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Shishodia S, Sethi G, Ahn KS, Aggarwal BBGuggulsterone inhibits tumor cell proliferation, induces S-phase arrest, and promotes apoptosis through activation of c-Jun N-terminal kinase, suppression of Akt pathway, and downregulation of antiapoptotic gene products. Biochem Pharm 74: 118-130

Cytokine Research Laboratory, Department of Experimental Therapeutics, Unit 143, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, United States.
Biochemical Pharmacology (Impact Factor: 4.65). 07/2007; 74(1):118-30. DOI: 10.1016/j.bcp.2007.03.026
Source: PubMed

ABSTRACT Guggulsterone is a plant polyphenol traditionally used to treat obesity, diabetes, hyperlipidemia, atherosclerosis, and osteoarthritis, possibly through an anti-inflammatory mechanism. Whether this steroid has any role in cancer is not known. In this study, we found that guggulsterone inhibits the proliferation of wide variety of human tumor cell types including leukemia, head and neck carcinoma, multiple myeloma, lung carcinoma, melanoma, breast carcinoma, and ovarian carcinoma. Guggulsterone also inhibited the proliferation of drug-resistant cancer cells (e.g., gleevac-resistant leukemia, dexamethasone-resistant multiple myeloma, and doxorubicin-resistant breast cancer cells). Guggulsterone suppressed the proliferation of cells through inhibition of DNA synthesis, producing cell cycle arrest in S-phase, and this arrest correlated with a decrease in the levels of cyclin D1 and cdc2 and a concomitant increase in the levels of cyclin-dependent kinase inhibitor p21 and p27. Guggulsterone-induced apoptosis as indicated by increase in the number of Annexin V- and TUNEL-positive cells, through the downregulation of anti-apoptototic products. The apoptosis induced by guggulsterone was also indicated by the activation of caspase-8, bid cleavage, cytochrome c release, caspase-9 activation, caspase-3 activation, and PARP cleavage. The apoptotic effects of guggulsterone were preceded by activation of JNK and downregulation of Akt activity. JNK was needed for guggulsterone-induced apoptosis, inasmuch as inhibition of JNK by pharmacological inhibitors or by genetic deletion of MKK4 (activator of JNK) abolished the activity. Overall, our results indicate that guggulsterone can inhibit cell proliferation and induce apoptosis through the activation of JNK, suppression of Akt, and downregulation of antiapoptotic protein expression.

