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The anti-promyelocytic leukemia mode of action of two endophytic secondary metabolites unveiled by a proteomic approach
- Source :
- Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual), Universidade de São Paulo (USP), instacron:USP
- Publication Year :
- 2014
-
Abstract
- As a result of a program to find antitumor compounds of endophytes from medicinal Asteraceae, the steroid (22E,24R)-8,14-epoxyergosta-4,22-diene-3,6-dione (a) and the diterpene aphidicolin (b) were isolated from the filamentous fungi Papulaspora immersa and Nigrospora sphaerica, respectively, and exhibited strong cytotoxicity against HL-60 cells. A proteomic approach was used in an attempt to identify the drugs' molecular targets and their respective antiproliferative mode of action. Results suggested that the (a) growth inhibition effect occurs by G2/M cell cycle arrest via reduction of tubulin alpha and beta isomers and 14-3-3 protein gamma expression, followed by a decrease of apoptotic and inflammatory proteins, culminating in mitochondrial oxidative damage that triggered autophagy-associated cell death. Moreover, the decrease observed in the expression levels of several types of histones indicated that (a) might be disarming oncogenic pathways via direct modulation of the epigenetic machinery. Effects on cell cycle progression and induction of apoptosis caused by (b) were confirmed. In addition, protein expression profiles also revealed that aphidicolin is able to influence microtubule dynamics, modulate proteasome activator complex expression, and control the inflammatory cascade through overexpression of thymosin beta 4, RhoGDI2, and 14-3-3 proteins. Transmission electron micrographs of (b)-treated cells unveiled dose-dependent morphological characteristics of autophagy- or oncosis-like cell death.
- Subjects :
- Aphidicolin
Proteomics
Programmed cell death
Proteome
Pharmaceutical Science
Antineoplastic Agents
HL-60 Cells
Biology
Asteraceae
Microtubules
Analytical Chemistry
chemistry.chemical_compound
Leukemia, Promyelocytic, Acute
rho Guanine Nucleotide Dissociation Inhibitor beta
Tubulin
Ergosterol
Drug Discovery
Endophytes
Humans
Proteasome activator complex
Mode of action
Cytotoxicity
Pharmacology
Inflammation
Biological Products
Cell Death
Organic Chemistry
Fungi
Cell Cycle Checkpoints
Molecular biology
Cell biology
Mitochondria
Thymosin beta-4
Gene Expression Regulation, Neoplastic
Thymosin
Oxidative Stress
Complementary and alternative medicine
chemistry
14-3-3 Proteins
Apoptosis
Molecular Medicine
METABOLISMO
Growth inhibition
Subjects
Details
- Database :
- OpenAIRE
- Journal :
- Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual), Universidade de São Paulo (USP), instacron:USP
- Accession number :
- edsair.doi.dedup.....5cbf4e58075337926e2001428d62e229