Molecular mechanisms of cell death induced in glioblastoma by experimental and antineoplastic drugs: New and old drugs induce apoptosis in glioblastoma

Glioblastoma multiforme (GBM) is one of the most aggressive astrocytic tumors; it is resistant to most chemotherapeutic agents currently available and is associated with a poor patient survival. Thus, the development of new anticancer compounds is urgently required. Herein, we studied the molecular...

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Published inHuman & experimental toxicology Vol. 39; no. 4; pp. 464 - 476
Main Authors Contreras-Ochoa, CO, López-Arellano, ME, Roblero-Bartolon, G, Díaz-Chávez, J, Moreno-Banda, GL, Reyna-Figueroa, J, Munguía-Moreno, JA, Madrid-Marina, V, Lagunas-Martínez, A
Format Journal Article
LanguageEnglish
Published London, England SAGE Publications 01.04.2020
Sage Publications Ltd
Subjects
Activation
Adenosine diphosphate
Antineoplastic drugs
Apoptosis
Astrocytes
Autophagy
Bcl-2 protein
Brain cancer
Cell death
Chemotherapy
Cisplatin
Cytotoxicity
Drugs
Etoposide
Gene expression
Glioblastoma
IAP protein
Mcl-1 protein
Molecular modelling
Mortality
p53 Protein
Permeability
Phagocytosis
Poly(ADP-ribose) polymerase
Resveratrol
Ribose
Survivin
Target recognition
Tumors
autophagy
Glioblastoma
antineoplastic drugs
MG132
apoptosis
resveratrol
p53
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Summary:Glioblastoma multiforme (GBM) is one of the most aggressive astrocytic tumors; it is resistant to most chemotherapeutic agents currently available and is associated with a poor patient survival. Thus, the development of new anticancer compounds is urgently required. Herein, we studied the molecular mechanisms of cell death induced by the experimental drugs resveratrol and MG132 or the antineoplastic drugs cisplatin and etoposide on a human GBM cell line (D54) and on primary cultured mouse astrocytes (PCMAs). Caspases, Bcl-2, inhibitors of apoptosis proteins (IAP) family members, and p53 were identified as potential molecular targets for these drugs. All drugs had a cytotoxic effect on D54 cells and PCMAs, with a similar inhibitory concentration (IC50) after 24 h. However, MG132 and cisplatin were more effective to induce apoptosis and autophagy than resveratrol and etoposide. Cell death by apoptosis involved the activation of caspases-3/7, -8, and -9, increased lysosomal permeability, LC3 lipidation, poly-(ADP-ribose) polymerase (PARP)-1 fragmentation, and a differential expression of genes related with apoptosis and autophagy like Mcl-1, Survivin, Noxa, LC3, and Beclin. In addition, apoptosis activation was partially dependent on p53 activation. Since experimental and antineoplastic drugs yielded similar results, further work is required to justify their use in clinical protocols.
ISSN:0960-3271
1477-0903
DOI:10.1177/0960327119892041