Natural Product MDM2 Inhibitors: Anticancer Activity and Mechanisms of Action

Qin, Jiang‐Jiang; Nag, Subhasree; Voruganti, Sukesh; Wang, W.; Zhang, Ruifeng

doi:10.2174/092986712803988910

Cited by 53 publications

(57 citation statements)

References 224 publications

(297 reference statements)

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“…The chemoresistant cell lines showed upregulation of MDM2 (significant in HLaC79-Tax, not significant in Hep2-Tax). Qin et al (41) reviewed the role of natural products such as flavonoids and isoflavonoids in inhibiting MDM2 expression. Reduction of MDM2 expression was reached with genistein, apigenin and oroxylin A.…”

Section: Discussionmentioning

confidence: 99%

Effect of Galium verum aqueous extract on growth, motility and gene expression in drug-sensitive and -resistant laryngeal carcinoma cell lines

Schmidt

Scholz²,

Gavril

et al. 2013

International Journal of Oncology

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Galium verum, also known as Lady's Bedstraw, is a herbaceous perennial plant of the family Rubiaceae, native to Europe and Asia and used in traditional medicine as an anticancer medicine. It is used as a decoction in most traditional recipes, applied externally as well as internally. We produced a Galium verum decoction and applied it in vitro to chemosensitive (Hep-2 and HLaC79) and chemoresistant, P-glycoprotein-overexpressing (Hep2-Tax, HLaC79-Tax) laryngeal carcinoma cell lines. It could be demonstrated that Galium aqueous extract is cytotoxic for all cell lines. A detailed spheroid-based 3D invasion analysis of Hep2 and Hep2-Tax in semisolid collagen gels and on different extracellular matrix coatings was performed, which showed an inhibition of invasion by sublethal concentrations of Galium decoction and proved to be even more pronounced in the more aggressively invading chemoresistant Hep2-Tax cell line. Gelatinolytic activity of MMP-2 was downregulated in three of the four cell lines. Angiogenesis (endothelial tube formation) in contrast, was not affected by Galium aqueous extract. Gene expression array on HLaC79 and Hep2 cell lines treated with Galium decoction vs. untreated controls revealed no unique pathway activation patterns in these cells. Results are discussed with respect to the use of herbal drugs as a preventive and/or a concomitant therapeutic approach in head and neck cancer.

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Section: Discussionmentioning

confidence: 99%

Effect of Galium verum aqueous extract on growth, motility and gene expression in drug-sensitive and -resistant laryngeal carcinoma cell lines

Schmidt

Scholz²,

Gavril

et al. 2013

International Journal of Oncology

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“…33). Such inhibition requires wild-type p53 expression in cancer cells 34,35 . Considering that the majority (50-75%) of breast cancers harbour mutant p53 and have high levels of MDM2, these MDM2 inhibitors are expected to have low or no efficacy against these types of breast cancer 36 .…”

mentioning

confidence: 99%

The pyrido[b]indole MDM2 inhibitor SP-141 exerts potent therapeutic effects in breast cancer models

et al. 2014

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A requirement for Mouse Double Minute 2 (MDM2) oncogene activation has been suggested to be associated with cancer progression and metastasis, including breast cancer. To date, most MDM2 inhibitors have been designed to block the MDM2–p53-binding interphase, and have low or no efficacy against advanced breast cancer with mutant or deficient p53. Here we use a high-throughput screening and computer-aided, structure-based rational drug design, and identify a lead compound, SP-141, which can directly bind to MDM2, inhibit MDM2 expression and induce its autoubiquitination and proteasomal degradation. SP-141 has strong in vitro and in vivo antibreast cancer activity, with no apparent host toxicity. While further investigation is needed, our data indicate that SP-141 is a novel targeted therapeutic agent that may especially benefit patients with advanced disease.

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“…28 Therefore, it has been suggested that MDM2 is a promising target for the treatment of human cancers, regardless of the p53 status in the tumor cells. 10-12,15-17,21,22,29 …”

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confidence: 99%

Identification of a New Class of MDM2 Inhibitor That Inhibits Growth of Orthotopic Pancreatic Tumors in Mice

et al. 2014

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BACKGROUND & AIMS: The oncogene MDM2, which encodes an E3 ubiquitin ligase, is overexpressed in pancreatic cancers and is therefore a therapeutic target. Current inhibitors of MDM2 target the interaction between MDM2 and P53; these would have no effect on cancer cells that do not express full-length P53, such as many pancreatic cancer cells. We searched for a compound that specifically inhibits MDM2 itself. METHODS: We performed a virtual screen and structure-based design to identify specific inhibitors of MDM2. We tested the activities of compounds identified on viability, proliferation, and protein levels of HPAC, Panc-1, AsPC-1, and Mia-Paca-2 pancreatic cancer cell lines. We tested whether intraperitoneal injections of one of the compounds identified affected growth of xenograft tumors from Panc-1 cells, or orthotopic tumors from Panc-1 and AsPC-1cells (injected into pancreata), in nude mice. RESULTS: We identified a compound, called SP141, which bound directly to MDM2, promoting its auto-ubiquitination and degradation by the proteasome. The compound reduced levels of MDM2 in pancreatic cancer cell lines, as well as their proliferation, with 50% inhibitory concentrations <0.5 μM (0.38–0.50 μM). Increasing concentrations of SP141 induced increasing levels of apoptosis and G2–M phase arrest of pancreatic cancer cell lines, whether or not they expressed functional P53. Injection of nude mice with SP141 (40 mg/kg/d) inhibited growth of xenograft tumors (by 75%, compared with control mice), and led to regression of orthotopic tumors. CONCLUSIONS: In a screen for specific inhibitors of MDM2, we identified a compound, called SP141, which reduces levels of MDM2 in pancreatic cancer cell lines, as well as their proliferation and ability to form tumors in nude mice. SP141 is a new class of MDM2 inhibitor that promotes MDM2 auto-ubiquitination and degradation. It might be further developed as a therapeutic agent for pancreatic cancer.

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Natural Product MDM2 Inhibitors: Anticancer Activity and Mechanisms of Action

Cited by 53 publications

References 224 publications

Effect of Galium verum aqueous extract on growth, motility and gene expression in drug-sensitive and -resistant laryngeal carcinoma cell lines

Effect of Galium verum aqueous extract on growth, motility and gene expression in drug-sensitive and -resistant laryngeal carcinoma cell lines

The pyrido[b]indole MDM2 inhibitor SP-141 exerts potent therapeutic effects in breast cancer models

Identification of a New Class of MDM2 Inhibitor That Inhibits Growth of Orthotopic Pancreatic Tumors in Mice

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