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
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.
Department of Pharmaceutical Sciences, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
PLoS One. 2015 Feb 12;10(2):e0117794. doi: 10.1371/journal.pone.0117794. eCollection 2015.
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.
肺癌是人类最致命的癌症类型，其中非小细胞肺癌（NSCLC）是最常见且侵袭性最强的肺癌类型，对放疗和化疗具有高度抗性。尽管抗肿瘤治疗取得了显著进展，但发现有效的抗肿瘤药物仍然是一项具有挑战性的任务。在此，我们描述了一种新的葫芦素B半合成衍生物（DACE），它是NSCLC细胞增殖的有效抑制剂。DACE使肺上皮细胞的细胞周期停滞在G2/M期，并通过干扰表皮生长因子受体（EGFR）激活及其下游信号传导（包括AKT、ERK和STAT3）诱导细胞凋亡。与我们的体外研究一致，腹腔注射DACE可显著抑制因人类致癌性c-RAF激酶（c-RAF-1-BxB）转基因在这些细胞中组成性表达而导致的II型肺泡上皮细胞来源的小鼠NSCLC的生长。综上所述，这些发现表明DACE是一种有前景的抗肺癌药物开发先导化合物。
