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Novel thiosemicarbazones induce high toxicity in estrogen-receptor-positive breast cancer cells (MCF7) and exacerbate cisplatin effectiveness in triple-negative breast (MDA-MB231) and lung adenocarcinoma (A549) cells

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Summary

Cis-diamminedichloroplatinum(II) (CDDP), known as cisplatin, has been extensively used against breast cancer, which is the most frequent cancer among women, and lung cancer, the leading cancer that causes death worldwide. Novel compounds such as thiazole derivatives have exhibited antiproliferative activity, suggesting they could be useful against cancer treatment. Herein, we synthesized two novel thiosemicarbazones and an aldehyde to combine with CDDP to enhance efficacy against ER-positive breast MCF7 cancer cells, triple-negative/basal-B mammary carcinoma cells (MDA-MB231) and lung adenocarcinoma (A549) human cells. We synthesized 2,3,5,6-tetrafluoro-4-(2-mercaptoetanothiolyl)benzaldehyde (ALD), 5-[(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl)thio]-2-furaldehyde thiosemicarbazone (TSC1) and 5-[(4-(trifluoromethyl)phenyl)thio]-2-furaldehyde thiosemicarbazone (TSC2) and used them alone or in combination with subtoxic CDDP concentrations to evaluate cytotoxicity, cytoskeleton integrity and mitochondrial function. We found that none of the synthesized compounds improved CDDP activity against MCF7 cell cultures; however, TSC2 was effective in enhancing the cytotoxicity of CDDP against MDA-MB231 and A549 cancer cell cultures. We demonstrated that the cytotoxic effect is related to the TSC2 capacity to induce disruption in the cytoskeleton network and to decrease mitochondrial function.

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Funding

This research was supported by Programa de Apoyo a los Profesores de Carrera para Promover Grupos de Investigación (PAPCA, Facultad de Estudios Superiores Iztacala, UNAM; FESI-DIP-PAPCA-2014-36) and the National Council of Science and Technology (CONACyT 268769). Medina-Reyes Estefany Ingrid is a doctoral student from Programa de Doctorado en Ciencias Biomédicas de la Universidad Nacional Autónoma de México (UNAM) and received fellowship 576227 from CONACYT.

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Authors and Affiliations

  1. Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Av. De los Barrios 1, Col. Los Reyes Iztacala, CP 54059, Tlalnepantla, Estado de México, Mexico

    Estefany Ingrid Medina-Reyes, Marco Antonio Mancera-Rodríguez, Norma Laura Delgado-Buenrostro, Stefanía Andrea Martínez-Alarcón, Luis Ignacio Terrazas-Valdés, Yolanda Irasema Chirino & Felipe Vaca-Paniagua

  2. Facultad de Ciencias Químicas, Universidad Autónoma Benito Juárez, Oaxaca, Mexico

    Adriana Moreno-Rodríguez & Juan Luis Bautista-Martínez

  3. Laboratorio Nacional en Salud: Diagnóstico Molecular y Efecto Ambiental en Enfermedades Crónico-Degenerativas, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Av. De los Barrios 1, Col. Los Reyes Iztacala, CP 54059, Tlalnepantla, Estado de México, Mexico

    Clara Estela Díaz-Velásquez, Luis Ignacio Terrazas-Valdés & Felipe Vaca-Paniagua

  4. Facultad de Química, Universidad Nacional Autónoma de México, Ciudad de México, México

    Hugo Torrens

  5. Carrera de Enfermería, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Av. De los Barrios 1, Col. Los Reyes Iztacala, CP 54059, Tlalnepantla, Estado de México, Mexico

    María de los Ángeles Godínez-Rodríguez

  6. Subdirección de Investigación Básica, Instituto Nacional de Cancerología, San Fernando No. 22, Tlalpan, CP 14080, Ciudad de México, Mexico

    Felipe Vaca-Paniagua

Authors
  1. Estefany Ingrid Medina-Reyes
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  2. Marco Antonio Mancera-Rodríguez
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  3. Norma Laura Delgado-Buenrostro
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Correspondence to Felipe Vaca-Paniagua.

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Highlights

• The compound 5-[(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl)thio]-2-furaldehyde thiosemicarbazone (TSC1) is highly cytotoxic in ER-positive breast and lung adenocarcinoma cancer cells.

• Due to its high toxicity, TSC1 was not able to synergize with cisplatin.

• 5-[(4-(trifluoromethyl)phenyl)thio]-2-furaldehyde thiosemicarbazone (TSC2) showed synergistic effects with cisplatin in triple-negative/basal-B mammary carcinoma cells.

• The synergistic mechanism of TSC2 cytotoxicity involves disorganization of the cytoskeleton and mitochondrial dysfunction in ER-positive breast, triple-negative/basal-B mammary carcinoma and lung adenocarcinoma cancer cells.

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Medina-Reyes, E.I., Mancera-Rodríguez, M.A., Delgado-Buenrostro, N.L. et al. Novel thiosemicarbazones induce high toxicity in estrogen-receptor-positive breast cancer cells (MCF7) and exacerbate cisplatin effectiveness in triple-negative breast (MDA-MB231) and lung adenocarcinoma (A549) cells. Invest New Drugs 38, 558–573 (2020). https://doi.org/10.1007/s10637-019-00789-1

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