-MB-231 cells. These findings underscore the therapeutic potential of compound U2 as a Bcl-2 inhibitor and provide insights into its molecular mechanisms of action.

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