Resveratrol, a multitargeted agent, can enhance antitumor activity of gemcitabine <i>in vitro</i> and in orthotopic mouse model of human pancreatic cancer

Harikumar, Kuzhuvelil B.; Kunnumakkara, Ajaikumar B.; Sethi, Gautam; Diagaradjane, Parmeswaran; Anand, Preetha; Pandey, Manoj K.; Gelovani, Juri G.; Krishnan, Sunil; Guha, Sushovan; Aggarwal, Bharat B.

doi:10.1002/ijc.25041

Cited by 187 publications

(149 citation statements)

References 44 publications

Supporting

Mentioning

137

Contrasting

Order By: Relevance

“…We also found that piperlongumine downregulated the constitutive activation of NF-kB in pancreatic cancer cell lines. These results on downregulation of NF-kB activation by piperlongumine are consistent with previous reports that piperlongumine inhibited activation of NF-kB in other cancer cell lines (30,39) and with reports that resveratrol (45), genistein (46), dihydroartemisinin (44), zyflamend (47), g-tocotrienol (48), curcumin (49), shikonin (9), and 3,3 0 -Diindolylmethane (50), all present within piperlongumine, are associated with NF-kB inactivation.…”

Section: Discussionsupporting

confidence: 92%

Piperlongumine Suppresses Growth and Sensitizes Pancreatic Tumors to Gemcitabine in a Xenograft Mouse Model by Modulating the NF-kappa B Pathway

Wang

Zhou

et al. 2016

Cancer Prevention Research

View full text Add to dashboard Cite

Pancreatic cancer is an aggressive malignancy, which generally respond poorly to chemotherapy. Hence, novel agents that are safe and effective are highly needed. The aim of this study was to investigate whether piperlongumine, a natural product isolated from the fruit of the pepper Piper longum, has any efficacy against human pancreatic cancer when used either alone or in combination with gemcitabine in vitro and in a xenograft mouse model. In vitro, piperlongumine inhibited the proliferation of pancreatic cancer cell lines, potentiated the apoptotic effects of gemcitabine, inhibited the constitutive and inducible activation of NF-kB, and suppressed the NF-kB-regulated expression of c-Myc, cyclin D1, Bcl-2, Bcl-xL, Survivin, XIAP, VEGF, and matrix metalloproteinase-9 (MMP-9). Furthermore, in an in vivo xenograft model, we found piperlongumine alone significantly suppressed tumor growth and enhanced the antitumor properties of gemcitabine. These results were consistent with the downregulation of NF-kB activity and its target genes, decreased proliferation (PCNA and Ki-67), decreased microvessel density (CD31), and increased apoptosis (TUNEL) in tumor remnants. Collectively, our results suggest that piperlongumine alone exhibits significant antitumor effects against human pancreatic cancer and it further enhances the therapeutic effects of gemcitabine, possibly through the modulation of NF-kB-and NF-kB-regulated gene products.Cancer Prev Res; 9(3); 234-44. Ó2015 AACR.

show abstract

Section: Discussionsupporting

confidence: 92%

Piperlongumine Suppresses Growth and Sensitizes Pancreatic Tumors to Gemcitabine in a Xenograft Mouse Model by Modulating the NF-kappa B Pathway

Wang

Zhou

et al. 2016

Cancer Prevention Research

View full text Add to dashboard Cite

show abstract

“…Weng et al [185] suggested that resveratrol and its related methoxy analogue MR-3 might exert anti-invasive activity against hepatoma cells through regulation of MMP-2 and -9 as well as TIMPs. Harikumar et al [186] reported that resveratrol can enhance chemopreventive activity of gemcitabine in vitro and in vivo mouse model of pancreatic cancer. In summary, anticancer activity of resveratrol is augmented by upregulation of TIMP and downregulation of MMP-9 expression.…”

Section: Resveratrolmentioning

confidence: 99%

Matrix metalloproteinases and gastrointestinal cancers: Impacts of dietary antioxidants

