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Volume 17
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10.3390/ph17030389
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Article

Cytotoxic and Antiproliferative Activity of LASSBio-2208 and the Attempts to Determine Its Drug Metabolism and Pharmacokinetics In Vitro Profile

by
Raysa Magali Pillpe-Meza
1,2,
Wesley Leandro Gouveia
1,2,
Gisele Barbosa
1,
Carlos A. M. Fraga
1,2,
Eliezer J. Barreiro
1,2 and
Lidia Moreira Lima
1,2,*
1
Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio®), Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
2
Programa de Pós-Graduação em Farmacologia e Química Medicinal, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
*
Author to whom correspondence should be addressed.
Pharmaceuticals 2024, 17(3), 389; https://doi.org/10.3390/ph17030389
Submission received: 13 February 2024 / Revised: 10 March 2024 / Accepted: 14 March 2024 / Published: 18 March 2024
(This article belongs to the Section Pharmacology)
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Abstract

Inappropriate expression of histone deacetylase (HDAC-6) and deregulation of the phosphatidylinositol 3-kinase (PI3K) signalling pathway are common aberrations observed in cancers. LASSBio-2208, has been previously described as a dual inhibitor in the nanomolar range of HDAC-6 and PI3Kα and is three times more potent in inhibiting HDAC-6. In this paper we described the cytotoxic and antiproliferative potency of LASSBio-2208 on different tumour cell lines, its possible synergism effect in association with PI3K and HDAC-6 inhibitors, and its drug metabolism and pharmacokinetics (DMPK) in vitro profile. Our studies have demonstrated that LASSBio-2208 has moderate cytotoxic potency on breast cancer cell line MCF-7 (IC50 = 23 µM), human leukaemia cell line CCRF-CEM (IC50 = 8.54 µM) and T lymphoblast cell line MOLT-4 (IC50 = 7.15 µM), with no cytotoxic effect on human peripheral blood mononuclear cells (hPBMC). In addition, it has a good antiproliferative effect on MCF-7 cells (IC50 = 5.44 µM), low absorption by parallel artificial membrane permeability—gastrointestinal tract (PAMPA—GIT) and low permeation by parallel artificial membrane permeability—blood–brain barrier (BBB) (PAMPA—BBB), exhibiting high metabolic stability in rat plasma. Moreover, LASSBio-2208 exhibited synergism when combined with getadolisib and tubastatin A, using the concentrations corresponding to their CC50 values on MOLT-4 and CCRF-CEM cells.
Keywords: cancer; PI3K; HDAC-6; cytotoxicity; antiproliferative activity; synergism; DMPK cancer; PI3K; HDAC-6; cytotoxicity; antiproliferative activity; synergism; DMPK
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MDPI and ACS Style

Pillpe-Meza, R.M.; Gouveia, W.L.; Barbosa, G.; Fraga, C.A.M.; Barreiro, E.J.; Lima, L.M. Cytotoxic and Antiproliferative Activity of LASSBio-2208 and the Attempts to Determine Its Drug Metabolism and Pharmacokinetics In Vitro Profile. Pharmaceuticals 2024, 17, 389. https://doi.org/10.3390/ph17030389

AMA Style

Pillpe-Meza RM, Gouveia WL, Barbosa G, Fraga CAM, Barreiro EJ, Lima LM. Cytotoxic and Antiproliferative Activity of LASSBio-2208 and the Attempts to Determine Its Drug Metabolism and Pharmacokinetics In Vitro Profile. Pharmaceuticals. 2024; 17(3):389. https://doi.org/10.3390/ph17030389

Chicago/Turabian Style

Pillpe-Meza, Raysa Magali, Wesley Leandro Gouveia, Gisele Barbosa, Carlos A. M. Fraga, Eliezer J. Barreiro, and Lidia Moreira Lima. 2024. "Cytotoxic and Antiproliferative Activity of LASSBio-2208 and the Attempts to Determine Its Drug Metabolism and Pharmacokinetics In Vitro Profile" Pharmaceuticals 17, no. 3: 389. https://doi.org/10.3390/ph17030389

APA Style

Pillpe-Meza, R. M., Gouveia, W. L., Barbosa, G., Fraga, C. A. M., Barreiro, E. J., & Lima, L. M. (2024). Cytotoxic and Antiproliferative Activity of LASSBio-2208 and the Attempts to Determine Its Drug Metabolism and Pharmacokinetics In Vitro Profile. Pharmaceuticals, 17(3), 389. https://doi.org/10.3390/ph17030389

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