Akt- and CREB-Mediated Prostate Cancer Cell Proliferation Inhibition by Nexrutine, a Phellodendron amurense Extract

Garcia, Gretchen E.; Nicole, A. Neuman; Bhaskaran, Shylesh; Gupta, A.K.; Kyprianou, Natasha; Kumar, Addanki P.

doi:10.1593/neo.05745

Cited by 60 publications

(83 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…(29,30) This is one of the most important signaling pathways involved in the negative regulation of autophagy. (31) Therefore, it is possible to speculate that berberine might induce autophagy in tumor cells.…”

Section: Discussionmentioning

confidence: 99%

Berberine induces cell death in human hepatoma cells in vitro by downregulating CD147

Hou

Xu²,

Liu

et al. 2011

Cancer Science

View full text Add to dashboard Cite

The isoquinoline plant alkaloid berberine has anti-tumor effects on a variety of carcinoma cells, mainly through inhibition of cell proliferation, apoptosis induction and cell cycle arrest. However, the mechanisms underlying its role in tumor progression are unknown. In the present study, we investigated the molecular mechanisms involved in berberine-induced cell death in human hepatoma carcinoma cell (HCC) lines HepG2 and SMMC7721. Our results showed that berberine inhibited tumor cell viability in a dose-and time-dependent manner, and induced cell death via apoptosis and autophagy. Moreover, berberine treatment significantly inhibited CD147 expression by HCC cells in a dosedependent manner. Overexpression of CD147 protein markedly reduced berberine-induced cell death. Our data provide the first experimental evidence that berberine induces cell death in HCC cells via downregulation of CD147 and suggest a new mechanism to explain its anti-tumor effects. (Cancer Sci 2011; 102: 1287-1292 B erberine is an isoquinoline alkaloid found in a number of important medicinal plant species such as Berberis aristata and Berberis aquifolium, and has antibacterial,(1) anti-hypertensive, (2) anti-inflammatory, (3) anti-diabetic (4) and anti-hyperlipidemic effects.(5) Recently, researchers have become interested in the anti-neoplastic activities of berberine and have demonstrated its anticancer effects against a variety of human cancer cells both in vitro and in vivo through suppression of tumor cell proliferation, induction of tumor cell apoptosis, and inhibition of both tumor invasion and metastasis.(6,7) These findings suggest that berberine is a promising candidate for clinical use in cancer chemotherapy.Hepatocellular carcinoma (HCC) is the sixth most common malignancy worldwide and the third leading cause of death from cancer because of its very poor prognosis. More than 1 million cases of HCC occur in the world each year.(8) Hepatocellular carcinoma is highly resistant to conventional systemic therapies and the prognosis for patients with advanced HCC remains poor. Although a lot of progress has been made in terms of chemotherapy, which provides significant survival benefits for patients with HCC, it is associated with significant side-effects, highlighting the need for therapeutic strategies that target tumor cells without compromising normal tissue function.(9,10) Thus, the development of novel systemic agents from natural products with low toxicity and few side-effects is being actively pursued. (11)(12)(13) Previous studies confirm the anti-tumor effects of berberine on HCC. (14)(15)(16) Berberine acts by inhibiting proliferation and inducing apoptosis in HCC cells. It can also inhibit the migration of HCC cells by downregulating the Rho ⁄ ROCK signaling pathway.(17) However, the exact mechanisms underlying the anti-tumor effects of berberine are still unknown. CD147, a glycosylated immunoglobulin super family transmembrane protein, is highly expressed by HCC cells. Several in vitro studies suggest that CD147 promotes...

show abstract

Section: Discussionmentioning

confidence: 99%

Berberine induces cell death in human hepatoma cells in vitro by downregulating CD147

Hou

Xu²,

Liu

et al. 2011

Cancer Science

View full text Add to dashboard Cite

show abstract

“…Tumors were paraffin embedded, sectioned, placed on poly-lysine slides, and stained with H&E to visualize cell nuclei and cytoplasm. Prostate lesions were scored using an established grading system for TRAMP mice (21,22). Noncancerous lesions were graded as 1, 2, or 3, indicating normal tissue, low PIN, and high PIN, respectively.…”

Section: Methodsmentioning

confidence: 99%

“…The tree is native to Asia and has been reported to contain isoquinoline alkaloids, phenolic compounds, and flavone glycosides (19,20). Recently, we showed for the first time that Nexrutine inhibits prostate cancer cell proliferation through modulation of Akt and cAMP-responsive element binding protein (CREB)-mediated signaling pathways (21). However, it is unknown if Nexrutine can be developed as a dietary supplement for the prevention of prostate cancer.…”

mentioning

confidence: 99%

Akt/cAMP-Responsive Element Binding Protein/Cyclin D1 Network: A Novel Target for Prostate Cancer Inhibition in Transgenic Adenocarcinoma of Mouse Prostate Model Mediated by Nexrutine, a Phellodendron Amurense Bark Extract

