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Mechanism of action of goniothalamin and derivatives: the use of fluorescent probes and folate receptors

Grant number: 12/18281-3
Support Opportunities:Scholarships in Brazil - Post-Doctoral
Effective date (Start): December 01, 2012
Effective date (End): November 30, 2015
Field of knowledge:Physical Sciences and Mathematics - Chemistry - Organic Chemistry
Principal Investigator:Ronaldo Aloise Pilli
Grantee:Débora Barbosa Vendramini Costa
Host Institution: Instituto de Química (IQ). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
Associated scholarship(s):14/05189-7 - Evaluation of the preventive and therapeutic potential of goniothalamin in colitis associated colon cancer and in sporadic colon cancer models, BE.EP.PD


The increasing understanding of tumor biology has provided molecular targets for screening of chemotherapeutic and chemopreventive agents, usually from natural sources or synthetic compounds based on natural products. The major classes of chemotherapeutic agents available in the therapy have as target events related to DNA, however other mechanisms are being explored, as in the case of piplartine, an alkaloid present in plants of the species Piper, which increases the concentration of reactive oxygen species (ROS) by inhibiting the action of the detoxificant enzyme glutathione-S-transferase PI1 (GSTP1), which is a selective mechanism for tumor cells. The toxicity displayed by most drugs available for chemotherapy is a major challenge for the search and development of new compounds aiming better therapeutic indices and selectivity for tumor cell lines. One strategy is the combination of active molecules with folic acid, which is selectively recognized by folate receptors present on the membrane of tumor cells, directing the drug into these cells. Over the last few years our laboratory has been developing collaborative work to assess the biological activity of dihydropyranones and goniothalamin (GTN) is the lead representative of this effort. Previous studies carried by our group and by the proponent during her PhD's project have shown that GTN displays antiproliferative activity against human tumor cell lines, presenting also in vivo antitumor an anti-inflammatory activities, with no signs of toxicity. In order to continue the studies with GTN, we propose strategies that will facilitate the study of the mechanism of action, as the combination of GTN with fluorescent probes and the evaluation of their genotoxic and mutagenic potential. Furthermore, aiming selectivity for tumor cells, we propose the combination of GTN with folate and pteroate, besides the production of GTN / piplartine hybrids. Given the anti-inflammatory and antitumor potential presented by GTN, it is proposed its evaluation in model of bladder carcinogenesis in rats, assessing the common mediators between inflammation and tumor development. This project will be developed in collaboration with laboratories at Biology Institute,UNICAMP, CPQBA,UNICAMP and Fox Chase Cancer Center, Philadelphia-USA, as an outgrowth of the thematic project "Chemical Biology: New Natural and Synthetic Molecular Targets Against Cancer. Structural Studies, Biological Evaluation and Mode of Action" Fapesp nº 2009/51602-5, coordinated by Dr. Ronaldo Pilli. (AU)

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Scientific publications (4)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
VENDRAMINI-COSTA, DEBORA BARBOSA; SPINDOLA, HUMBERTO MOREIRA; DE MELLO, GLAUCIA COELHO; ANTUNES, EDSON; PILLI, RONALDO ALOISE; DE CARVALHO, JOAO ERNESTO. Anti-inflammatory and antinociceptive effects of racemic goniothalamin, a styryl lactone. Life Sciences, v. 139, p. 83-90, . (12/18281-3, 09/51602-5)
VENDRAMINI-COSTA, DEBORA BARBOSA; ALCAIDE, ANTONIO; PELIZZARO-ROCHA, KARIN JULIANE; TALERO, ELENA; AVILA-ROMAN, JAVIER; GARCIA-MAURINO, SOFIA; PILLI, RONALDO ALOISE; DE CARVALHO, JOAO ERNESTO; MOTILVA, VIRGINIA. Goniothalamin prevents the development of chemically induced and spontaneous colitis in rodents and induces apoptosis in the HT-29 human colon tumor cell line. Toxicology and Applied Pharmacology, v. 300, p. 1-12, . (12/18281-3, 09/51602-5)
BARCELOS, ROSIMEIRE COURA; PASTRE, JULIO CEZAR; VENDRAMINI-COSTA, DEBORA BARBOSA; CAIXETA, VANESSA; LONGATO, GIOVANNA BARBARINI; MONTEIRO, PAULA ARAUJO; DE CARVALHO, JOAO ERNESTO; PILLI, RONALDO ALOISE. Design and Synthesis of N-Acylated Aza-Goniothalamin Derivatives and Evaluation of Their in vitro and in vivo Antitumor Activity. CHEMMEDCHEM, v. 9, n. 12, p. 2725-2743, . (12/18281-3, 09/51602-5, 10/16990-1)
VENDRAMINI-COSTA, DEBORA BARBOSA; MONTEIRO, KARIN MAIA; IWAMOTO, LEILANE HESPPORTE; JORGE, MICHELLE PEDROZA; TINTI, SIRLENE VALERIO; PILLI, RONALDO ALOISE; DE CARVALHO, JOAO ERNESTO. Gastroprotective effects of goniothalamin against ethanol and indomethacin-induced gastric lesions in rats: Role of prostaglandins, nitric oxide and sulfhydryl compounds. Chemico-Biological Interactions, v. 224, p. 206-212, . (12/18281-3, 09/51602-5)

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