title: In vitro and in vivo antitumor activity of a novel semisynthetic derivative of cucurbitacin B.
abstract: Lung cancer is the most deadly type of cancer in humans, with non-small-cell lung cancer (NSCLC) being the most frequent and aggressive type of lung cancer showing high resistance to radiation and chemotherapy. Despite the outstanding progress made in anti-tumor therapy, discovering effective anti-tumor drugs is still a challenging task. Here we describe a new semisynthetic derivative of cucurbitacin B (DACE) as a potent inhibitor of NSCLC cell proliferation. DACE arrested the cell cycle of lung epithelial cells at the G2/M phase and induced cell apoptosis by interfering with EGFR activation and its downstream signaling, including AKT, ERK, and STAT3. Consistent with our in vitro studies, intraperitoneal application of DACE significantly suppressed the growth of mouse NSCLC that arises from type II alveolar pneumocytes due to constitutive expression of a human oncogenic c-RAF kinase (c-RAF-1-BxB) transgene in these cells. Taken together, these findings suggest that DACE is a promising lead compound for the development of an anti-lung-cancer drug.
authors: Department of Pharmaceutical Sciences, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil; Institute of Molecular Virology (IMV), Center of Molecular Biology of Inflammation (ZMBE), Westfaelische-Wilhelms-University, Muenster, Germany.
authors: Izabella T
authors: IT
authors: Silva
authors: Department of Pharmaceutical Sciences, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
authors: Annelise
authors: A
authors: Carvalho
authors: Department of Chemistry, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
authors: Karen L
authors: KL
authors: Lang
authors: Institute of Molecular Virology (IMV), Center of Molecular Biology of Inflammation (ZMBE), Westfaelische-Wilhelms-University, Muenster, Germany.
authors: Sabine E
authors: SE
authors: Dudek
authors: Institute of Molecular Virology (IMV), Center of Molecular Biology of Inflammation (ZMBE), Westfaelische-Wilhelms-University, Muenster, Germany.
authors: Dörthe
authors: D
authors: Masemann
authors: UMYMFOR, Department of Organic Chemistry, Universidad de Buenos Aires, Buenos Aires, Argentina.
authors: Fernando J
authors: FJ
authors: Durán
authors: Department of Chemistry, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
authors: Miguel S B
authors: MS
authors: Caro
authors: Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
authors: Ulf R
authors: UR
authors: Rapp
authors: Institute of Molecular Virology (IMV), Center of Molecular Biology of Inflammation (ZMBE), Westfaelische-Wilhelms-University, Muenster, Germany; Cells in Motion, Cluster of Excellence, Westfaelische-Wilhelms-University, Muenster, Germany.
authors: Viktor
authors: V
authors: Wixler
authors: Department of Pharmaceutical Sciences, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
authors: Eloir P
authors: EP
authors: Schenkel
authors: Department of Pharmaceutical Sciences, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
authors: Cláudia M O
authors: CM
authors: Simões
authors: Institute of Molecular Virology (IMV), Center of Molecular Biology of Inflammation (ZMBE), Westfaelische-Wilhelms-University, Muenster, Germany; Cells in Motion, Cluster of Excellence, Westfaelische-Wilhelms-University, Muenster, Germany; Interdisciplinary Center of Clinical Research (IZKF), Westfaelische-Wilhelms-University, Muenster, Germany.
authors: Stephan
authors: S
authors: Ludwig
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003599:Cytoskeleton / Q000378:metabolism; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014315:Triterpenes / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D014410:Tumor Stem Cell Assay; D023041:Xenograft Model Antitumor Assays; D048490:raf Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D050796:STAT3 Transcription Factor; D014315:Triterpenes; C041246:cucurbitacin B; D019869:Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D048490:raf Kinases; D053148:Caspase 3