Kumar¹,

Bhaskaran²,

Ganapathy³

et al. 2007

Clinical Cancer Research

Self Cite

View full text Add to dashboard Cite

Purpose: Development of prostate cancer prevention strategies is an important priority to overcome high incidence, morbidity, and mortality. Recently, we showed that Nexrutine, an herbal extract, inhibits prostate cancer cell proliferation through modulation of Akt and cAMP-responsive element binding protein (CREB)^mediated signaling pathways. However, it is unknown if Nexrutine can be developed as a dietary supplement for the prevention of prostate cancer. In this study, we used the transgenic adenocarcinoma of mouse prostate (TRAMP) model to examine the ability of Nexrutine to protectTRAMP mice from developing prostate cancer. Experimental Design: Eight-week-oldTRAMP mice were fed with pelleted diet containing 300 and 600 mg/kg Nexrutine for 20 weeks. Efficacy of Nexrutine was evaluated by magnetic resonance imaging at 18 and 28 weeks of progression and histologic analysis of prostate tumor or tissue at the termination of the experiment. Tumor tissue was analyzed for modulation of various signaling molecules. Results: We show that Nexrutine significantly suppressed palpable tumors and progression of cancer in the TRAMP model. Expression of total and phosphorylated Akt, CREB, and cyclin D1 was significantly reduced in prostate tissue from Nexrutine intervention group compared with tumors from control animals. Nexrutine also inhibited cyclin D1 transcriptional activity in androgen-independent PC-3 cells. Overexpression of kinase dead Akt mutant or phosphorylationdefective CREB inhibited cyclin D1transcriptional activity. Conclusions: The current study shows that Nexrutine-mediated targeting of Akt/CREBî nduced activation of cyclin D1prevents the progression of prostate cancer. Expression of CREB and phosphorylated CREB increased in human prostate tumors compared with normal tissue, suggesting their potential use as prognostic markers.Prostate cancer is the second leading cause of cancer-related deaths in men and expected to lead to f27,350 deaths in 2006 (1). African American men have the highest incidence of prostate cancer in the world, whereas Asian men native to their countries who consume a low-fat, high-fiber diet have the lowest risk (2). Epidemiologic studies suggest that a reduced risk of cancer is associated with the consumption of a phytochemical-rich diet that includes fruits and vegetables (3). Evidence suggests that prostate cancer progresses from normal epithelium to proliferative inflammatory atrophy, to low-grade prostatic intraepithelial neoplasia (PIN), and to high-grade PIN that eventually progresses to the more aggressive-metastatic and clinically evident prostate cancer (ref. 4 and references therein). Such preneoplastic lesions have been found in young men in their 20s and are common in men in their 50s (5). However, clinically detectable prostate cancer does not generally manifest itself until the 60s. In addition, the occurrence of precancerous lesions is more prevalent (about 1 in three men) than the incidence of carcinoma (about one in nine men; ref. 6). Therefore, the develop...

show abstract

“…It also has chemotherapeutic potential, and arrests cell cycle progression at the G0/G1 phase in prostate cancer cells [15]. The extract exhibits various biological effects, such as an inhibitory effect on prostatic contractility [49], an anti-osteoarthritic effect [23], an anti-inflammatory property [48], and anticancer activity [16,18,26], but antiangiogenic effects have not been reported yet.…”

Section: Discussionmentioning

confidence: 99%

“…amurense has multiple pharmacological activities and has been used to treat inflammation, gastroenteritis, abdominal pain, diarrhea and psychosomatic diseases, and is shown to exhibit minimal toxicity to normal tissues [25,28,39,53]. P. amurense extract containing isoquinoline alkaloids, phenolic compounds and flavone glycosides has been reported to inhibit proliferation of prostate and lung cancer cells, and its antiproliferative effects are comparable with those of berberine, which is a well-known chemopreventative agent [15,20,34,36]. In addition, P. amurense ex-tract prevents the development and progression of prostate tumors [16,28], and inhibits pancreatic cancer cell growth [17] and tumorigenesis in mouse skin, and induces apoptotic cell death in human squamous carcinoma and melanoma cells [26].…”

Section: Introductionmentioning

confidence: 99%

The Anti-angiogenic Potential of a Phellodendron amurense Hot Water Extract in Vitro and ex Vivo

Kim¹,

Kim²,

Bae³

et al. 2015

Journal of Life Science

View full text Add to dashboard Cite

Blocking new blood-vessel formation (angiogenesis) is now recognized as a useful approach to the therapeutic treatment of many solid tumors. The best validated approach to date is to target the vascular endothelial growth-factor (VEGF) pathway, a key regulator of angiogenesis. Many natural products and extracts that contain a variety of chemopreventive compounds have been shown to suppress the development of malignancies through their anti-angiogenic properties. Phellodendron amurense, which is widely used in Korean traditional medicine, has been shown to possess antitumor, antimicrobial, and anti-inflammatory properties, among others. The present study investigated the effects of P. amurense hot-water extract (PAHWE) on angiogenesis, a key process in tumor growth, invasion, and metastasis. To investigate PAHWE's anti-angiogenic properties, this study's authors performed an analysis of angiogenesis and endothelial-cell proliferation, migration, invasion, and tube formation, as well as zymogram assays and the rat aortic ring-sprouting assay. PAHWE inhibited cell growth, mobility, and vessel formation in response to VEGF in vitro and ex vivo. Furthermore, it reduced VEGF-induced intracellular signaling events, such as the activation of matrix metalloproteinases (MMPs) -2 and -9. These results indicate that PAHWE's anti-angiogenic properties might lead to the development of potential drugs for treating angiogenesis-associated diseases such as cancer.

show abstract

Akt- and CREB-Mediated Prostate Cancer Cell Proliferation Inhibition by Nexrutine, a Phellodendron amurense Extract

Cited by 60 publications

References 35 publications

Berberine induces cell death in human hepatoma cells in vitro by downregulating CD147

Berberine induces cell death in human hepatoma cells in vitro by downregulating CD147

Akt/cAMP-Responsive Element Binding Protein/Cyclin D1 Network: A Novel Target for Prostate Cancer Inhibition in Transgenic Adenocarcinoma of Mouse Prostate Model Mediated by Nexrutine, a Phellodendron Amurense Bark Extract

The Anti-angiogenic Potential of a Phellodendron amurense Hot Water Extract in Vitro and ex Vivo

Contact Info

Product

Resources

About