New Cytotoxic Cucurbitacins from<i>Wilbrandia ebracteata</i>Cogn.

Lang, Karen L.; Guimarães, Tatiana da Rosa; Machado, Vanessa Rocha; Zimmermann, Lizandra M.; Silva, Izabella Thaís; Teixeira, Marina Rodrigues; Durán, Fernando Javier; Palermo, Jorge Alejandro; Simões, Cláudia Maria Oliveira; Miguel, S. B.; Schenkel, Eloir Paulo

doi:10.1055/s-0030-1270962

Cited by 13 publications

(8 citation statements)

References 11 publications

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“…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 ].…”

Section: Introductionmentioning

confidence: 99%

In Vitro and In Vivo Antitumor Activity of a Novel Semisynthetic Derivative of Cucurbitacin B

et al. 2015

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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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Section: Introductionmentioning

confidence: 99%

In Vitro and In Vivo Antitumor Activity of a Novel Semisynthetic Derivative of Cucurbitacin B

et al. 2015

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“…Compounds 1 (dihydrocucurbitacin B), 3 (cucurbitacin R), 4 (25-deacetyl-dihydrocucurbitacin B), 5 (cayaponoside A), and 6 (dihydrocucurbitacin B-2- O -glucoside) were isolated from the roots of Wilbrandia ebracteata Cogn. (Cucurbitaceae), as previously described. , Compound 2 (cucurbitacin B) was isolated from the fruits of Luffa operculata (L.) Cogn. (Cucurbitaceae) .…”

Section: Methodsmentioning

confidence: 99%

“…(Cucurbitaceae), as previously described. 29,30 Compound 2 (cucurbitacin B) was isolated from the fruits of Luffa operculata (L.) Cogn. (Cucurbitaceae).…”

Section: ■ Introductionmentioning

confidence: 99%

Chemical Modification Produces Species-Specific Changes in Cucurbitacin Antifeedant Effect

Lang

Deagosto

Zimmermann

et al. 2013

J. Agric. Food Chem.

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Cucurbitacins are secondary metabolites that mediate insect plant interactions not only as allomones against generalists but also as kairomones for specialist herbivores. This study was undertaken to identify the potential of cucurbitacin derivatives as insect antifeedant agents. The antifeedant capacity against a Cucurbitaceae specialist [ Epilachna paenulata (Coleoptera: Coccinellidae)] and a polyphagous insect [ Pseudaletia adultera (Lepidoptera: Noctuidae)] was evaluated in preference tests in which the insects were given a choice between food plants either treated with the cucurbitacin derivatives or treated with the solvent. The activity was found not to be related to the basic cucurbitacin skeleton, as only 15 of the 28 tested cucurbitacin derivatives were active. Only one of the tested compounds was phagostimulant to the specialist insect (the hemissuccinate of 16-oxo-dihydrocucurbitacin B derivative), while all other active derivatives were deterrent against one of the insects (13 compounds) or both of them (3 compounds). Changes in ring A of the cucurbitacins, as well as in the side chain, modified the activity. As a general trend, when chemical modifications of the basic structure produced a change in activity, the response was opposite in both insects used as biodetectors, indicating that a selective variation in the activity may be achieved by chemical modifications of the cucurbitacin skeleton.

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“…Cucurbitacin B is one of the most abundant and widely studied members of this group. , Recently, a novel cucurbitacin B semisynthetic derivative (DACE) (Figure ) was investigated by our research group and showed potent antiproliferative activity against nonsmall cell lung cancer in vitro and in vivo a mouse model of lung cancer . Other cucurbitacins with potential antiproliferative effects have also been described by our research group. − As described by Silva et al, DACE presents advantages from the chemical synthesis perspective when compared with the precursor cucurbitacin B. The semisynthesis process is simple, short, and might represent a new route to generate new anticancer compounds.…”

Section: Introductionmentioning

confidence: 99%

Synergistic Antiproliferative Effects of a New Cucurbitacin B Derivative and Chemotherapy Drugs on Lung Cancer Cell Line A549

Marostica

Silva

Kratz

et al. 2015

Chem. Res. Toxicol.

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Nonsmall cell lung cancer (NSCLC) represents an important cause of mortality worldwide due to its aggressiveness and growing resistance to currently available therapy. Cucurbitacins have emerged as novel potential anticancer agents showing strong antiproliferative effects and can be promising candidates for combined treatments with clinically used anticancer agents. This study investigates the synergistic antiproliferative effects of a new semisynthetic derivative of cucurbitacin B (DACE) with three chemotherapy drugs: cisplatin (CIS), irinotecan (IRI), and paclitaxel (PAC) on A549 cells. The most effective combinations were selected for studies of the mechanism of action. Using an in silico tool, DACE seems to act by a different mechanism of action when compared with that of different classes of drugs already used in clinical settings. DACE also showed potent synergic effects with drugs, and the most potent combinations induced G2/M cell cycle arrest by modulating survivin and p53 expression, disruption of F-actin cytoskeleton, and cell death by apoptosis. These treatments completely inhibited the clonogenic potential and did not reduce the proliferation of nontumoral lung cells (MRC-5). DACE also showed relevant antimigratory and anti-invasive effects, and combined treatments modulated cell migration signaling pathways evolved with metastasis progression. The effects of DACE associated with drugs was potentiated by the oxidant agent l-buthionine-sulfoximine (BSO), and attenuated by N-acetilcysteine (NAC), an antioxidant agent. The antiproliferative effects induced by combined treatments were attenuated by a pan-caspase inhibitor, indicating that the effects of these treatments are dependent on caspase activity. Our data highlight the therapeutic potential of DACE used in combination with known chemotherapy drugs and offer important insights for the development of more effective and selective therapies against lung cancer.

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New Cytotoxic Cucurbitacins fromWilbrandia ebracteataCogn.

Cited by 13 publications

References 11 publications

In Vitro and In Vivo Antitumor Activity of a Novel Semisynthetic Derivative of Cucurbitacin B

In Vitro and In Vivo Antitumor Activity of a Novel Semisynthetic Derivative of Cucurbitacin B

Chemical Modification Produces Species-Specific Changes in Cucurbitacin Antifeedant Effect

Synergistic Antiproliferative Effects of a New Cucurbitacin B Derivative and Chemotherapy Drugs on Lung Cancer Cell Line A549

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