WIN55,212-2 induces caspase-independent apoptosis on human glioblastoma cells by regulating HSP70, p53 and Cathepsin D.

Abstract

Despite the standard approaches to treat the highly aggressive and invasive glioblastoma (GBM), it remains incurable. In this sense, cannabinoids highlight as a promising tool, because this tumor overexpresses CB1 and/or CB2 receptors and being, therefore, can be susceptible to cannabinoids treatment. Thus, this work investigated the action of the cannabinoid agonist WIN55-212-2 on GBM cell lines and non-malignant cell lines, in vitro and in vivo. WIN was selectively cytotoxic to GBM cells. These presented blebbing and nuclear alterations in addition to cell shrinkage and chromatin condensation. WIN also significantly inhibited the migration of GAMG and U251 cells. Finally, the data also showed that the antitumor effects of WIN are exerted, at least to some extent, by the expression of p53 and increased cathepsin D in addition to the decreased expression of HSP70.This data can indicate caspase-independent cell death mechanism. In addition, WIN decreased tumoral perimeter as well as caused a reduction the blood vessels in this area, without causing lysis, hemorrhage or blood clotting. So, the findings herein presented reinforce the usefulness of cannabinoids as a candidate for further evaluation in treatment in glioblastoma treatment.

• Authors: Ana Gabriela Silva, Caio Fabio Baeta Lopes, Clóvis Gomes Carvalho Júnior, Ralph Gruppi Thomé, Hélio Batista Dos Santos, Rui Reis, Rosy Iara Maciel de Azambuja Ribeiro
• Journal: Toxicology in vitro : an international journal published in association with BIBRA (Toxicol In Vitro) Vol. 57 Pg. 233-243 (Jun 2019) ISSN: 1879-3177 [Electronic] England
• PMID: 30776504 (Publication Type: Journal Article)
• Copyright: Copyright © 2019 Elsevier Ltd. All rights reserved.

Chemical References

• Benzoxazines
• HSP70 Heat-Shock Proteins
• Morpholines
• Naphthalenes
• Tumor Suppressor Protein p53
• (3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone
• Caspases

Topics

• Animals
• Apoptosis (drug effects)
• Benzoxazines (pharmacology)
• Caspases
• Cell Line
• Cell Movement (drug effects)
• Chickens
• Chorioallantoic Membrane (drug effects, physiology)
• Glioblastoma (metabolism)
• HSP70 Heat-Shock Proteins (metabolism)
• Humans
• Morpholines (pharmacology)
• Naphthalenes (pharmacology)
• Tumor Suppressor Protein p53 (metabolism)