Drug repositioning for triple negative breast and colorectal cancers treatment: Exploring the use of metformin and propranolol

MARÍA VIRGINIA BAGLIONI; LUCIANO ANSELMINO; NAHUEL CESATTI LALUCE; FLORENCIA MALIZIA; GUSTAVO CHAPO; LEANDRO E MAINETTI; VIVIANA R. ROZADOS; GRACIELA O. SCHAROVSKY; MARÍA JOSÉ RICO; MAURICIO MENACHO MÁRQUEZ

Congreso; American Association for Cancer Research Meeting; 2020

AACR

According to new global cancer data, breast and colorectal cancer (CRC) are part of the 5 types of tumors with the highest incidence and mortality. Triple negative breast cancer (TNBC) is a particularly aggressive type of breast cancer, associated with younger age, recurrence, high metastatic rate, poor prognosis and limited therapeutic options. Regarding CRC, this type of tumor is often diagnosed at advanced stages, when probability of development of distal or local recurrence due to chemotherapy resistance (usually 5-FU) is higher. For both types of tumors, the available treatment modalities are expensive and produce severe side effects. Drug repositioning refers to new uses outside the scope of the original medical indications for existing drugs or compounds; this approach fastens the process of drug development and offers more effective, cheaper and safer drugs with less side effects. We studied the effect of combining Metformin (M; antidiabetic drug) and Propranolol (P; antihypertensive agent) on in vitro and in vivo models of TNBC and CRC. We performed an in vitro screening of drugs under reposition on different TNBC and CCR cell lines and determined that M+P combination was particularly efficient in reducing proliferation in all cell lines tested. Indeed, M+P showed synergistic effect on proliferation, affecting significantly clonogenicity, apoptosis, migration and invasion. In order to explore the mechanisms associated with tumor growth/metastasis development involved in the treatment we evaluated the impact of M+P on cell signaling after proliferative stimuli and epithelial/mesenchymal transition. M+P combination reduced Erk phosphorylation levels after serum induction and promoted the expression of epithelial markers as β-catenin and E-cadherin. In vivo models (4T1, M-406, HCT116 and CT26 cells) demonstrated that M+P [M(2g/l)+P(25mg/l)] was effective reducing tumor growth and metastasis development. To further characterize the cellular events associated to these processes, we evaluated in 4T1 TNBC model the impact of M+P on different steps associated to tumor progression. The treatment affected intravasation (P=0.06), survival (P