Potential effect of chloroquine and propranolol combination to treat colorectal and triple-negative breast cancers.

Drug repositioning explores the reuse of non-cancer drugs to treat tumors. In this work, we evaluated the effect of the combination of chloroquine and propranolol on colorectal and triple-negative breast cancers. Using as in vitro models the colorectal cancer cell lines HCT116, HT29, and CT26, and as triple-negative breast cancer models the 4T1, M-406, and MDA-MB-231 cell lines, we evaluated the effect of the drugs combination on the viability, apoptosis, clonogenicity, and cellular migratory capacity. To explore the in vivo effects of the combination on tumor growth and metastasis development we employed graft models in BALB/c, nude, and CBi mice. In vitro studies showed that combined treatment decreased cell viability in a dose-dependent manner and increased apoptosis. Also, we demonstrated that these drugs act synergically and that it affects clonogenicity and migration. In vivo studies indicated that this drug combination was effective on colorectal models but only partially on breast cancer. These results contributed to the search for new and safe treatments for colorectal and triple-negative carcinomas.

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

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.

hCCR4/cNOT6 targets DNA-damage response proteins.

Radio and chemotherapy are the election options besides surgical resection, in cancer treatment. However, resistance to chemotherapy limits the effectiveness of therapy in the clinic. An improved knowledge of the mechanisms underlying the resistance to treatment would generate new therapeutic strategies. Genetic suppressor elements (GSEs) are short, biologically active, cDNA fragments that interfere with the function of their cognate gene. By selection of genetic suppressor elements (GSEs) conferring resistance to cisplatin, we identified the GSE11, that corresponds to the hCCR4/CNOT6 gene that mediates cellular sensitivity to the drug. Expression of GSE11-hCCR4 reduces hCCR4 protein levels in cells. Targeting hCCR4 with GSE11 or with siRNA, decreases sensitivity of mammalian cells to DNA-damaging agents. Overexpression of hCCR4 targets Chk2 following exposure to cisplatin, without interfering with the upstream ATM/ATR pathway, however histone gammaH2AX is strongly phosphorylated in these cells compared to control cells. Our results uncover a new function for a human protein involved in chemotherapy response. This finding introduces a new pharmacological target in the treatment of solid tumours.

Yeast on drugs: Saccharomyces cerevisiae as a tool for anticancer drug research.

The budding yeast Saccharomyces cerevisiae is being widely used as a model for investigating fundamental processes relevant to all living organisms. Many of these processes are affected by genetic and epigenetic alterations in cancer such as cell cycle progression, DNA replication and segregation, maintenance of genomic integrity and stress responses. Therefore, yeast emerges as an attractive model for anticancer drug research. The genetic tractability of budding yeast, its ease of manipulation and the wealth of functional genomics tools available in this organism makes it ideal for genome-wide analysis of biological functions and chemical screenings. The present review will discuss some of the innovative advantages based on yeast genetics and genomics for antitumour drug target identification and drug discovery.

Yeast on drugs: saccharomyces cerevisiae as a tool for anticancer drug research

The budding yeast Saccharomyces cerevisiae is being widely used as a model for investigating fundamental processes relevant to all living organisms. Many of these processes are affected by genetic and epigenetic alterations in cancer such as cell cycle progression, DNA replication and segregation, maintenance of genomic integrity and stress responses. Therefore, yeast emerges as an attractive model for anticancer drug research. The genetic tractability of budding yeast, its ease of manipulation and the wealth of functional genomics tools available in this organism makes it ideal for genome-wide analysis of biological functions and chemical screenings. The present review will discuss some of the innovative advantages based on yeast genetics and genomics for antitumour drug target identification and drug discovery (AU)