Dietary Curcumin Attenuates Glioma Growth in a Syngeneic Mouse Model by Inhibition of the JAK1,2/STAT3 Signaling Pathway

Abstract

Purpose: Glioblastomas are the most common and most deadly primary brain tumors. Here, we evaluated the chemotherapeutic effect of the natural polyphenol curcumin on glioma cells in vitro and in vivo using an immunocompetent orthotopic mouse model.Experimental Design: Curcumin's effects on proliferation, cell cycle, migration, invasion, JAK/STAT3 signaling, STAT3 target gene expression, and STAT3C rescue experiments were determined in murine glioma cell lines in vitro. Therapeutic effects of curcumin in vivo were evaluated in tumor-bearing mice fed a Western-type diet fortified with curcumin (0.05%, w/w) and in control animals. Tumor growth patterns and survival were evaluated by immunohistochemistry, morphometric analyses, and Kaplan-Meier plots.Results: In vitro, curcumin inhibited JAK1,2/STAT3 tyrosine-phosphorylation in a dose-dependent fashion in murine glioma cell lines. Real-time RT-PCR revealed that curcumin downregulated transcription of the STAT3 target genes c-Myc, MMP-9, Snail, and Twist, and of the proliferation marker Ki67. Curcumin dose-dependently suppressed cell proliferation by inducing a G2/M phase arrest. In wound healing and Matrigel invasion assays, curcumin treatment resulted in a dose-dependent attenuation of the glioma cells' migratory and invasive behavior, which could be rescued by constitutively active STAT3C. In vivo, curcumin intake reduced the growth and midline crossing of intracranially implanted tumors and proliferation of tumor cells ensuing in significant long-term survival compared with control diet.Conclusion: This preclinical study shows that curcumin is capable of suppressing malignant glioma growth in vitro and in vivo. Our data suggest that the pharmacologically safe agent curcumin holds promise for clinical application in glioma therapy. Clin Cancer Res; 16(23); 5781-95. Ó2010 AACR.

The Molecular Basis for the Pharmacokinetics and Pharmacodynamics of Curcumin and Its Metabolites in Relation to Cancer

“…This has been observed in multiple studies, although often with varying results depending on the cancer cell line Kunnumakkara et al, 2009;Lin et al, 2010;Weissenberger et al, 2010;Sun et al, 2011). uPA levels were also decreased in curcumin-treated cells, in which inhibition of NF-kB activity was identified as the chief culprit .…”

“…uPA levels were also decreased in curcumin-treated cells, in which inhibition of NF-kB activity was identified as the chief culprit . Similarly, inhibition of tumor metastasis by curcumin has been frequently observed and attributed to the reduction in MMP-2, MMP-9, uPA, and aquaporin 3 protein levels Weissenberger et al, 2010;Wong et al, 2010;Soung and Chung, 2011). Although the mechanism is relatively elusive, aquaporins play a role in tumor growth and metastasis (Nico and Ribatti, 2010), during which MMPs are upregulated via the PI3K-Akt pathway to facilitate these processes.…”

“…Moreover, curcumin treatment is associated with increased levels of E-cadherin (Wong et al, 2010), possibly as a result of downregulating its transcriptional repressor SNAIL. SNAIL is induced by the ErbB-1-Ras and Akt pathways (De Craene et al, 2005;Weissenberger et al, 2010), which are inhibited by curcumin (section III.E.1.b.i and III.E.1.b.ii, respectively).…”

Targeting the STAT3 signaling pathway in cancer: Role of synthetic and natural inhibitors

“…Glioblastomas are known to be the most common and most deadly of primary brain tumors [251]. The anti-cancer effects of curcumin were evaluated on glioma cells were evaluated in vitro and in vivo using an immunocompetent orthotopic mouse model.…”

The relationship among serum levels of manganese superoxide dismutase and mtDNA 8-hydroxy-2'-deoxyguanosine, and dietary antioxidants intake in Type 2 Diabetes

“…The dietary intake of antioxidant foods or supplements may reduce oxidative stress and, subsequently, lessen mtDNA damage (Weissenberger et al, 2010). Generally it is believed that the identification of dietary factors that play a key role in the protection of the mitochondria and the alleviation of symptoms associated with diabetes is crucial to the development of preventive measures.…”