Mebendazole targets essential proteins in glucose metabolism leading gastric cancer cells to death.

Autor: da Silva EL; Laboratory of Pharmacogenetics, Drug Research and Development Center (NPDM), Federal University of Ceará, Cel. Nunes de Melo, 1000 - Rodolfo Teófilo, Fortaleza, Brazil., Mesquita FP; Laboratory of Pharmacogenetics, Drug Research and Development Center (NPDM), Federal University of Ceará, Cel. Nunes de Melo, 1000 - Rodolfo Teófilo, Fortaleza, Brazil., Aragão DR; Laboratory of Pharmacogenetics, Drug Research and Development Center (NPDM), Federal University of Ceará, Cel. Nunes de Melo, 1000 - Rodolfo Teófilo, Fortaleza, Brazil., de Sousa Portilho AJ; Laboratory of Pharmacogenetics, Drug Research and Development Center (NPDM), Federal University of Ceará, Cel. Nunes de Melo, 1000 - Rodolfo Teófilo, Fortaleza, Brazil., Marinho AD; Laboratory of Pharmacogenetics, Drug Research and Development Center (NPDM), Federal University of Ceará, Cel. Nunes de Melo, 1000 - Rodolfo Teófilo, Fortaleza, Brazil., de Oliveira LLB; Laboratory of Pharmacogenetics, Drug Research and Development Center (NPDM), Federal University of Ceará, Cel. Nunes de Melo, 1000 - Rodolfo Teófilo, Fortaleza, Brazil., Lima LB; Laboratory of Pharmacogenetics, Drug Research and Development Center (NPDM), Federal University of Ceará, Cel. Nunes de Melo, 1000 - Rodolfo Teófilo, Fortaleza, Brazil., de Moraes MEA; Laboratory of Pharmacogenetics, Drug Research and Development Center (NPDM), Federal University of Ceará, Cel. Nunes de Melo, 1000 - Rodolfo Teófilo, Fortaleza, Brazil., Souza PFN; Laboratory of Pharmacogenetics, Drug Research and Development Center (NPDM), Federal University of Ceará, Cel. Nunes de Melo, 1000 - Rodolfo Teófilo, Fortaleza, Brazil; Department of Biochemistry and Molecular Biology, Federal University of Ceará, Mister Hull Avenue- Pici, Fortaleza, Brazil., Montenegro RC; Laboratory of Pharmacogenetics, Drug Research and Development Center (NPDM), Federal University of Ceará, Cel. Nunes de Melo, 1000 - Rodolfo Teófilo, Fortaleza, Brazil. Electronic address: rmontenegro@ufc.br.
Jazyk: angličtina
Zdroj: Toxicology and applied pharmacology [Toxicol Appl Pharmacol] 2023 Sep 15; Vol. 475, pp. 116630. Date of Electronic Publication: 2023 Jul 18.
DOI: 10.1016/j.taap.2023.116630
Abstrakt: Gastric cancer (GC) is among the most-diagnosed and deadly malignancies worldwide. Deregulation in cellular bioenergetics is a hallmark of cancer. Based on the importance of metabolic reprogramming for the development and cancer progression, inhibitors of cell metabolism have been studied as potential candidates for chemotherapy in oncology. Mebendazole (MBZ), an antihelminthic approved by FDA, has shown antitumoral activity against cancer cell lines. However, its potential in the modulation of tumoral metabolism remains unclear. Results evidenced that the antitumoral and cytotoxic mechanism of MBZ in GC cells is related to the modulation of the mRNA expression of glycolic targets SLC2A1, HK1, GAPDH, and LDHA. Moreover, in silico analysis has shown that these genes are overexpressed in GC samples, and this increase in expression is related to decreased overall survival rates. Molecular docking revealed that MBZ modifies the protein structure of these targets, which may lead to changes in their protein function. In vitro studies also showed that MBZ induces alterations in glucose uptake, LDH's enzymatic activity, and ATP production. Furthermore, MBZ induced morphologic and intracellular alterations typical of the apoptotic cell death pathway. Thus, this data indicated that the cytotoxic mechanism of MBZ is related to an initial modulation of the tumoral metabolism in the GC cell line. Altogether, our results provide more evidence about the antitumoral mechanism of action of MBZ towards GC cells and reveal metabolic reprogramming as a potential area in the discovery of new pharmacological targets for GC chemotherapy.
Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest.
(Copyright © 2023. Published by Elsevier Inc.)
Databáze: MEDLINE
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