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Cytotoxic evaluation of YSL-109 in a triple negative breast cancer cell line and toxicological evaluations

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Abstract

Breast cancer (BC) is the leading cause of cancer-related death in women worldwide. Triple negative breast cancer (TNBC) is the most aggressive form of BC being with the worst prognosis and the worst survival rates. There is no specific pharmacological target for the treatment of TNBC; conventional therapy includes the use of non-specific chemotherapy that generally has a poor prognosis. Therefore, the search of effective therapies against to TNBC continues at both preclinical and clinical level. In this sense, the exploration of different pharmacological targets is a continue task that pave the way to epigenetic modulation using novel small molecules. Lately, the inhibition of histone deacetylases (HDACs) has been explored to treat different BC, including TNBC. HDACs remove the acetyl groups from the ɛ-amino lysine resides on histone and non-histone proteins. In particular, the inhibition of HDAC6 has been suggested to be useful for the treatment of TNBC due to it is overexpressed in TNBC. Therefore, in this work, an HDAC6 selective inhibitor, the (S)-4-butyl-N-(1-(hydroxyamino)-3-(naphthalen-1-yl)-1-oxopropan-2-yl) benzamide (YSL-109), was assayed on TNBC cell line (MDA-MB231) showing an antiproliferative activity (IC50 = 50.34 ± 1.11 µM), whereas on fibroblast, it was lesser toxic. After corroborating the in vitro antiproliferative activity of YSL-109 in TNBC, the toxicological profile was explored using combined approach with in silico tools and experimental assays. YSL-109 shows moderate mutagenic activity on TA-98 strain at 30 and 100 µM in the Ames test, whereas YSL-109 did not show in vivo genotoxicity and its oral acute toxicity (LD50) in CD-1 female mice was higher than 2000 mg/kg, which is in agreement with our in silico predictions. According to these results, YSL-109 represents an interesting compound to be explored for the treatment of TNBC under preclinical in vivo models.

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All data generated or analyzed during the present study are included in this published article.

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Acknowledgements

YSL thanks to CONACYT for Ph. D. scholarship and to SECTEI (Secretaria de Educación, Ciencia, Tecnología e Innovación de la Ciudad de México) for Postdoctoral Fellowship.

Funding

This work was supported by Instituto Politécnico Nacional (SIP), BEIFI, COFAA-IPN with grants CB-254600, CB-241339, Infraestructura: 317214, SEP-CONACYT-ANUIES-ECOS Francia: 296636.

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Authors and Affiliations

  1. Laboratorio de Diseño Y Desarrollo de Nuevos Fármacos E Innovación Biotecnológica (Laboratory for the Design and Development of New Drugs and Biotechnological Innovation)-SEPI, Escuela Superior de Medicina, Instituto Politécnico Nacional, 11340, Mexico City, Mexico

    Yudibeth Sixto-López & José Correa-Basurto

  2. Departamento de Química Farmacéutica Y Orgánica, Facultad de Farmacia, Universidad de Granada, 18071, Granada, Spain

    Yudibeth Sixto-López & José Antonio Gómez-Vidal

  3. Laboratorio de Biología Celular Y Productos Naturales, Escuela Nacional de Medicina Y Homeopatía, Instituto Politécnico Nacional, 07320, Mexico City, Mexico

    Cynthia Ordaz-Pichardo

  4. Laboratorio de Biofísica Y Biocatálisis, Sección de Estudios de Posgrado E Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, 11340, Ciudad de México, Mexico

    Martha Cecilia Rosales-Hernández

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  1. Yudibeth Sixto-López
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  2. Cynthia Ordaz-Pichardo
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  3. José Antonio Gómez-Vidal
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  4. Martha Cecilia Rosales-Hernández
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Contributions

JCB was the grant holder. YSL, COP, and MCRH performed the biological experiments. YSL, JAGV, and JCB performed the chemical synthesis of the compound. All the authors have contributed to the analysis of the data. YSL drafted the manuscript. JCB revised the manuscript. All authors read and approved the published version of the manuscript.

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Correspondence to José Correa-Basurto.

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Sixto-López, Y., Ordaz-Pichardo, C., Gómez-Vidal, J.A. et al. Cytotoxic evaluation of YSL-109 in a triple negative breast cancer cell line and toxicological evaluations. Naunyn-Schmiedeberg's Arch Pharmacol 396, 1211–1222 (2023). https://doi.org/10.1007/s00210-023-02396-7

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