Tocotrienols-enriched Self-nanoemulsifying Drug Delivery System Enhances the Antileukemic Activity of All-trans Retinoic Acid but not Electrocardiogram Alterations Evoked by Its Combination with Arsenic Trioxide.

Autor: Borges GSM; Department of Pharmaceutics, Faculty of Pharmacy, Universidade Federal de Minas Gerais (UFMG), Avenida Antônio Carlos, Campus Pampulha, Belo Horizonte, Minas Gerais, 6627CEP 31270-901, Brazil.; PhyMedExp, Inserm, University of Montpellier, Montpellier, France., Sicard P; PhyMedExp, Inserm, University of Montpellier, Montpellier, France.; IPAM, Biocampus, INSERM, CNRS, University of Montpellier, Montpellier, France., de Mello Gomides Loures C; Departamento de Análises Clínicas e Toxicológicas, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil., Evangelista FGC; Departamento de Análises Clínicas e Toxicológicas, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil., Sales CC; Departamento de Análises Clínicas e Toxicológicas, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil., de Paula Sabino A; Departamento de Análises Clínicas e Toxicológicas, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil., Fernandes C; Department of Pharmaceutics, Faculty of Pharmacy, Universidade Federal de Minas Gerais (UFMG), Avenida Antônio Carlos, Campus Pampulha, Belo Horizonte, Minas Gerais, 6627CEP 31270-901, Brazil., Ferreira LAM; Department of Pharmaceutics, Faculty of Pharmacy, Universidade Federal de Minas Gerais (UFMG), Avenida Antônio Carlos, Campus Pampulha, Belo Horizonte, Minas Gerais, 6627CEP 31270-901, Brazil. lucaufmg@gmail.com., Richard S; PhyMedExp, Inserm, University of Montpellier, Montpellier, France. sylvain.richard@inserm.fr.; IPAM, Biocampus, INSERM, CNRS, University of Montpellier, Montpellier, France. sylvain.richard@inserm.fr.
Jazyk: angličtina
Zdroj: AAPS PharmSciTech [AAPS PharmSciTech] 2023 Mar 14; Vol. 24 (3), pp. 79. Date of Electronic Publication: 2023 Mar 14.
DOI: 10.1208/s12249-023-02531-w
Abstrakt: All-trans retinoic acid and arsenic trioxide are the leading choices for the treatment of acute promyelocytic leukemia. Notwithstanding the impressive differentiative properties of all-trans retinoic acid and the apoptotic properties of arsenic trioxide, some problems still occur in acute promyelocytic leukemia treatment. These problems are due to patients' relapses, mainly related to changes in the ligand-binding domain of RARα (retinoic acid receptor α) and the cardiotoxic effects caused by arsenic trioxide. We previously developed a self-nanoemulsifying drug delivery system enriched with tocotrienols to deliver all-trans retinoic acid (SNEDDS-TRF-ATRA). Herein, we have evaluated if tocotrienols can help revert ATRA resistance in an APL cell line (NB4-R2 compared to sensitive NB4 cells) and mitigate the cardiotoxic effects of arsenic trioxide in a murine model. SNEDDS-TRF-ATRA enhanced all-trans retinoic acid cytotoxicity in NB4-R2 (resistant) cells but not in NB4 (sensitive) cells. Moreover, SNEDDS-TRF-ATRA did not significantly change the differentiative properties of all-trans retinoic acid in both NB4 and NB4-R2 cells. Combined administration of SNEDDS-TRF-ATRA and arsenic trioxide could revert QTc interval prolongation caused by ATO but evoked other electrocardiogram alterations in mice, such as T wave flattening. Therefore, SNEDDS-TRF-ATRA may enhance the antileukemic properties of all-trans retinoic acid but may influence ECG changes caused by arsenic trioxide administration. SNEDDS-TRF-ATRA presents cytotoxicity in resistant APL cells (NB4-R2). Combined administration of ATO and SNEDDS-TRF-ATRA in mice prevented the prolongation of the QTc interval caused by ATO but evoked ECG abnormalities such as T wave flattening.
(© 2023. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)
Databáze: MEDLINE
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