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Repositioning metformin and propranolol for colorectal and triple negative breast cancers treatment.

ABSTRACT: Drug repositioning refers to new uses for existing drugs outside the scope of the original medical indications. This approach fastens the process of drug development allowing finding effective drugs with reduced side effects and lower costs. Colorectal cancer (CRC) is often diagnosed at advanced stages, when the probability of chemotherapy resistance is higher. Triple negative breast cancer (TNBC) is the most aggressive type of breast cancer, highly metastatic and difficult to treat. For both tumor types, available treatments are generally associated to severe side effects. In our work, we explored the effect of combining metformin and propranolol, two repositioned drugs, in both tumor types. We demonstrate that treatment affects viability, epithelial-mesenchymal transition and migratory potential of CRC cells as we described before for TNBC. We show that combined treatment affects different steps leading to metastasis in TNBC. Moreover, combined treatment is also effective preventing the development of 5-FU resistant CRC. Our data suggest that combination of metformin and propranolol could be useful as a putative adjuvant treatment for both TNBC and CRC and an alternative for chemo-resistant CRC, providing a low-cost alternative therapy without associated toxicity.

SUBMITTER: Anselmino LE

PROVIDER: S-EPMC8047046 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Repositioning metformin and propranolol for colorectal and triple negative breast cancers treatment.

Anselmino L E LE Baglioni M V MV Malizia F F Laluce N Cesatti NC Etichetti C Borini CB Marignac V L Martínez VLM Rozados V V Scharovsky O G OG Girardini J J Rico M J MJ Menacho Márquez M M

Scientific reports 20210414 1

Drug repositioning refers to new uses for existing drugs outside the scope of the original medical indications. This approach fastens the process of drug development allowing finding effective drugs with reduced side effects and lower costs. Colorectal cancer (CRC) is often diagnosed at advanced stages, when the probability of chemotherapy resistance is higher. Triple negative breast cancer (TNBC) is the most aggressive type of breast cancer, highly metastatic and difficult to treat. For both tu ...[more]

PMID: 33854147

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Project description:BackgroundTreatment for triple-negative breast cancer (TNBC) remains a significant challenge due to a lack of targeted therapies. While photodynamic therapy (PDT) has been utilized as a treatment approach for several types of cancer, oxyphotodynamic therapy (OPDT) is a novel method that improves treatment efficacy by increasing local oxygen concentration. Metformin (MET) has been demonstrated utility as an anti-tumor agent by acting through the adenosine monophosphate-activated protein kinase (AMPK) pathway. We hypothesized that MET in combination with heme, a byproduct of 5-aminolevulinic acid (ALA), may increase cytotoxicity for cancer treatment. This study aimed to investigate the synergistic effect of MET and ALA with PDT or OPDT on TNBC tumorigenic cells.MethodsThe treatment efficacy and phototoxicity of PDT or OPDT were determined using a cell viability assay. PDT/OPDT experiments were carried out in nine groups based on different combinations and concentrations of ALA and/or MET. To calculate the synergistic effect by compuSyn soft for different groups, cells were incubated with ALA and/or MET at the following concentrations (0, 0.25, 0.5,1, 2, 4, 8, 16, 24, and 32 mM). The fluorescence of ALA-induced protoporphyrin IX (PpIX) and MitoTracker Green were observed under a confocal microscope.ResultsThe optimized therapeutic concentration ratio of ALA and MET was determined to be 1:1. The inhibition of cancer growth (IC50) for each group was 14.03, 10.62, 7.71, 18.27, 22.09, 23.96, 4.57, 10.20, and 8.18 mM, respectively. The combination index (CI) values (fa =0.5) of the last three combination groups (groups 7, 8, and 9) were 0.44, 1.70, and 1.47, respectively. PpIX fluorescence intensity of group 9 (ALA-MET-OPDT group) remained the highest among all groups, indicating an enhanced therapeutic effect.ConclusionsThis study introduces OPDT as a novel anti-tumor therapy for TNBC. Furthermore, the combined use of ALA and MET had a synergistic anti-tumor effect in TNBC cells when combined with OPDT.

Project description:BackgroundAbundant evidence shows that triple-negative breast cancer (TNBC) is heterogeneous, and many efforts have been devoted to identifying TNBC subtypes on the basis of genomic profiling. However, few studies have explored the classification of TNBC specifically based on immune signatures that may facilitate the optimal stratification of TNBC patients responsive to immunotherapy.MethodsUsing four publicly available TNBC genomics datasets, we classified TNBC on the basis of the immunogenomic profiling of 29 immune signatures. Unsupervised and supervised machine learning methods were used to perform the classification.ResultsWe identified three TNBC subtypes that we named Immunity High (Immunity_H), Immunity Medium (Immunity_M), and Immunity Low (Immunity_L) and demonstrated that this classification was reliable and predictable by analyzing multiple different datasets. Immunity_H was characterized by greater immune cell infiltration and anti-tumor immune activities, as well as better survival prognosis compared to the other subtypes. Besides the immune signatures, some cancer-associated pathways were hyperactivated in Immunity_H, including apoptosis, calcium signaling, MAPK signaling, PI3K-Akt signaling, and RAS signaling. In contrast, Immunity_L presented depressed immune signatures and increased activation of cell cycle, Hippo signaling, DNA replication, mismatch repair, cell adhesion molecule binding, spliceosome, adherens junction function, pyrimidine metabolism, glycosylphosphatidylinositol (GPI)-anchor biosynthesis, and RNA polymerase pathways. Furthermore, we identified a gene co-expression subnetwork centered around five transcription factor (TF) genes (CORO1A, STAT4, BCL11B, ZNF831, and EOMES) specifically significant in the Immunity_H subtype and a subnetwork centered around two TF genes (IRF8 and SPI1) characteristic of the Immunity_L subtype.ConclusionsThe identification of TNBC subtypes based on immune signatures has potential clinical implications for TNBC treatment.

Dataset Information

Repositioning metformin and propranolol for colorectal and triple negative breast cancers treatment.

Publications

Repositioning metformin and propranolol for colorectal and triple negative breast cancers treatment.

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