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Biochemical mapping of antitumor mechanism of calix[6]arene in human pancreatic cancer cell: investigation of intracellular trafficking, of kinome and microRNA expression

Grant number: 13/08896-3
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): August 01, 2013
Effective date (End): July 31, 2016
Field of knowledge:Biological Sciences - Biochemistry
Principal Investigator:Carmen Veríssima Ferreira
Grantee:Karin Juliane Pelizzaro Rocha
Home Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil

Abstract

Pancreatic cancer is one of the most common neoplasms of the gastrointestinal tract and is the fourth leading cause of cancer-related death in the United States. Minimal progress has been made in diagnosis and treatment of patients with early-stage of this tumor. Moreover, the pancreatic cancer aggressiveness is closely related to high levels of pro-survival mediators, which ultimately can lead to fast disease progression, resistance and metastasis. In this context, in order to obtain more effective and specific drugs, with less side effects, the better knowledge of tumor biology, as well as, the drug candidate on the molecular aspect are needed. In a preliminary study (process number 2010/15496-3 FAPESP) Karin Pelizzaro-Rocha showed that the calix[6]arene acts as a potent agent against the aggressiveness of pancreatic cancer. Calix[6]arene inhibited signal transduction pathways dependent on receptor tyrosine kinases (Mer, AXL and PDGFR). In addition, we observed induction of reticulum stress, process associated with cell death. Interestingly, it was also observed that the calix[6]arene reduced cell adhesion and migration and this behavior was associated with the modulation of integrin/FAK, metalloproteinase and LMWPTP. However, there are still many biochemical questions to be addressed in order to validate the calix[6]arene as a potential antitumor agent, specifically on pancreatic cancer, and thus it could provide support for further trials in other models, including in vivo. In this sense, we will employ different experimental strategies to investigate the cellular trafficking of calix[6]arene and biochemical correlations to provide information about the global activity of this compound in the metabolism of pancreatic cancer cells, specifically quinone and in the microRNAs expression profile. Thus, besides refining the calix[6]arene mechanism of action, the data will help us to predict possible side effects and the suitability of this compound in treating other tumor types.

Scientific publications
(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)
GONCALVES, PAOLA R.; ROCHA-BRITO, KARIN J. P.; FERNANDES, MARUSKA R. N.; ABRANTES, JULIA L.; DURAN, NELSON; FERREIRA-HALDER, CARMEN V. Violacein induces death of RAS-mutated metastatic melanoma by impairing autophagy process. TUMOR BIOLOGY, v. 37, n. 10, p. 14049-14058, OCT 2016. Web of Science Citations: 7.
TONETO NOVAES, LUIZ FERNANDO; AVILA, CAROLINA MARTINS; PELIZZARO-ROCHA, KARIN JULIANE; VENDRAMINI-COSTA, DEBORA BARBOSA; DIAS, MARINA PEREIRA; BARBOSA TRIVELLA, DANIELA BARRETO; DE CARVALHO, JOAO ERNESTO; FERREIRA-HALDER, CARMEN VERISSIMA; PILLI, RONALDO ALOISE. (-)-Tarchonanthuslactone: Design of New Analogues, Evaluation of their Antiproliferative Activity on Cancer Cell Lines, and Preliminary Mechanistic Studies. CHEMMEDCHEM, v. 10, n. 10, p. 1687-1699, OCT 2015. Web of Science Citations: 5.

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