Verma

Kesh

Ganguly

et al. 2014

WJBC

View full text Add to dashboard Cite

teinase (TIMP) which bind MMPs with a 1:1 stoichiometry. In addition, RECK (reversion including cysteinerich protein with kazal motifs) is a membrane bound glycoprotein that inhibits MMP-2, -9 and -14. Moreover, α2-macroglobulin mediates the uptake of several MMPs thereby inhibit their activity. Cancerous conditions increase intrinsic reactive oxygen species (ROS) through mitochondrial dysfunction leading to altered protease/ anti-protease balance. ROS, an index of oxidative stress is also involved in tumorigenesis by activation of different MAP kinase pathways including MMP induction. Oxidative stress is involved in cancer by changing the activity and expression of regulatory proteins especially MMPs. Epidemiological studies have shown that high intake of fruits that rich in antioxidants is associated with a lower cancer incidence. Evidence indicates that some antioxidants inhibit the growth of malignant cells by inducing apoptosis and inhibiting the activity of MMPs. This review is discussed in six subchapters, as follows. AbstractThe process of carcinogenesis is tightly regulated by antioxidant enzymes and matrix degrading enzymes, namely, matrix metalloproteinases (MMPs). Degradation of extracellular matrix (ECM) proteins like collagen, proteoglycan, laminin, elastin and fibronectin is considered to be the prerequisite for tumor invasion and metastasis. MMPs can degrade essentially all of the ECM components and, most MMPs also substantially contribute to angiogenesis, differentiation, proliferation and apoptosis. Hence, MMPs are important regulators of tumor growth both at the primary site and in distant metastases; thus the enzymes are considered as important targets for cancer therapy. The implications of MMPs in cancers are no longer mysterious; however, the mechanism of action is yet to be explained. Herein, our major interest is to clarify how MMPs are tied up with gastrointestinal cancers. Gastrointestinal cancer is a variety of cancer types, including the cancers of gastrointestinal tract and organs, i.e., esophagus, stomach, biliary system, pancreas, small intestine, large intestine, rectum and anus. The activity of MMPs is regulated by its endogenous inhibitor tissue inhibitor of metallopro-

show abstract

“…8,9) and/or its ability to trigger tumor cell death by apoptosis (4,(10)(11)(12). There is also compelling evidence that resveratrol can sensitize tumor cells to various anticancer drugs (13,14) and cytokines such as TRAIL (11), possibly because of the clustering of death receptors in detergent-resistant membranes (DRM) known as lipid rafts (4,11,15).…”

Section: Introductionmentioning

confidence: 99%

Endocytosis of Resveratrol via Lipid Rafts and Activation of Downstream Signaling Pathways in Cancer Cells

Colin

Limagne²,

Jeanningros³

et al. 2011

Cancer Prevention Research

View full text Add to dashboard Cite

trans-Resveratrol has been proposed to prevent tumor growth and to sensitize cancer cells to anticancer agents. Polyphenol entry into the cells has remained poorly understood. Here, we show that [ 3 H]-resveratrol enters colon cancer cells (SW480, SW620, HT29) and leukemia U937 cells through a monensin (5-20 mmol/L) -sensitive process that suggests clathrin-independent endocytosis. Uptake of the molecule can be prevented by methyl-b-cyclodextrin (2-12 mg/mL), nystatin (12 ng/mL), and filipin (1 mg/mL), which all disrupt plasma membrane lipid rafts. Accordingly, radiolabeled resveratrol accumulates in sphingomyelin-and cholesterol-enriched cell fractions. Interestingly, extracellular signalregulated kinases (ERK), c-Jun NH 2 -terminal kinases (JNK), and Akt also accumulate in lipid rafts on resveratrol exposure (IC 50 at 48 h % 30 mmol/L in SW480 and U937 cells). In these rafts also, resveratrol promotes the recruitment, by the integrin a V b 3 (revealed by coimmunoprecipitation with an anti-integrin a V b 3 antibody), of signaling molecules that include the FAK (focal adhesion kinase), Fyn, Grb2, Ras, and SOS proteins. Resveratrol-induced activation of downstream signaling pathways and caspase-dependent apoptosis is prevented by endocytosis inhibitors, lipid raft-disrupting molecules, and the integrin antagonist peptide arginine-glycine-aspartate (500 nmol/L). Altogether, these data show the role played by lipid rafts in resveratrol endocytosis and activation of downstream pathways leading to cell death.

show abstract

Resveratrol, a multitargeted agent, can enhance antitumor activity of gemcitabine in vitro and in orthotopic mouse model of human pancreatic cancer

Cited by 187 publications

References 44 publications

Piperlongumine Suppresses Growth and Sensitizes Pancreatic Tumors to Gemcitabine in a Xenograft Mouse Model by Modulating the NF-kappa B Pathway

Piperlongumine Suppresses Growth and Sensitizes Pancreatic Tumors to Gemcitabine in a Xenograft Mouse Model by Modulating the NF-kappa B Pathway

Matrix metalloproteinases and gastrointestinal cancers: Impacts of dietary antioxidants

Endocytosis of Resveratrol via Lipid Rafts and Activation of Downstream Signaling Pathways in Cancer Cells

Contact Info

Product

Resources

About