Synergistic effect of low-dose cucurbitacin B and low-dose methotrexate for treatment of human osteosarcoma

Lee, Der-Horng; Thoennissen, Nils H.; Goff, Catherine; Iwanski, Gabriela B.; Forscher, Charles; Doan, Ngan; Said, Jonathan W.; Koeffler, H. Phillip

doi:10.1016/j.canlet.2011.03.001

Cited by 50 publications

(44 citation statements)

References 35 publications

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“…In this study, we first demonstrated that cucurbitacin I inhibited viability of human OS cell lines in monolayer and collagen 3D cultures. A similar result was previously shown for cucurbitacin B in combination with methotrexate, which showed promising anti-proliferative activity against human OS (30). However, in this study, comparison of the effect of cucurbitacin I and cucurbitacin B alone in vitro indicated that cucurbitacin I showed greater inhibition of tumor cell viability than cucurbitacin B.…”

Section: Discussionsupporting

confidence: 87%

STAT3 inhibitor, cucurbitacin I, is a novel therapeutic agent for osteosarcoma

Asanuma

Matsumine

et al. 2016

International Journal of Oncology

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The development of clinical agents remains a costly and time-consuming process. Although identification of new uses of existing drugs has been recognized as a more efficient approach for drug discovery than development of novel drugs, little screening of drugs that might be used for a rare malignant tumor such as osteosarcoma (OS) has been performed. In this study, we attempted to identify new molecular targeted agents for OS by employing Screening Committee of Anticancer Drugs (SCADS) kits. To screen compounds for OS treatment, their effect on cell viability of the OS cell lines 143B, MG63, HOS, SAOS-2, and HUO9 were evaluated. Candidate drugs were narrowed down based on a global anti-proliferative effect against these five OS cell lines. After excluding cytotoxic compounds and compounds unsuitable for in vivo administration, cucurbitacin I was extracted. Cucurbitacin I has been found to have cytotoxic and anti-proliferative properties against several tumors through inhibition of signal transducer and activator of transcription 3 (STAT3) activation. Cucurbitacin I dose- and time-dependently inhibited the proliferation of all five OS cell lines. Following cucurbitacin I treatment, STAT3 was inactivated and analysis of Mcl-1, cleaved PARP and caspase-3 indicated apoptosis induction. Expression of cell cycle regulator proteins, such as phospho-cyclin D1, c-Myc and survivin, were suppressed. Finally, cucurbitacin I potently inhibited the tumor growth of human OS 143B cells in nude mice. Our in vitro and in vivo results suggest that STAT3 inhibition by cucurbitacin I will be an effective and new approach for the treatment of OS.

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Section: Discussionsupporting

confidence: 87%

STAT3 inhibitor, cucurbitacin I, is a novel therapeutic agent for osteosarcoma

Asanuma

Matsumine

et al. 2016

International Journal of Oncology

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“…Cuc B inhibits proliferation of a series of cancer cell lines, such as laryngeal squamous cell carcinoma [3], pancreatic cancer [4], hepatocellular carcinoma [5,6], melanoma [7], lung cancer [8], among others. Furthermore, it enhances the anticancer effects of clinical chemotherapeutic drugs: cisplatin, gemcitabine, methotrexate, docetaxel, and gemcitabine [9][10][11][12]. Documented results also demonstrate that Cuc B potently inhibits the proliferation of breast cancer cell lines both in vitro and in vivo [13][14][15][16][17].…”

Section: Introductionmentioning

confidence: 78%

Cucurbitacin B induces DNA damage and autophagy mediated by reactive oxygen species (ROS) in MCF-7 breast cancer cells

et al. 2015

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Cucurbitacin B (Cuc B), a natural compound extracted from cucurbitaceous plants, demonstrated potent anticancer activities, while the underlying mechanisms remain unclear. We investigated the anticancer effect of Cuc B on MCF-7 breast cancer cells. Cuc B drastically decreased cell viability in a concentration-dependent manner. Cuc B treatment caused DNA damage, as shown by long tails in the comet assay and increased γH2AX protein expression. Immunofluorescence staining showed that Cuc B treatment induced nuclear γH2AX foci. Cuc B activated DNA damage pathways by phosphorylation of ATM/ATR [two large phosphatidylinositol-3-kinase-like kinase family (PIKKs) members]. Furthermore, it also induced autophagy, as evidenced by monodansylcadaverine (MDC) staining and autophagic protein expression. In addition, Cuc B treatment led to increased reactive oxygen species (ROS) formation, which was inhibited by N-acetyl-L-cysteine (NAC) pretreatment. NAC pretreatment inhibited Cuc-B-induced DNA damage and autophagy. Taken together, these results suggest that ROS-mediated Cuc-B-induced DNA damage and autophagy in MCF-7 cells, which provides new insights into the anticancer molecular mechanism of Cuc B.

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“…Different cucurbitacin E derivatives, however, have been described as potential anti-cancer drugs (34), suggesting that their mechanism of actin binding may be less toxic to cells and may therefore be worth exploring in a clinical setting.…”

Section: Resultsmentioning

confidence: 99%

The Natural Product Cucurbitacin E Inhibits Depolymerization of Actin Filaments

et al. 2012

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Although small molecule actin modulators have been widely used as research tools, only one cell permeable small molecule inhibitor of actin depolymerization (jasplakinolide) is commercially available. We report that the natural product cucurbitacin E inhibits actin depolymerization and show that its mechanism of action is different from jasplakinolide. In assays using pure fluorescently labeled actin, cucurbitacin E specifically affected depolymerization without affecting polymerization. It inhibited actin depolymerization at sub-stoichiometric concentrations up to 1:6 cucurbitacin:actin E. Cucurbitacin E specifically binds to filamentous actin (F-actin) forming a covalent bond at residue Cys257, but not to monomeric actin (G-actin). Based on its compatibility with phalloidin staining, we show that cucurbitacin E occupies a different binding site on actin filaments. Using loss of fluorescence after localized photoactivation, we found that cucurbitacin E inhibited actin depolymerization in live cells. Cucurbitacin E is a widely available plant-derived natural product, making it a useful tool to study actin dynamics in cells and actin-based processes such as cytokinesis.

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Synergistic effect of low-dose cucurbitacin B and low-dose methotrexate for treatment of human osteosarcoma

Cited by 50 publications

References 35 publications

STAT3 inhibitor, cucurbitacin I, is a novel therapeutic agent for osteosarcoma

STAT3 inhibitor, cucurbitacin I, is a novel therapeutic agent for osteosarcoma

Cucurbitacin B induces DNA damage and autophagy mediated by reactive oxygen species (ROS) in MCF-7 breast cancer cells

The Natural Product Cucurbitacin E Inhibits Depolymerization of Actin Filaments

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