Inhibitory effect of ursolic acid on B16 proliferation through cell cycle arrest

Es-Saady, D.; Simon, Alain; Ollier, Monique; Maurizis, Jean‐Claude; Chulia, Albert J.; Delage, Christiane

doi:10.1016/0304-3835(96)04312-1

Cited by 93 publications

(52 citation statements)

References 10 publications

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“…One such compound is ursolic acid (UA), 2 a pentacyclic triterpenoid that has been identified in a large variety of medicinal herbs and other plants, including rosemary (Rosemarinus officinalis), apples (Malus domestica), cranberries (Vaccinium macrocarpon), beefsteak (Perilla frutescens), pears (Pyrus pyrifolia), plum (Prunus domestica), bearberries (Arctostaphylos alpina), loquat (Eriobotrya japonica), scotch heather (Calluna vulgaris), basil (Ocimum sanctum), and jamun (Eugenia jambolana) (2). It has been shown that UA can inhibit cell growth and induce apoptosis in various tumors (3)(4)(5)(6)(7)(8)(9). UA induces apoptosis through multiple pathways, such as inhibiting DNA replication (7,10); inducing Ca 2ϩ release (8); activating caspases (9,11); activating JNK (12); down-regulating antiapoptotic genes (13,14); inhibiting COX2 and iNOS (15,16); suppressing MMP-9 (17); and inhibiting protein tyrosine kinase (10), STAT3 (18), and NF-B activities (13).…”

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confidence: 99%

Ursolic Acid, a Pentacyclin Triterpene, Potentiates TRAIL-induced Apoptosis through p53-independent Up-regulation of Death Receptors

Prasad

Yadav

Kannappan

et al. 2011

Journal of Biological Chemistry

113

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Discovery of the molecular targets of traditional medicine and its chemical footprints can validate the use of such medicine. In the present report, we investigated the effect of ursolic acid (UA), a pentacyclic triterpenoid found in rosemary and holy basil, on apoptosis induced by TRAIL. We found that UA potentiated TRAIL-induced apoptosis in cancer cells. In addition, UA also sensitized TRAIL-resistant cancer cells to the cytokine. When we investigated the mechanism, we found that UA down-regulated cell survival proteins and induced the cell surface expression of both TRAIL receptors, death receptors 4 and 5 (DR4 and -5). Induction of receptors by UA occurred independently of cell type. Gene silencing of either receptor by small interfering RNA reduced the apoptosis induced by UA and the effect of TRAIL. In addition, UA also decreased the expression of decoy receptor 2 (DcR2) but not DcR1. Induction of DRs was independent of p53 because UA induced DR4 and DR5 in HCT116 p53؊/؊ cells. Induction of DRs, however, was dependent on JNK because UA induced JNK, and its pharmacologic inhibition abolished the induction of the receptors. The down-regulation of survival proteins and up-regulation of the DRs required reactive oxygen species (ROS) because UA induced ROS, and its quenching abolished the effect of the terpene. Also, potentiation of TRAIL-induced apoptosis by UA was significantly reduced by both ROS quenchers and JNK inhibitor. In addition, UA was also found to induce the expression of DRs, down-regulate cell survival proteins, and activate JNK in orthotopically implanted human colorectal cancer in a nude mouse model. Overall, our results showed that UA potentiates TRAIL-induced apoptosis through activation of ROS and JNK-mediated up-regulation of DRs and down-regulation of DcR2 and cell survival proteins.More than 80% of people around the world, for their dayto-day medicinal needs, rely on traditional medicine, which has been around for centuries. Even modern medicine in most instances relies on natural products, and 70% of anticancer drugs have their roots in products derived from nature (1). The search for signature genes of different cancers has shown that most cancers are due to dysregulation of multiple genes and multiple cell signaling pathways; thus, drugs that are multitargeted (once called "dirty drugs") are needed. Compounds from natural sources have an advantage in that they are usually multitargeted. One such compound is ursolic acid (UA), 2 a pentacyclic triterpenoid that has been identified in a large variety of medicinal herbs and other plants, including rosemary (Rosemarinus officinalis), apples (Malus domestica), cranberries (Vaccinium macrocarpon), beefsteak (Perilla frutescens), pears (Pyrus pyrifolia), plum (Prunus domestica), bearberries (Arctostaphylos alpina), loquat (Eriobotrya japonica), scotch heather (Calluna vulgaris), basil (Ocimum sanctum), and jamun (Eugenia jambolana) (2). It has been shown that UA can inhibit cell growth and induce apoptosis in various tumors (3-9). UA induces...

