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

Izabella T Silva; Annelise Carvalho; Karen L Lang; Sabine E Dudek; Dörthe Masemann; Fernando J Durán; Miguel S B Caro; Ulf R Rapp; Viktor Wixler; Eloir P Schenkel; Cláudia M O Simões; Stephan Ludwig

doi:10.1371/journal.pone.0117794

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

PLoS One. 2015 Feb 12;10(2):e0117794. doi: 10.1371/journal.pone.0117794. eCollection 2015.

Authors

Affiliations

¹ 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.
² Department of Pharmaceutical Sciences, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
³ Department of Chemistry, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
⁴ Institute of Molecular Virology (IMV), Center of Molecular Biology of Inflammation (ZMBE), Westfaelische-Wilhelms-University, Muenster, Germany.
⁵ UMYMFOR, Department of Organic Chemistry, Universidad de Buenos Aires, Buenos Aires, Argentina.
⁶ Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
⁷ 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.
⁸ 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.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / administration & dosage
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Apoptosis / genetics
Apoptosis Regulatory Proteins / genetics
Apoptosis Regulatory Proteins / metabolism
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 Checkpoints / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Cytoskeleton / metabolism
Disease Models, Animal
ErbB Receptors / metabolism
Humans
Lung Neoplasms / drug therapy
Lung Neoplasms / genetics
Lung Neoplasms / metabolism
Lung Neoplasms / pathology
Male
Mice
Mice, Transgenic
Phosphatidylinositol 3-Kinases / metabolism
Phosphorylation
Proto-Oncogene Proteins c-akt / metabolism
STAT3 Transcription Factor / metabolism
Signal Transduction / drug effects
Triterpenes / administration & dosage
Triterpenes / chemical synthesis
Triterpenes / pharmacology*
Tumor Stem Cell Assay
Xenograft Model Antitumor Assays
raf Kinases / genetics
raf Kinases / metabolism

Substances

Antineoplastic Agents
Apoptosis Regulatory Proteins
STAT3 Transcription Factor
Triterpenes
cucurbitacin B
Phosphatidylinositol 3-Kinases
ErbB Receptors
Proto-Oncogene Proteins c-akt
raf Kinases
Caspase 3

Grants and funding

This study was supported in part by Brazilian funding agencies, as CNPq/MCTI (grant number 472979/2011-6) and PRONEX/FAPESC (grant number 2671/2012-9) as well as by different grants from the Deutsche Forschungsgemeinschaft (DFG) and Interdisciplinary Center of Clinical Research (IZKF) Muenster. The authors also acknowledge support by Open Access Publication Fund of University of Muenster, Germany. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.