Ursolic acid induces apoptosis through mitochondrial intrinsic pathway and caspase-3 activation in M4Beu melanoma cells

Harmand, Pierre-Olivier; Duval, Raphaël E.; Delage, Christiane; Simon, Alain

doi:10.1002/ijc.20588

Cited by 142 publications

(85 citation statements)

References 46 publications

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“…In those studies, we demonstrated for the first time that UA has a significant antiproliferative effect associated with the induction of the apoptotic process (14,15). In the literature, it is well established that the activation of the apoptotic transduction pathway is dependent on cell type and subcellular targets.…”

Section: Introductionmentioning

confidence: 64%

“…Western blot analysis was performed as previously described (15). Briefly, anti-Bax and anti-Bcl-2 were used at a dilution of 1:200, while anti-ß-actin was used at 1:5000 and horseradish-peroxidaselinked secondary antibody at 1:1000.…”

Section: Protein Extraction and Western Blot Analysismentioning

confidence: 99%

“…Caspase activities were analyzed using their specific substrates as previously described (15). Briefly, after incubation with UA for 24 or 48 h, cells were harvested, lysed and fluorometric assays were measured using 360 nm excitation and 460 nm emission.…”

Section: Introductionmentioning

confidence: 99%

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Differential involvement of mitochondria during ursolic acid-induced apoptotic process in HaCaT and M4Beu cells

Duval¹,

Harmand²,

Jayat-Vignoles³

et al. 2008

Oncol Rep

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Abstract. Ursolic acid (UA) is a pentacyclic triterpenoid compound which exists widely in nature and is known to have a pleitropic biological activity profile. For the last few decades, extensive work has been carried out to establish its biological activities and pharmacological actions. It is described as a promising chemopreventive agent with an antiproliferative effect on cancer cells that stems from its ability to induce apoptosis. We investigated and compared the role played by mitochondria during the apoptotic process induced by UA in human HaCaT-derived keratinotic cells and M4Beu human melanoma cells. In both cell lines, UA induced significant caspase-3 activation, the downstream central effector of apoptosis. Subsequent JC-1/TOTO-3 double staining clearly demonstrated that UA induces strong mitochondrial-transmembrane potential collapse in M4Beu cells, while mitochondria from HaCaT-treated cells remain largely unstimulated. This was confirmed by Western blot analysis, which revealed a Bax/Bcl-2-balance change in favor of Bax, the proapoptotic member, in UA-treated M4Beu cells. It can be concluded that UA induces apoptosis in M4Beu through the mitochondrial pathway, while other mechanisms are activated in the case of HaCaT cells. IntroductionAmong natural compounds, ursolic acid (UA), the most frequently studied natural triterpenic acid (1), seems to be a promising chemical entity for the protection of human skin. Indeed, in cosmetology UA is often used for photoaging protection (2). It prevents and improves the appearance of wrinkles and age spots by restoring skin collagen structure and elasticity, stimulates collagen production in cultured fibroblasts and increases the production of ceramides in human epidermal keratinocytes and skin (3). UA may also be an effective inhibitor of the UVA-modulated signal transduction pathway in human HaCaT cells, in which it significantly suppresses UVA-induced reactive oxygen species production and lipid peroxidation (4). Moreover, it possesses anti-tumor properties including the inhibition of skin tumorigenesis (5) and tumor promotion (6). UA also induces apoptosis in several cancer cell lines (7-13).Previously, we studied the effect of UA on human HaCaTderived keratinotic cells and M4Beu human melanoma cells with the intention of confirming its role as a promising candidate for skin cancer prevention. In those studies, we demonstrated for the first time that UA has a significant antiproliferative effect associated with the induction of the apoptotic process (14,15). In the literature, it is well established that the activation of the apoptotic transduction pathway is dependent on cell type and subcellular targets. The two main apoptotic pathways are the extrinsic and intrinsic pathways (16). The extrinsic pathway is characterized by death ligand attachment on extracellular receptors (e.g. TNF/TNF-R) with a subsequent caspase-8 activation, which in turn cleaves and activates caspase-3 (17). The intrinsic pathway is triggered by different mitochondrial stresses and i...

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Section: Introductionmentioning

confidence: 64%

Section: Protein Extraction and Western Blot Analysismentioning

confidence: 99%

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Differential involvement of mitochondria during ursolic acid-induced apoptotic process in HaCaT and M4Beu cells

Duval¹,

Harmand²,

Jayat-Vignoles³

et al. 2008

Oncol Rep

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“…Moreover, their beneficial effects have been analysed by extensive preclinical and epidemiological studies [1][2][3][4]. Some natural triterpenoids such as oleanolic, betulinic and ursolic acids have shown notable effects in suppressing tumourigenesis as well as inhibiting tumours [1,[5][6][7][8][9]. Also, a range of newly developed synthetic triterpenoids are more potent than the naturally occurring parent structure [10,11].…”

