In vitro and in vivo antitumor activity of a novel semisynthetic derivative of cucurbitacin B

• Published in: PloS one Vol. 10; no. 2; p. e0117794
• Main Authors: Silva, Izabella T, Carvalho, Annelise, Lang, Karen L, Dudek, Sabine E, Masemann, Dörthe, Durán, Fernando J, Caro, Miguel S B, Rapp, Ulf R, Wixler, Viktor, Schenkel, Eloir P, Simões, Cláudia M O, Ludwig, Stephan
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 12.02.2015; Public Library of Science (PLoS)
• Subjects: AKT protein; Alveoli; Animals; Anticancer properties; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; Antitumor activity; Apoptosis; Apoptosis - drug effects; Apoptosis - genetics; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; Cancer; Cancer therapies; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - pathology; Caspase 3 - metabolism; Cell cycle; Cell Cycle Checkpoints - drug effects; Cell Line, Tumor; Cell proliferation; Cell Proliferation - drug effects; Chemotherapy; Cytoskeleton - metabolism; Cytotoxicity; Disease Models, Animal; Drug dosages; Epidermal growth factor receptors; Epithelial cells; Extracellular signal-regulated kinase; High resistance; Humans; Inflammation; Kinases; Leukemia; Lung cancer; Lung diseases; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Lungs; Male; Mice; Mice, Transgenic; Molecular biology; Non-small cell lung cancer; Non-small cell lung carcinoma; Pharmaceutical sciences; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation; Pneumocytes; Proto-Oncogene Proteins c-akt - metabolism; Radiation; Radiation tolerance; raf Kinases - genetics; raf Kinases - metabolism; Raf protein; Receptor, Epidermal Growth Factor - metabolism; Signal transduction; Signal Transduction - drug effects; Stat3 protein; STAT3 Transcription Factor - metabolism; Triterpenes - administration & dosage; Triterpenes - chemical synthesis; Triterpenes - pharmacology; Tumor Stem Cell Assay; Tumors; Virology; Xenograft Model Antitumor Assays; Brazil; Germany
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0117794

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.