Evaluation of EcTI protease inhibitor and it derived peptide associated with Paclitaxel and Doxorubicin in triple-negative breast Cancer cells

• Grant number: 21/13061-4
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: January 01, 2022
• End date: December 31, 2022
• Field of knowledge: Biological Sciences - Biochemistry - Chemistry of Macromolecules
• Principal Investigator: Maria Luiza Vilela Oliva
• Grantee: Vitória Morais da Rocha
• Host Institution: Instituto Nacional de Farmacologia (INFAR). 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

Breast Cancer is characterized by uncontrolled and atypical proliferation of breast cells and can occur in both men and women, although it is less frequent in males. It is cancer that most affects women around the world, especially before the age of 40 in pre-menopause. There are three groups into which breast cancer can be classified: positive for estrogen (ER) or progesterone (PR) receptors, positive for human epidermal growth factor receptor (HER-2), or triple-negative tumors that do not have receptors for estrogen, progesterone, and neither express nor amplify HER-2. In the first two classifications, cells respond to hormonal stimuli for cell division to occur, enabling hormone therapy or targeted therapy for receptors. In the triple-negative subtype, tumor cells do not respond to these hormones and have more aggressive characteristics, such as advanced-stage diagnosis, early incidence compared to other subtypes, higher mortality rate, and higher incidences of metastasis. In this condition, chemotherapy becomes the only therapeutic option. The most used classes of chemotherapeutics are taxanes and anthracyclines. Taxanes, such as Paclitaxel, have a cytotoxic action mechanism by stabilizing actin microtubules, preventing dissociation, and blocking cell cycle progression. Side effects often associated with the use of Paclitaxel are peripheral neuropathy and myalgia. Anthracyclines, such as Doxorubicin, are capable of interconnecting to DNA and inhibiting the polymerase enzyme, blocking DNA synthesis. However, Doxorubicin has high toxicity, especially to the heart and brain. Cardiotoxicity is the most common effect, and it can occur even years after the end of treatment. Even with the availability of chemotherapy, there is no one that is sufficiently effective and safe, due to the significant occurrence of side effects. Therefore, there is a need for further studies on the mechanisms involved in tumorigenesis. Studies with protease inhibitors showed promising results in the treatment of tumors, and EcTI, in preliminary studies, showed an anti-tumor and anti-inflammatory effect in breast cancer. For this reason, we intend to evaluate the association of synthetic peptides derived from the native inhibitor EcTI in association with Paclitaxel and Doxorubicin, as a possible alternative for reducing side effects and treating triple-negative breast Cancer.(AU)