In vivo effects of the association of the psychoactive phenotiazine thioridazine on antitumor activity and hind limb paralysis induced by the native polypeptide crotamine.

Autor: Porta LC; Departamento de Farmacologia, Escola Paulista de Medicina (EPM), Universidade Federal de São Paulo (UNIFESP), SP, Brazil., Campeiro JD; Departamento de Farmacologia, Escola Paulista de Medicina (EPM), Universidade Federal de São Paulo (UNIFESP), SP, Brazil., Papa GB; Departamento de Farmacologia, Escola Paulista de Medicina (EPM), Universidade Federal de São Paulo (UNIFESP), SP, Brazil., Oliveira EB; Departamento de Bioquímica e Imunologia, Universidade de São Paulo (USP-RP), Ribeirão Preto, Brazil., Godinho RO; Departamento de Farmacologia, Escola Paulista de Medicina (EPM), Universidade Federal de São Paulo (UNIFESP), SP, Brazil., Rodrigues T; Universidade Federal do ABC, Santo André, SP, Brazil., Hayashi MAF; Departamento de Farmacologia, Escola Paulista de Medicina (EPM), Universidade Federal de São Paulo (UNIFESP), SP, Brazil. Electronic address: mhayashi@unifesp.br.
Jazyk: angličtina
Zdroj: Toxicon : official journal of the International Society on Toxinology [Toxicon] 2020 Oct 15; Vol. 185, pp. 64-71. Date of Electronic Publication: 2020 Jul 02.
DOI: 10.1016/j.toxicon.2020.06.017
Abstrakt: Crotamine is a cationic polypeptide composed by 42 amino acid residues with several pharmacological and biological properties, including the selective ability to enter and kill actively proliferating tumour cells, which led us to propose its use as a theranostic agent for cancer therapy. At the moment, the improvement of crotamine antitumoral efficacy by association with chemotherapeutic adjuvants is envisioned. In the present work, we evaluated the association of crotamine with the antitumoral adjuvant phenotiazine thioridazine (THD). In spite of the clear efficacy of these both compounds as anticancer agents in long-term in vivo treatment of animal model bearing implanted xenograph melanoma tumor, the expected mutual potentiation of the antitumor effects was not observed here. Moreover, this association revealed for the first time the influence of THD on crotamine ability to trigger the hind limb paralysis in mice, and this discovery may represent the first report suggesting the potential involvement of the CNS in the action of this snake polypeptide on the skeletal muscle paralysis, which was classically believed to be essentially limited to a direct action in peripheral tissues as the skeletal muscle. This is also supported by the observed ability of crotamine to potentiate the sedative effects of THD which action was consistently demonstrated to be based on its central action. The better characterization of crotamine properties in CNS may certainly bring important insights for the knowledge needed to pave the way toward the use of this molecule as a theranostic compound in human diseases as cancer.
(Copyright © 2020 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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