Ursolic acid induces apoptosis by activating p53 and caspase-3 gene expressions and suppressing NF-κB mediated activation of bcl-2 in B16F-10 melanoma cells

Manu, Kanjoormana Aryan; Kuttan, Girija

doi:10.1016/j.intimp.2008.02.013

Cited by 131 publications

(110 citation statements)

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“…A natural compound, the pentacyclic triterpenoid ursolic acid (UA) (3 b-hydroxy-urs-12-en-28-oic-acid) (Liu 1995), has been reported to be a potent inhibitor of constitutive and inducible STAT3 as well as NF-jB activation in prostate cancer cells ). The authors also showed that UA significantly suppressed the growth of prostate cancer xenografts in vivo while it was previously reported to be able to inhibit tumor promotion, metastasis, angiogenesis and proliferation of a variety of tumor cells, including human multiple myeloma cells ) melanoma cells (Manu and Kuttan 2008) and breast cancer cells (Kassi et al 2009). Predictive analysis using a virtual tumor cell platform that allows for the determining of the primary target of UA in the prostate cancer cells showed that UA mediates an increase in the apoptotic phenotype by inhibiting STAT3 as well as NF-jB activity.…”

Section: Prostate Cancermentioning

confidence: 88%

Dietary compounds as potent inhibitors of the signal transducers and activators of transcription (STAT) 3 regulatory network

et al. 2012

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Signal transducers and activators of transcription (STAT) proteins were described as a family of latent cytosolic transcription factors whose activation is dependent on phosphorylation via growth factor-and cytokine-membrane receptors including interferon and interleukin, or by nonreceptor intracellular tyrosine kinases, including Src. A vast majority of natural substances are capable of modulating mitogenic signals, cell survival, apoptosis, cell cycle regulation, angiogenesis as well as processes involved in metastasis development. The inhibition of STAT3 phosphorylation by natural and dietary compounds leads to decreased protein expression of STAT3 targets essentially involved in regulation of the cell cycle and apoptotic cell death. This review details the cell signaling pathways involving STAT transcription factors as well as the corresponding compounds from nature able to interfere with this regulatory system in human cancer.The family of STAT transcription factors Structure and function STAT (signal transducers and activators of transcription) proteins were originally described as a family of cytoplasmic transcription factors. In mammals, seven members of this family, each consisting of 750-900 amino acids, have been identified: STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b and STAT6. These transcription factors act as dimers (homo-or hetero-dimers), and their activation is dependent on their phosphorylation or via membrane receptors stimulated by either extracellular factors, including interferon (IFN) and interleukin (IL-6), or by intracellular kinases independent of receptors, including Src. Activation of STATs is usually transient and highly regulated. STAT proteins contain seven conserved structural and functional domains ( First, the amino terminal NH 2 domain is involved in the dimerization of STAT proteins and in the stabilization of the interaction established between these dimers and DNA response elements (Braunstein et al. 2003;Mertens et al. 2006). The coiled-coil domain is responsible for controlling the process of import and export of proteins into and from the nucleus (Schindler et al. 2007). The domain that binds DNA, or the DBD (DNA binding domain), is involved in the physical interaction with STAT3-response elements in the promoters of target genes. With the exception of STAT2, all activated STAT homodimers bind directly to a palindromic sequence, the GAS (IFN-gammaactivated site), TTTCCNGGAAA (Becker et al. 1998). The ''linker'' domain localizes the active dimer to the DNA binding site. The transcriptional activation domain (TAD) contains sites of phosphorylation of serine residues that allow the recruitment of coactivators such as RNA polymerase II, histone acetyltransferase (HAT) (Paulson et al. 2002), histone deacetylase (HDAC) (Rascle et al. 2003) and chromatin modification complexes.Finally, two sites are particularly critical for the activity of STAT. These are the SH2 domain (Src homology 2, amino acids 575-680), which is linked to the DBD by the linker domain, and a conser...

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Section: Prostate Cancermentioning

confidence: 88%

Dietary compounds as potent inhibitors of the signal transducers and activators of transcription (STAT) 3 regulatory network

et al. 2012

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“…They also demonstrated that UA induce the intracellular ca 2+ release which may be involved in UA induced apoptosis in HL-60 cells [23]. So there is not much work regarding the mechanism of action of UA in the induction of apoptosis in HL-60 cells though several studies on other cell line such as gastric cancer cell line BGC-803, HT-29, HepG2 human hepatoblastoma cell, human breast cancer cell line MDA-MB-231 [24][25][26][27][28].…”

Section: Discussionmentioning

confidence: 99%

Apoptosis Induction by Cestrum parqui L’Hér. leaves on HL-60 Cell Line: Identification of Active Phytomolecules