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confidence: 99%

Ursolic Acid, a Pentacyclin Triterpene, Potentiates TRAIL-induced Apoptosis through p53-independent Up-regulation of Death Receptors

Prasad

Yadav

Kannappan

et al. 2011

Journal of Biological Chemistry

113

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“…Sitosterol was reported to inhibit the growth of tumoral cell lines, and the mechanisms by which this compound act include induction of apoptosis, inhibition of cell cycle progression, prostaglandin synthesis and the production of reactive oxygen species (ROS) (Awad et al, 2003;Choi et al, 2003;Awad et al, 2005). The ursolic acid, also present in the DCM fraction of A. schottii as the major compound (Navarro Schmidt et al, 2006), is recognized as a potent antiproliferative agent, which blocks cell cycle progression (Es-saady et al, 1996;Li et al, 2002;Hsu et al, 2004). It is important to stress that ursolic acid is also an inhibitor of DNA polymerase and DNA topoisomerase, two important cellular targets for chemical intervention in the development of anti-cancer agents (Mizushina et al, 2000).…”

Section: Resultsmentioning

confidence: 99%

Anti-mitotic activity towards sea urchin eggs of dichloromethane fraction obtained from Allamanda schottii Pohl (Apocynaceae)

Sousa¹,

Monte-Neto²,

Schmidt³

et al. 2009

Rev. bras. farmacogn.

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RESUMO: "Atividade anti-mitótica da fração diclorometano obtida de Allamanda schottii Pohl (Apocynaceae) sobre ovos do ouriço do mar." Allamanda (Apocynacea) é um gênero de arbustos escandentes conhecido por produzir compostos com várias atividades biológicas. Trabalhos anteriores têm mostrado um efeito anti-proliferativo do extrato etanólico de Allamanda schottii sobre células leucêmicas. O presente trabalho foi realizado para avaliar o efeito da fração diclorometano, obtida de Allamanda schotti, sobre os ovos de ouriço-do-mar de Echinometra lucunter, como um modelo multicelular para estudar atividade anti-tumoral. Nossos resultados mostram uma inibição do desenvolvimento dos ovos de uma maneira dose-dependente na presença da fração diclorometano. Os valores de IC 50 para a primeira e terceira clivagem e para o estágio de blástula foram de 103,7 µg/mL, 33.1 µg/mL e 10,2 µg/mL, respectivamente. Estes resultados também demonstram um efeito acumulativo da fração sobre os embriões do ouriço-do-mar. No presente trabalho, esta expressiva atividade anti-mitótica da fração diclorometano sobre o desenvolvimento embrionário do ouriço-do-mar, um modelo multicelular, reforça o potencial antitumoral de Allamanda schotti. Unitermos: Allamanda schottii, ouriço do mar, atividade anti-mitótica, anti-tumoral.ABSTRACT: Allamanda (Apocynaceae) is a genus of climbing shrubs known for producing compounds with a range of biological activities. Previous works have shown the anti-proliferative effect of the ethanolic extract of Allamanda schottii on leukemic cells. The present work was conducted to evaluate the effects of dichloromethane fraction, obtained from Allamanda schottii, on sea urchin Echinometra lucunter eggs, as a multicellular model for evaluating anti-tumor activity. Our results show an inhibition of sea urchin development in a dose-dependent manner in the presence of dichloromethane fraction. The IC 50 values for first and third cleavage and blastulae stage were 103.7 µg/mL, 33.1 µg/mL and 10.2 µg/mL, respectively. These results also demonstrate the cumulative effect of this fraction on sea urchin embryos. In the present work, the expressive anti-mitotic activity of dichloromethane fraction towards sea urchin eggs, a multicellular model, reinforces the anti-tumor potential of the Allamanda schotti.

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“…It can also be a potential candidate in treatment or prevention of skin cancer and a new promising anticancer agent in treatment of melanoma by apoptosis induction [13]. It is obviously a potent inhibitor of MCF-7 in the light of both cytostatic and cytotoxic activity [14]. However, the literature review reveals that only limited synthetic analogues have been reported for the purpose of bioactivity evaluation.…”

Section: Introductionmentioning

confidence: 99%

“…Indeed, UA and its derivatives display cytotoxic dose-dependent activity by inhibiting the growth of implanted ascetic tumor cells in vivo [11]. The cytotoxic potential of UA has also been found by inhibition of B16 cell growth (mouse melanoma cell lines) [12]. It can also be a potential candidate in treatment or prevention of skin cancer and a new promising anticancer agent in treatment of melanoma by apoptosis induction [13].…”

Section: Introductionmentioning

confidence: 99%

Synthesis of phosphonodipeptide conjugates of ursolic acid and their homologs

Deng

Baglin

Nour³

et al. 2008

Heteroatom Chemistry

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Inhibitory effect of ursolic acid on B16 proliferation through cell cycle arrest

Cited by 93 publications

References 10 publications

Ursolic Acid, a Pentacyclin Triterpene, Potentiates TRAIL-induced Apoptosis through p53-independent Up-regulation of Death Receptors

Ursolic Acid, a Pentacyclin Triterpene, Potentiates TRAIL-induced Apoptosis through p53-independent Up-regulation of Death Receptors

Anti-mitotic activity towards sea urchin eggs of dichloromethane fraction obtained from Allamanda schottii Pohl (Apocynaceae)

Synthesis of phosphonodipeptide conjugates of ursolic acid and their homologs

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