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    • "Apoptosis is a cellular process that involves a series of conditions that begin cell death. Currently, a highly effective tool to detect changes caused by this process include the analysis of DNA fragmentation, changes in the size and granularity, cell surface modification, changes in mitochondrial membrane permeability and activation of caspases (Shishodia et al., 2007; Wang et al., 2009 Zhou et al., 2008). In the present study we evaluated the changes in mitochondrial membrane permeability and activation of caspases. "
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    ABSTRACT: Acalypha californica Benth., is a plant in the northwestern region from Mexico, commonly known as " cancer herb " and used in traditional medicine for treating cancer. In the present study we have investigated the antiproliferative activity of methanolic extract of A. californica and its fractions in cancer cell lines and phytochemical analysis and mechanism of apoptosis of the fractions with antiproliferative activity. The antiproliferative activity of methanol extract and its fractions of solvents were evaluated by MTT assay against the M12.A k .C3.F6, RAW 264.7, HeLa and L929 cell lines. Active fractions were fractionated by molecular exclusion chromatography, HPLC and MPLC. The identification of compounds was performed by NMR and FIA-ESI-IT-MS/MS analysis. Apoptotic mechanism was analyzed by flow cytometry, determining the reduction in the mitochondrial membrane potential (JC-1) and the activity of caspases 3, 8 and 9. Cell viability assays showed that the hexane fraction of the methanol extract of the plant has significant effects against cancer lines RAW 264.7 (IC 50 = 52.08 ± 1.06 ␮g/mL) and HeLa (IC 50 = 46.77 ± 1.09 ␮g/mL), the residual fraction showed a selective effect on cell lines M12.A k .C3.F6 (IC 50 = 59.90 ± 1.05 ␮g/mL), RAW 264.7 (IC 50 = 58.93 ± 1.26 ␮g/mL) and HeLa (IC 50 = 50.11 ± 1.135 ␮g/mL) compared to the control cell line L929 (IC 50 = 100.00 ± 1.09 ␮g/mL). The chemical characterization of the active fractions allowed the identification of ␤-sitosterol and stigmasterol in hexane fraction and some phenolic acids, proanthocyanidins and flavonoids in the residual fraction. The methanol extract and hexane fraction reduces mitochon-drial membrane potential significantly and activates caspases 3, 8 and 9. Because of the antiproliferative activity observed, our results provide a rational basis for the use of extracts of A. californica in treating various types of cancer in traditional medicine from Mexico. The extracts induce apoptosis via activation of caspases.
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    • "Apoptosis is a cellular process that involves a series of conditions that begin cell death. Currently, a highly effective tool to detect changes caused by this process include the analysis of DNA fragmentation, changes in the size and granularity, cell surface modification, changes in mitochondrial membrane permeability and activation of caspases (Shishodia et al., 2007; Wang et al., 2009 Zhou et al., 2008). In the present study we evaluated the changes in mitochondrial membrane permeability and activation of caspases. "
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    ABSTRACT: Asclepias subulata Decne. (Apocynaceae) is a shrub used in the Mexican traditional medicine for the treatment of cancer. The objective of this study was to evaluate the antiproliferative activity of methanol extract of aerial parts of A. subulata and its fractions against different cancer cell lines. Additionally, we analyzed the mechanism of action of the active fractions. Methanol extract fractions were prepared by serial extraction with n-hexane, ethyl acetate, and ethanol. The antiproliferative activity of methanol extract and its fractions was evaluated, against several murine (M12.C3.F6, RAW 264.7, and L929) and human (HeLa, A549, PC-3, LS 180, and ARPE-19) cell lines by the MTT assay, using concentrations of 0.4-400 µg/mL for 48 h. Ethanol and residual fractions were separated using silica gel column. Apoptosis induction of cancer cells was evaluated by Annexin and JC-1 staining using flow cytometry. Methanol extract and its fractions showed antiproliferative activity against all human cancer cell lines tested. Methanol extract had the highest antiproliferative activity on A549 and HeLa cells (IC50 values < 0.4 and 8.7 µg/mL, respectively). Ethanol and residual fractions exerted significant antiproliferative effect on A549 (IC50 < 0.4 µg/mL) and PC3 cells (IC50 1.4 and 5.1 µg/mL). Apoptotic assays showed that CEF7, CEF9, CRF6, and CRF5 fractions induced mitochondrial depolarization in A549 cells, 70, 73, 77, and 80%, respectively. Those fractions triggered the apoptosis mitochondrial pathway. Our data show that A. subulata extracts have potent antiproliferative properties on human cancer cell lines. This plant should be considered an important source of potent anticancer compounds.
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    • "Guggulsterone (GS), (4, 17(20)-pregnadiene-3,16- dione), a plant polyphenol derived from the exudates of plant Commiphora mukkul, has been used in traditional medicine for treating several ailments including obesity, hyperlipidemia, atherosclerosis, diabetes and osteoarthritis [5]. Recent studies indicate therapeutic and anti-proliferative activity of GS against several human cancers including head and neck, prostate, lung, breast, colon and ovarian cancer, with no apparent signs of toxicity on normal human fibroblast cells, immortalized esophageal cells, non-transformed prostate and colon epithelial cells [6] [7] [8] [9] [10] [11] [12] [13] [14]. Besides inhibiting cell proliferation and inducing apoptosis, GS inhibits cell motility and invasion of cancer cells in vitro and angiogenesis and metastasis in vivo [7] [9] [12] [14]. "
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    ABSTRACT: Inadequate efficacy, high toxicity and drug resistance associated with existing chemotherapeutic agents mandate a need for novel therapeutic strategies for highly aggressive pancreatic cancer (PC). Guggulsterone (GS) exhibits potent anti-proliferative effects against various cancer cells and has emerged as an attractive candidate for use in complementary or preventive cancer therapies. However, the knowledge regarding the therapeutic potential of GS in PC is still limited and needs to be explored. We studied the effect of GS on PC cell growth, motility and invasion and elucidated the molecular mechanisms associated with its anti-tumor effects. Treatment of Capan1 and CD18/HPAF PC cells with GS resulted in dose- and time-dependent growth inhibition and decreased colony formation. Further, GS treatment induced apoptosis and cell cycle arrest as assessed by Annexin-V assay and FACS analysis. Increased apoptosis following GS treatment was accompanied with Bad dephosphorylation and its translocation to the mitochondria, increased Caspase-3 activation, decreased Cyclin D1, Bcl-2 and xIAP expression. Additionally, GS treatment decreased motility and invasion of PC cells by disrupting cytoskeletal organization, inhibiting activation of FAK and Src signaling and decreased MMP9 expression. More importantly, GS treatment decreased mucin MUC4 expression in Capan1 and CD18/HPAF cells through transcriptional regulation by inhibiting Jak/STAT pathway. In conclusion, our results support the utility of GS as a potential therapeutic agent for lethal PC.
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