Guggulsterone induces apoptosis in colon cancer cells and inhibits tumor growth in murine colorectal cancer xenografts

Department of Internal Medicine and Institute of Gastroenterology, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, 134 Shinchon-dong, Seodaemun-gu, Seoul 120-752, Republic of Korea.
Cancer letters (Impact Factor: 5.62). 03/2009; 279(1):93-100. DOI: 10.1016/j.canlet.2009.01.026
Source: PubMed


The plant sterol guggulsterone has recently been shown to have anti-tumorigenic potential. This study was designed to investigate the anti-tumor efficacy of guggulsterone and to elucidate its molecular mechanisms in colon cancer. Guggulsterone significantly increased apoptosis in HT-29 cells by activating caspases-3 and -8. Furthermore, guggulsterone decreased cIAP-1, cIAP-2, and Bcl-2 levels and increased the levels of truncated Bid, Fas, p-JNK, and p-c-Jun. The size of HT-29 xenograft tumors in guggulsterone-treated mice was significantly smaller than of the size of tumors in control mice. The present study suggests a potential therapeutic use for this compound in the treatment of colorectal cancer.

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    • "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]. GS has also been reported to inhibit invasion and metastasis of PC cells through antagonizing Farnesoid X receptor [15]. "
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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.
    Cancer letters 08/2013; 341(2). DOI:10.1016/j.canlet.2013.07.037 · 5.62 Impact Factor
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    • "Because guggulsterone exhibits anti-proliferative effects on several malignancies including melanoma, breast carcinoma, prostate cancer and leukemias [36], [37], [38], [39], [40], it was proposed as a potential anti-cancer therapeutic [41]. However, in the present study, we showed that guggulsterone caused robust proliferation of two human colon cancer cell lines through Src-mediated activation of EGFR and post-EGFR signaling. "
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    ABSTRACT: Besides its essential role in controlling bile acid and lipid metabolism, the farnesoid X receptor (FXR) protects against intestinal tumorigenesis by promoting apoptosis and inhibiting cell proliferation. However, the mechanisms underlying these anti-proliferative actions of FXR remain to be elucidated. In the present study, we examined the effects of FXR activation (FXR overexpression and treatment with an FXR agonist GW4064) and inactivation (treatment with FXR siRNA and an FXR antagonist guggulsterone) on colon cancer cell proliferation in vitro using human colon cancer cell lines (H508, SNU-C4 and HT-29) and in vivo using xenografts in nude mice. Blocking FXR activity with guggulsterone stimulated time- and dose-dependent EGFR (Tyr845) phosphorylation and ERK activation. In contrast, FXR overexpression and activation with GW4064 attenuated cell proliferation by down-regulating EGFR (Tyr845) phosphorylation and ERK activation. Treatment with guggulsterone and GW4064 also caused dose-dependent changes in Src (Tyr416) phosphorylation. In stably-transfected human colon cancer cells, overexpression of FXR reduced EGFR, ERK, Src phosphorylation and cell proliferation, and in nude mice attenuated the growth of human colon cancer xenografts (64% reduction in tumor volume; 47% reduction in tumor weight; both P<0.01). Moreover, guggulsterone-induced EGFR and ERK phosphorylation and cell proliferation were abolished by inhibiting activation of Src, EGFR and MEK. Collectively these data support the novel conclusion that in human colon cancer cells Src-mediated cross-talk between FXR and EGFR modulates ERK phosphorylation, thereby regulating intestinal cell proliferation and tumorigenesis.
    PLoS ONE 10/2012; 7(10):e48461. DOI:10.1371/journal.pone.0048461 · 3.23 Impact Factor
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    • "GS has been evaluated as an anti-hyperlipidemia agent with several clinical trials yielding inconclusive results (Szapary et al., 2003; Nohr et al., 2009). The anti-tumor activity of GS appears to be related to apoptotic mechanisms in a variety of tumor cell lines (Shishodia and Aggarwal, 2004; Samudio et al., 2005; Singh et al., 2005, 2007; Shishodia et al., 2007; An et al., 2009) and also in differentiating 3T3-L1 adipocytes (Yang et al., 2008), implicating consideration of GS in obesity. Our initial interest in GS came from studies showing that GS inhibits the activation of NF-κB a nuclear transcription factor that activates pro-survival pathways (Wang et al., 1996; Shishodia and Aggarwal, 2004). "
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    ABSTRACT: Purpose: To observe the effect of guggulsterone (GS) on the radiation response in human cancer cell lines. Materials and methods: The radiation response of cancer cells treated with GS was observed by cell survival studies, cell growth assay, NF-κB activity assay, western blotting of some key growth promoting receptors, the DNA repair protein γH2AX, and flow cytometry for DNA analyses. Results: GS inhibited radiation induced NF-κB activation and enhanced radiosensitivity in the pancreatic cell line, PC-Sw. It reduced both cell cycle movement and cell growth. GS reduced ERα protein in MCF7 cells and IGF1-Rβ protein in colon cancer cells and pancreatic cancer cells and inhibited DNA double strand break (DSB) repair following radiation. Conclusion: GS induced radiation sensitization may be due to several different mechanisms including the inhibition of NF-κB activation and reductions in IGF1-Rβ. In addition, GS induced γH2AX formation, primarily in the S-phase, indicates that DNA DSB's in the S-phase may be another reason for GS induced radiosensitivity. ERα down-regulation in response to GS suggests that it can be of potential use in the treatment of estrogen positive tumors that are resistant to tamoxifen.
    Frontiers in Oncology 07/2011; 1:19. DOI:10.3389/fonc.2011.00019
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