Journal Information
Vol. 42. Issue S2.
Pages 172 (November 2020)
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Vol. 42. Issue S2.
Pages 172 (November 2020)
Open Access
K. Limaa,b, H.P. Vicaria, C. Hirakataa, J.A.E.G. Carlosa, J.C.L. Silvaa, F. Trainac, L.L.F. Pontesc, L.V. Costa-Lotufoa, E.M. Regob, J.A. Machado-Netoa
a Departamento de Farmacologia, Instituto de Ciências Biomédicas, Universidade de São Paulo (USP), São Paulo, SP, Brazil
b Laboratório de Investigação Médica em Hematologia Molecular (LIM-31), Departamento de Hematologia, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo (HCFMUSP),São Paulo, SP, Brazil
c Departamento de Imagens Médicas, Hematologia e Oncologia Clínica, Faculdade de Medicina de Ribeirão Preto (FMRP), Universidade de São Paulo (USP), Ribeirão Preto, SP, Brazil
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Objectives: In acute myeloid leukemia (AML) therapy, venetoclax (ABT-199), a selective inhibitor of BCL2, has been introduced in clinical practice, presenting interesting results in unfavorable molecular markers or older AML patients when combined with epigenetic modulators. In a previous study, we characterized the sensitivity to venetoclax in four AML cellular models, being two sensitive models (MOLM13 and MV4-11), one intermediate response model (Kasumi 1), and one drug resistant model (OCI-AML3). Some molecular mechanisms involved in venetoclax resistance have been described in AML, including the overexpression of other antiapoptotic BCL2 family members (e.g. MCL1). In the present study, we characterized the effects of obatoclax, a pan BCL2 inhibitor, in those four leukemia cell lines with different levels of sensitivity to venetoclax. Material and methods: MOLM13, MV4-11 (both FLT3-ITD positive), Kasumi 1 [t(8;21), and KIT-mutated], and OCI-AML3 (NPM1- and DNMT3A-mutated) leukemia cell lines were used. Methylthiazoltetrazolium (MTT) assay was used to detect the 50% inhibiting concentration (IC50) upon exposure to increasing obatoclax concentrations (Ø; 3; 10; 30; 100; 300, and 1000 nM) for 24, 48, and 72 hours. The data obtained from at least three independent experiments analyzed by linear regression for determination of IC50 and statistical analysis was performed by ANOVA and Bonferroni post-test using GraphPad Prism software. A p-value < 0.05 was considered significant. Results: All AML cell lines presented a dose and time-sensitivity to obatoclax, displaying IC50 values in low nM range (MOLM13: 160, 6, and 4 nM; MV4-11: 46, 17, and 6 nM; Kasumi 1: 845, 329, and 8 nM; OCI-AML3: 382, 29, and 12 nM for 24, 48, and 72 hours of exposure to obatoclax, respectively, all p < 0.05 compared to vehicle-treated cells). Discussion and conclusion: Our results indicate that obatoclax reduces cell viability in AML cells, independently of their sensitivity to venetoclax, suggesting that pan-BCL2 inhibition by this drug may overcome intrinsic resistance in AML cellular models. These findings provide pharmacological tools for direct additional investigation of molecular mechanisms involved in intrinsic resistance to venetoclax and highlighted obatoclax as a potential therapeutic option in this context. Funding: Supported by FAPESP, CAPES, and CNPq.

Hematology, Transfusion and Cell Therapy

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