Chenni¹,

Torres²,

Estévez³

et al. 2015

IJCR

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IntroductionCancer, one of the leading causes of human death, has attracted more attention due to the complexity of etiology, diagnosis and treatment [1]. In recent years, chemotherapeutic management against various types of cancer including leukemia has been increased rapidly though some times cancer cells resistance against chemotherapy [2,3]. In this respect, search for effective anticancer agent that inhibit the proliferation of the cells as well as inhibit the resistance nature of the cancer cells and induce differentiation of the monocytes is an ongoing challenge. Therefore to find out anticancer agent with multi-target efficacies, attention has been focused on plant products as the plant products have been used as remedies for several human diseases including cancer from ancient times with lower side effects [4]. The reasons for using them that they contain variety of chemical compounds usually secondary metabolites with therapeutic values [5]. Cestrum parqui is belonging to the family Solanaceae, usually known as "green or Chilean cestrum" in Tunisia, are rich in various secondary metabolites such as saponins, polyhydroxylated terpenes (C13 norisoprenoids, sesquiterpenes, spirostanes and pseudosapogenins) and ent-kaurene glycosides (parquin and carboxyparquin) [6][7][8]. Several scientific reports demonstrate that C. parqui exhibits a wide spectrum of pharmacological activity when administered systemically or in isolated organ preparations. For example, it is used to treat headache, rheumatic pain, scabies, dermatosis, diarrhaea and metrorraghia [7]. The plant is also used in Chilean folk Abstract Background: In our time, there is an urgent need to discover natural anticancer products without toxic side's effects. Objective: The present study was conducted to investigate the anticancer activity of the methanolic extract of Cestrum parqui leaves as well as identification of the active compounds in this concern. Materials and Methods: Eight column chromatographic fractions were tested against human leukaemia cell line (HL-60) and the cell viability was measured by dimethylthiazol tetrazolium assay. Studies of apoptosis, cell cycle and DNA fragmentation were carried out following the standard protocol. Effective fractions were analysed by high performance liquid chromatography-ultra violet, HPLC-evaporative light scattering detector and preparative-HPLC. Finally the active compounds were identified by gas chromatography coupled to mass spectrometry. Results: Out of eight, fraction II showed remarkable inhibition on the growth of HL-60 cell line and fraction I showed moderate activity on such inhibition. Mechanisms of the inhibition were identified as cell cycle arrestation and apoptosis induction by the said fractions. Chromatographic and mass spectrometric analysis of the fraction II indicated the presence of oleanolic and ursolic acids as biologically active compounds. Conclusion: This study is the first investigation that shows Cestrum parqui has anticancer activity and the responsible compounds are olea...

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“…Recent results indicated a modulation of the Bcl-2 protein family due to a suppression of NF-κB by ursolic acid (50 µM) in B16.F10 mouse melanoma cells. Induction of apoptosis was accompanied by activation of p53 and caspase-3 gene expression [31]. Oleanolic acid (80 µM) showed apoptosis induction in leukaemia cells (HL60) via activation of caspase-9 and caspase-3 accompanied by the cleavage of poly(ADP-ribose) polymerase (PARP) [32].…”

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confidence: 99%

“…Efforts to work out the underlying mechanism in vitro are in progress (reviewed in [7,8,[57][58][59]) and several potential targets have been discovered. Besides direct effects on the morphology or the activity of immune cells, such as macrophages, dendritic cells, T cells or other leukocytes, which may suppress the immune response [60][61][62][63], an influence on pro-inflammatory cytokines, e.g., TNF-α, INFγ, IL-1β, IL-6, IL-2, IL-4, IL-5, IL-8, or IL-13 [31,50,60,[64][65][66] has been reported. The expression of these cytokines is regulated by the transcription factor NF-κB, which is therefore a pivotal target.…”

mentioning

confidence: 99%

“…In contrast, in 2003 Takada and Aggarwal described an inhibition of NF-κB regulated cyclooxygenase-2 (COX-2) expression and determined a maximal suppressive effect of betulinic acid at a concentration of 30 µM on NF-κB in colon carcinoma cells [68]. Similarly NF-κB in melanoma cells was inhibited by ursolic acid (50 µM) accompanied by downregulation of pro-inflammatory cytokines such as TNF-α; IL-1β, IL-6, and GM-CSF and apoptosis occurred after 48 h [31]. Also, carcinogen-induced NF-κB expression is decreased by ursolic acid [69].…”

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confidence: 99%

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Planta Med

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Ursolic acid induces apoptosis by activating p53 and caspase-3 gene expressions and suppressing NF-κB mediated activation of bcl-2 in B16F-10 melanoma cells

Cited by 131 publications

References 63 publications

Dietary compounds as potent inhibitors of the signal transducers and activators of transcription (STAT) 3 regulatory network

Dietary compounds as potent inhibitors of the signal transducers and activators of transcription (STAT) 3 regulatory network

Apoptosis Induction by Cestrum parqui L’Hér. leaves on HL-60 Cell Line: Identification of Active Phytomolecules

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