Oleanolic acid initiates apoptosis in non-small cell lung cancer cell lines and reduces metastasis of a B16F10 melanoma model in vivo

Drug resistance, a process mediated by multiple mechanisms, is a critical determinant for treating lung cancer. The aim of this study is to determine if oleanolic acid (OA), a pentacyclic triterpene present in several plants, is able to circumvent the mechanisms of drug resistance present in non-sma...

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Bibliographic Details
Published in:PloS one 2011-12, Vol.6 (12), p.e28596
Main Authors: Lúcio, Kelly Araújo, Rocha, Gleice da Graça, Monção-Ribeiro, Leonardo Campos, Fernandes, Janaina, Takiya, Christina Maeda, Gattass, Cerli Rocha
Format: Article
Language:English
Subjects:
Acids
Angiogenesis
Animals
Apoptosis
Apoptosis - drug effects
Bax protein
Bcl-2 protein
Biology
Biotechnology
Blotting, Western
Cancer
Cancer metastasis
Cancer therapies
Cancer treatment
Carcinoma, Non-Small-Cell Lung - drug therapy
Carcinoma, Non-Small-Cell Lung - enzymology
Carcinoma, Non-Small-Cell Lung - pathology
Caspase
Caspase-3
Caspases - metabolism
Cell death
Cell Line, Tumor
Cell Survival - drug effects
Chemotherapy
Cloning
Deoxyribonucleic acid
DNA
DNA fragmentation
DNA Fragmentation - drug effects
Drug resistance
Humans
Kinases
Lung cancer
Lung diseases
Lung Neoplasms - drug therapy
Lung Neoplasms - enzymology
Lung Neoplasms - pathology
Medical research
Medicine
Melanoma
Melanoma - drug therapy
Melanoma - enzymology
Melanoma - pathology
Metastases
Metastasis
Mice
Mice, Inbred C57BL
Microbial drug resistance
Mortality
Multidrug resistance
Multidrug Resistance-Associated Proteins - metabolism
Neoplasm Metastasis
Neovascularization, Pathologic - drug therapy
Non-small cell lung cancer
Non-small cell lung carcinoma
Oleanolic acid
Oleanolic Acid - pharmacology
Oleanolic Acid - therapeutic use
Proteins
Signal transduction
Signal Transduction - drug effects
Small cell lung cancer
Studies
Survivin
Tumor cell lines
Tumors
Vascular endothelial growth factor
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Summary:Drug resistance, a process mediated by multiple mechanisms, is a critical determinant for treating lung cancer. The aim of this study is to determine if oleanolic acid (OA), a pentacyclic triterpene present in several plants, is able to circumvent the mechanisms of drug resistance present in non-small cell lung cancer (NSCLC) cell lines and to induce their death. OA decreased the cell viability of the NSCLC cell lines A459 and H460 despite the presence of active, multidrug-resistant (MDR) MRP1/ABCC1 proteins and the anti-apoptotic proteins Bcl-2 and survivin. These effects are due to apoptosis, as evidenced by the capacity of OA to induce fragmentation of DNA and activate caspase 3. Induction of NSCLC cell death by OA cannot be explained by inhibition of the MDR proteins, since treatment with triterpene had little or no effect on the activity or expression of MRP1. Moreover, treatment with OA had no effect on the expression of the anti-apoptotic protein Bcl-2, but increased the expression of the pro-apoptotic protein Bax, altering the Bcl-2/Bax balance towards a pro-apoptotic profile. OA also decreased the expression of the anti-apoptotic protein survivin. Furthermore, OA decreased the expression of the angiogenic vascular endothelial growth factor (VEGF) and decreased the development of melanoma-induced lung metastasis. Our data provide a significant insight into the antitumoral and antimetastatic activity of OA in NSCLC and suggest that including OA in the NSCLC regimens may help to decrease the number of relapses and reduce the development of metastases.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0028596