Section: Introductionmentioning

confidence: 99%

(2α,3β)‐2,3‐Dihydroxyolean‐12‐en‐28‐oic acid, a new natural triterpene from Olea europea, induces caspase dependent apoptosis selectively in colon adenocarcinoma cells

et al. 2006

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Triterpenoids are known to induce apoptosis and to be anti-tumoural. Maslinic acid, a pentacyclic triterpene, is present in high concentrations in olive pomace. This study examines the response of HT29 and Caco-2 colon-cancer cell lines to maslinicacid treatment. At concentrations inhibiting cell growth by 50-80% (IC50HT29 = 61 ± 1 lM, IC80HT29 = 76 ± 1 lM and IC50Caco-2 = 85 ± 5 lM, IC80Caco-2 = 116 ± 5 lM), maslinic acid induced strong G0/G1 cell-cycle arrest and DNA fragmentation, and increased caspase-3 activity. However, maslinic acid did not alter the cell cycle or induce apoptosis in the nontumoural intestine cell lines IEC-6 and IEC-18. Moreover, maslinic acid induced cell differentiation in colon adenocarcinoma cells. These findings support a role for maslinic acid as a tumour suppressant and as a possible new therapeutic tool for aberrant cell proliferation in the colon. In this report, we demonstrate for the first time that, in tumoural cancer cells, maslinic acid exerts a significant anti-proliferation effect by inducing an apoptotic process characterized by caspase-3 activation by a p53-independent mechanism, which occurs via mitochondrial disturbances and cytochrome c release.

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“…He and Liu first isolated and identified 20 pure compounds from cranberries, including UA and showed that these compounds have potent anti-proliferative activities against HepG2, liver cancer cells and MCF7, breast cancer cells [170]. In vitro, UA has been shown to induce apoptosis in a variety of tumor cells, including HL-60, human leukemia cancer cells [171,172], K562 [173], HEC108 and SCG-II, human endometrial cancer cells [174,175], M4Beu human melanoma cells [176], A549, human non-small cell lung cancer cells [177], PC-3 and LNCaP, human prostate cancer cells [178], HaCaT, human keratinocyte cells [179], human Burkitt's lymphoma Daudi cells [180] in a dose-and time-dependent manner. The major mechanisms by which UA induces apoptosis is through inhibition of DNA replication [171], caspases activation [181,182] inactivation of protein tyrosine kinases [183], and induction of Ca 2+ release [172,180].…”

Section: Ursolic Acid (Ua)mentioning

confidence: 99%

Targeted inhibition of tumor proliferation, survival, and metastasis by pentacyclic triterpenoids: Potential role in prevention and therapy of cancer

et al. 2012

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a b s t r a c tOver the last two decades, extensive research on plant-based medicinal compounds has revealed exciting and important pharmacological properties and activities of triterpenoids. Fruits, vegetables, cereals, pulses, herbs and medicinal plants are all considered to be biological sources of these triterpenoids, which have attracted great attention especially for their potent anti-inflammatory and anti-cancer activities. Published reports in the past have described the molecular mechanism(s) underlying the various biological activities of triterpenoids which range from inhibition of acute and chronic inflammation, inhibition of tumor cell proliferation, induction of apoptosis, suppression of angiogenesis and metastasis. However systematic analysis of various pharmacological properties of these important classes of compounds has not been done. In this review, we describe in detail the pre-clinical chemopreventive and therapeutic properties of selected triterpenoids that inhibit multiple intracellular signaling molecules and transcription factors involved in the initiation, progression and promotion of various cancers. Molecular targets modulated by these triterpenoids comprise, cytokines, chemokines, reactive oxygen intermediates, oncogenes, inflammatory enzymes such as COX-2, 5-LOX and MMPs, anti-apoptotic proteins, transcription factors such as NF-jB, STAT3, AP-1, CREB, and Nrf2 (nuclear factor erythroid 2-related factor) that regulate tumor cell proliferation, transformation, survival, invasion, angiogenesis, metastasis, chemoresistance and radioresistance. Finally, this review also analyzes the potential role of novel synthetic triterpenoids identified recently which mimic natural triterpenoids in physical and chemical properties and are moving rapidly from bench to bedside research.

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Ursolic acid induces apoptosis through mitochondrial intrinsic pathway and caspase-3 activation in M4Beu melanoma cells

Cited by 142 publications

References 46 publications

Differential involvement of mitochondria during ursolic acid-induced apoptotic process in HaCaT and M4Beu cells

Differential involvement of mitochondria during ursolic acid-induced apoptotic process in HaCaT and M4Beu cells

(2α,3β)‐2,3‐Dihydroxyolean‐12‐en‐28‐oic acid, a new natural triterpene from Olea europea, induces caspase dependent apoptosis selectively in colon adenocarcinoma cells

Targeted inhibition of tumor proliferation, survival, and metastasis by pentacyclic triterpenoids: Potential role in prevention and therapy of cancer

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