title: Synergistic effect of low-dose cucurbitacin B and low-dose methotrexate for treatment of human osteosarcoma.
abstract: We investigated the use of cucurbitacin B, a plant-derived tetracyclic triterpenoid, as a single agent or in combination with methotrexate (MTX) for human osteosarcoma (OS) treatment. Cucurbitacin B showed antiproliferative activity against seven human OS cell lines in vitro accompanying G2/M cell cycle arrest, apoptosis, and inhibition of ERK, Akt, and mTOR proteins. Cucurbitacin B in combination with MTX synergistically inhibited OS cell growth in vitro. Low-dose cucurbitacin B (LD-CuB, 0.5 mg/kg body weight) or low-dose MTX (LD-MTX, 150 mg/kg) failed to decrease the size of human OS xenografts in nude mice. However, combined therapy at identical concentrations inhibited tumor growth by 62% vs. LD-CuB and 81% vs. LD-MTX (p<0.001). Strikingly, the effect persisted even when the dose of MTX was decreased by two thirds (VLD-MTX, 50 mg/kg). In conclusion, cucurbitacin B alone or in combination with MTX shows promising antiproliferative activity against human OS.
authors: Division of Hematology and Oncology, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA, USA.|Department of Biomedical Engineering, University of California, Los Angeles, CA, USA.
authors: Dhong Hyun
authors: DH
authors: Lee
authors: Division of Hematology and Oncology, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA, USA.
authors: Nils H
authors: NH
authors: Thoennissen
authors: Division of Hematology and Oncology, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA, USA.|Department of Molecular and Cellular Biology, University of California, Davis, CA, USA.
authors: Catherine
authors: C
authors: Goff
authors: Division of Hematology and Oncology, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA, USA.
authors: Gabriela B
authors: GB
authors: Iwanski
authors: Division of Hematology and Oncology, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA, USA.
authors: Charles
authors: C
authors: Forscher
authors: Department of Pathology and Laboratory Medicine, Santa Monica-University of California-Los Angeles Medical Center, Los Angeles, CA, USA.
authors: Ngan B
authors: NB
authors: Doan
authors: Department of Pathology and Laboratory Medicine, Santa Monica-University of California-Los Angeles Medical Center, Los Angeles, CA, USA.
authors: Jonathan W
authors: JW
authors: Said
authors: Division of Hematology and Oncology, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA, USA.|Department of Biomedical Engineering, University of California, Los Angeles, CA, USA.|National Cancer Institute and Cancer Science Institute, National University of Singapore, Singapore.
authors: H Phillip
authors: HP
authors: Koeffler
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D008727:Methotrexate / Q000627:therapeutic use*; D051379:Mice; D008819:Mice, Nude; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D012516:Osteosarcoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014315:Triterpenes / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000964:Antimetabolites, Antineoplastic; D014315:Triterpenes; C041246:cucurbitacin B; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases; D008727:Methotrexate