title: Antitumor activity of melinjo (Gnetum gnemon L.) seed extract in human and murine tumor models in vitro and in a colon-26 tumor-bearing mouse model in vivo.
abstract: Melinjo (Gnetum gnemon L.) seed extract (MSE) and its active ingredient gnetin C (GC), a resveratrol dimer, have been shown to possess a broad spectrum of pharmacological activities. In this study, we investigated the antitumor activity of MSE and GC using human and murine tumor cell culture models in vitro. The antitumor activity of GC was compared with trans-resveratrol (tRV), a stilbenoid polyphenol. Our results show that MSE and GC at clinically achievable concentrations significantly inhibited the proliferation of pancreatic, prostate, breast, and colon cancer cell types (P < 0.05), without affecting normal cells. Interestingly, GC exerts enhanced antitumor activity than that of tRV (P < 0.05). MSE and GC significantly induced apoptosis in all the cancer cells, indicating MSE and GC inhibit tumor cell growth by inducing apoptosis (P < 0.001). Our findings provide evidence that MSE might induce apoptosis in cancer cells via caspase-3/7-dependent and -independent mechanisms. However, GC might trigger both early and late stage apoptosis in cancer cells, at least in part by activating caspase 3/7-dependent mechanisms. Furthermore, the antitumor efficacy of MSE observed in vitro was also validated in a widely used colon-26 tumor-bearing mouse model. Oral administration of MSE at 50 and 100 mg/kg per day significantly inhibited tumor growth, intratumoral angiogenesis, and liver metastases in BALB/c mice bearing colon-26 tumors (P < 0.05). In conclusion, our findings provide evidence that MSE and GC have potent antitumor activity. Most importantly, we provide the first evidence that MSE inhibits tumor growth, intratumoral angiogenesis, and liver metastasis in a colon-26 tumor-bearing mice.
authors.affiliation: Department of Environmental Medicine, New York University School of Medicine, New York, New York.
authors.forename: Narayanan K
authors.initials: NK
authors.lastname: Narayanan
authors.affiliation: Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Koto-ku, Tokyo, Japan.|Institution for World Health Development, Mukogawa Women's University, Nishinomiya, Hyogo, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Kunimasa
authors.affiliation: Institution for World Health Development, Mukogawa Women's University, Nishinomiya, Hyogo, Japan.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Yamori
authors.affiliation: Institution for World Health Development, Mukogawa Women's University, Nishinomiya, Hyogo, Japan.
authors.forename: Mari
authors.initials: M
authors.lastname: Mori
authors.affiliation: Institution for World Health Development, Mukogawa Women's University, Nishinomiya, Hyogo, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Mori
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Mukogawa Women's University, Nishinomiya, Hyogo, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Nakamura
authors.affiliation: Departments of Surgery and Cell Biology, New York University School of Medicine, New York, New York.
authors.forename: George
authors.initials: G
authors.lastname: Miller
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Upender
authors.initials: U
authors.lastname: Manne
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, College of Pharmacy & Pharmaceutical Sciences, University of Toledo, Toledo, Ohio.
authors.forename: Amit K
authors.initials: AK
authors.lastname: Tiwari
authors.affiliation: Department of Environmental Medicine, New York University School of Medicine, New York, New York.
authors.forename: Bhagavathi
authors.initials: B
authors.lastname: Narayanan
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D005260:Female; D035684:Gnetum / Q000737:chemistry*; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000556:secondary; D051379:Mice; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology*; D012639:Seeds / Q000737:chemistry*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D010936:Plant Extracts; D020169:Caspases
keywords: Cancer prevention; gnetin C; in vitro and in vivo tumor models; melinjo seed extract; trans-resveratrol