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

Silva IT, Carvalho A, Lang KL, Dudek SE, Masemann D, Durán FJ, Caro MS, Rapp UR, Wixler V, Schenkel EP, Simões CM, Ludwig S - PLoS ONE (2015)

Bottom Line: Despite the outstanding progress made in anti-tumor therapy, discovering effective anti-tumor drugs is still a challenging task.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.Taken together, these findings suggest that DACE is a promising lead compound for the development of an anti-lung-cancer drug.

View Article: PubMed Central - PubMed

Affiliation: 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.

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.

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Scheme for preparation of a novel semisynthetic derivative of cucurbitacin B (DACE).
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pone.0117794.g001: Scheme for preparation of a novel semisynthetic derivative of cucurbitacin B (DACE).

Mentions: Recently, we described novel cytotoxic cucurbitacins isolated from Wilbrandia ebracteata Cogn. [21] and unraveled the apoptotic mechanism in NSCLC cells for the most active compound [27]. We also described new semisynthetic derivatives of cucurbitacin B that are highly cytotoxic against A549 cells [22]. In the present study, we have elucidated the in vitro mechanism of cell death induced by a new semisynthetic derivative of cucurbitacin B, the 2-deoxy-2-amine-cucurbitacin E (Fig. 1) (named here as DACE) on A549 cells. We evaluated its effects on cell growth, cell cycle distribution, apoptosis, morphological changes, and expression of regulatory proteins as well as signaling pathways involved in such processes. Furthermore, this potent derivative was also evaluated in vivo in a transgenic mouse lung cancer model expressing a mutated and constitutively active c-RAF kinase (c-RAF-1-BxB) under the control of the human surfactant protein C (SP-C) promoter in type II alveolar pneumocytes [28].


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

Silva IT, Carvalho A, Lang KL, Dudek SE, Masemann D, Durán FJ, Caro MS, Rapp UR, Wixler V, Schenkel EP, Simões CM, Ludwig S - PLoS ONE (2015)

Scheme for preparation of a novel semisynthetic derivative of cucurbitacin B (DACE).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4326133&req=5

pone.0117794.g001: Scheme for preparation of a novel semisynthetic derivative of cucurbitacin B (DACE).
Mentions: Recently, we described novel cytotoxic cucurbitacins isolated from Wilbrandia ebracteata Cogn. [21] and unraveled the apoptotic mechanism in NSCLC cells for the most active compound [27]. We also described new semisynthetic derivatives of cucurbitacin B that are highly cytotoxic against A549 cells [22]. In the present study, we have elucidated the in vitro mechanism of cell death induced by a new semisynthetic derivative of cucurbitacin B, the 2-deoxy-2-amine-cucurbitacin E (Fig. 1) (named here as DACE) on A549 cells. We evaluated its effects on cell growth, cell cycle distribution, apoptosis, morphological changes, and expression of regulatory proteins as well as signaling pathways involved in such processes. Furthermore, this potent derivative was also evaluated in vivo in a transgenic mouse lung cancer model expressing a mutated and constitutively active c-RAF kinase (c-RAF-1-BxB) under the control of the human surfactant protein C (SP-C) promoter in type II alveolar pneumocytes [28].

Bottom Line: Despite the outstanding progress made in anti-tumor therapy, discovering effective anti-tumor drugs is still a challenging task.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.Taken together, these findings suggest that DACE is a promising lead compound for the development of an anti-lung-cancer drug.

View Article: PubMed Central - PubMed

Affiliation: 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.

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.

Show MeSH
Related in: MedlinePlus