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Effects of peptides related to the recombinant Bauhinia bauhinioides chimeric inhibitor, rBbKIm, and Crataeva tapia bark lectin, CrataBL, on the Melanoma Cancer model

Grant number: 18/21372-7
Support type:Scholarships in Brazil - Doctorate (Direct)
Effective date (Start): December 01, 2018
Effective date (End): November 30, 2022
Field of knowledge:Biological Sciences - Biochemistry - Chemistry of Macromolecules
Principal researcher:Maria Luiza Vilela Oliva
Grantee:Kathleen Chwen Ming Lie
Home Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
Associated research grant:17/06630-7 - Fragments derived from the structure of protease inhibitors with selectivity for inhibition of mammalian and microorganism enzymes and its role as an anti-inflammatory, antimicrobial, antithrombotic and anti- tumor agent: mechanism of action, AP.TEM

Abstract

Among the types of Cancer that most affect humans, melanoma stand out, a Cancer of malignant Skin developed in melanocytes, in which it presents a high lethality. Once diagnosed late and due to a lack of efficient chemotherapeutic drugs on the market, it is necessary research for new drugs. The estimate of new cases for melanoma Skin Cancer for the 2018-2019 biennium will be of 2,920 cases for men and 3,340 cases for women, according to INCA. In tumors, proteolysis is facilitated by proteases of tumor cells that are secreted or bound to their surface. Overexpression or activation of a protease provides a proteolytically active environment surrounding the tumor. Inhibitors of these activities, especially the protease inhibitors found in legumes, are potential candidates for the control of these events by blocking the progression of Cancer. Inhibitors present in legumes characterized by the group of Profa. Maria Luiza Oliva present atypical features both in structural and functional aspects and are being used in models of inflammation, thrombosis and Câncer. The group also constructed a chimeric form (Sumikawa et al., 2010) named rBbKIm (Bauhinia bauhinoides Kallikrein inhibitor modified) whose base structure is that of the inhibitor present in B. bauhinoides but modified so as to contain the EPVARGDG sequences (position 21-28) and GERD (position 127-130) of BrTI (characterized inhibitor of B. rufa by Nakahata et al., 2006). The deleterious effect of this protein on Prostate Cancer DU145 and PC3 lines was observed by Ferreira et al., 2014. Studies already initiated show that rBbKIm is capable of inhibiting the tissue kallikreins KLK 6 and 7, serine protease with important developmental role of melanoma (Thierauf et al., 2017; Delaunay et al., 2017). Another inhibitor, the Crataeva tapia Bark Lectin protein, extracted from the bark of the Crataeva tapia tree, for being a lectin, it presents a specificity to sulfated oligosaccharides present in glycosylated proteins overexpressed in the tumor microenvironment responsible for the tumor progression and for also being an inhibitor of protease, it has been reported its efficacy in inhibiting cell adhesion and invasion of U87 glioblastoma cells and its induction in apoptosis in DU-145 and PC-3 Prostate Cancer cells. It was also determined its sequence of amino acids and the three-dimensional structure as well characterized its selection in terms of biochemical and biological properties. Its effectiveness in blocking coagulation and forming arterial thrombus without increasing bleeding time was also described by the group. Thus, this project proposes to extend the studies using the two protease inhibitors alone or in combination treatment, in addition to using fragments of the inhibitor structures on human melanoma cells SK-MEL-28 in vitro in an attempt to establish the mechanisms involved and the relationship between the structure and the kinetic parameters of inhibition relative to the target proteases. (AU)

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