Efficacy and Mechanisms of Therapeutic Cells Containing Metformin versus Tri-Negative Breast Cancer

Name: ISABELLA DOS SANTOS GUIMARÃES

Publication date: 26/01/2018
Advisor:

Namesort descending Role
LETICIA BATISTA AZEVEDO RANGEL Advisor *

Examining board:

Namesort descending Role
ADRIANA MADEIRA ALVARES DA SILVA Internal Examiner *
JONES BERNARDES GRACELI External Examiner *
JULIANA BARBOSA COITINHO GONCALVES External Examiner *
LETICIA BATISTA AZEVEDO RANGEL Advisor *
LUCAS CUNHA DIAS DE REZENDE External Examiner *

Summary: Breast cancer is a heterogeneous disease that can be subdivided into distinct tumor types based upon expression of molecular markers predicting patient outcomes and response to therapy. Triple-negative breast cancer (TNBC) is known for its poor prognosis and high recurrence probability. There is no effective targeted treatment for TNBC, but only adjuvant chemotherapies (anthracyline/taxane therapy). Many chemotherapeutic drugs alter cellular states, including the induction of senescence, in cancer cells and the tumor microenvironment. Cellular senescence is an important tumor-suppressive mechanism. However, acquisition of a senescence-associated secretory phenotype (SASP) in senescent cells has deleterious effects on the tissue microenvironment and, paradoxically, promotes tumor progression. Epidemiological and laboratory studies have suggested that metformin has antineoplastic activity. The effects of metformin alone or in combination with conventional drugs on resistant breast cancer cell lines were investigated using the MTT assay for cell proliferation and clonogenic assays; Gene, protein expression and secreted proteins were determined in breast cancer cells by real time real-time PCR, western blotting and ELISA assay respectively. We also used Flow Cytometry analysis for apoptosis and SA-β-Gal staining for senescence detection. We found that metformin exhibited antiproliferative effects in several TNBC cell lines. The combined therapy containing conventional drugs (paclitaxel and doxorubicin) and safe doses of metformin improved the effect of the treatment in cell proliferation rate. We characterize SASP in our model of paclitaxel resistant cell. Additionally several pathways related with chemoresistant are also altered in paclitaxel resistant cell line (CSC, Autophagy, MAPK and GSK-3β). We also show that the antidiabetic drug metformin inhibits the expression of genes coding for multiple inflammatory cytokines seen during cellular senescence. Remarkably, metformin reverse the resistance of paclitaxel in parental tumor cells with the presence of conditioned medium from resistant cell. Our findings support that metformin is a potential agent in the treatment of TNBC, a major challenge of clinical oncology, especially in tumors refractory to taxanes.

Access to document

Acesso à informação
Transparência Pública

© 2013 Universidade Federal do Espírito Santo. Todos os direitos reservados.
Av. Marechal Campos, 1468 - Bonfim, Vitória - ES | CEP 29047-105