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Study of New Therapeutic Strategies to Combat Breast Cancer Using Drug Combinations.

ABSTRACT: Cancer is a disease that affects and kills millions of people worldwide. Breast cancer, especially, has a high incidence and mortality, and is challenging to treat. Due to its high impact on the health sector, oncological therapy is the subject of an intense and very expensive research. To improve this therapy and reduce its costs, strategies such as drug repurposing and drug combinations have been extensively studied. Drug repurposing means giving new usefulness to drugs which are approved for the therapy of various diseases, but, in this case, are not approved for cancer therapy. On the other hand, the purpose of combining drugs is that the response that is obtained is more advantageous than the response obtained by the single drugs. Using drugs with potential to be repurposed, combined with 5-fluorouracil, the aim of this project was to investigate whether this combination led to therapeutic benefits, comparing with the isolated drugs. We started with a screening of the most promising drugs, with verapamil and itraconazole being chosen. Several cellular viability studies, cell death and proliferation studies, mainly in MCF-7 cells (Michigan Cancer Foundation-7, human breast adenocarcinoma cells) were performed. Studies were also carried out to understand the effect of the drugs at the level of possible therapeutic resistance, evaluating the epithelial-mesenchymal transition. Combining all the results, the conclusion is that the combination of verapamil and itraconazole with 5-fluorouracil had benefits, mainly by decreasing cell viability and proliferation. Furthermore, the combination of itraconazole and 5-fluorouracil seemed to be the most effective, being an interesting focus in future studies.

SUBMITTER: Correia A

PROVIDER: S-EPMC6315516 | biostudies-other | 2018 Dec

REPOSITORIES: biostudies-other

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Study of New Therapeutic Strategies to Combat Breast Cancer Using Drug Combinations.

Correia Ana A Silva Dany D Correia Alexandra A Vilanova Manuel M Gärtner Fátima F Vale Nuno N

Biomolecules 20181214 4

Cancer is a disease that affects and kills millions of people worldwide. Breast cancer, especially, has a high incidence and mortality, and is challenging to treat. Due to its high impact on the health sector, oncological therapy is the subject of an intense and very expensive research. To improve this therapy and reduce its costs, strategies such as drug repurposing and drug combinations have been extensively studied. Drug repurposing means giving new usefulness to drugs which are approved for ...[more]

PMID: 30558247

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Project description:Our group developed a new model of drug combination consisting of the use of antineoplastic drugs and different repurposed drugs, having demonstrated that antimalarial and central nervous system (CNS) drugs have a promising anticancer profile as standalone agents, as well as in combined regimens. Here, we evaluated the anticancer profiles of two different CNS drugs (edaravone and quetiapine), both alone and in combination with antineoplastic agents for breast and colon cancer, to explore whether these repurposed drugs could synergistically enhance the anticancer potential of chemotherapeutic drugs. We also developed a new model of combination using two repurposed drugs, to explore whether this model of combination could also be suitable for application in breast and colon cancer therapy. MCF-7 and HT-29 cancer cells were incubated for 48 h with each individual drug (0.01-100 µM) to determine their IC50. Cells were then treated with the IC50 value for doxorubicin or paclitaxel (MCF-7) or 5-fluorouracil (HT-29) and combined with increasing concentrations of edaravone or quetiapine for 48 h. Both cell lines were also treated with a combination of two antimalarial drugs (mefloquine and pyronaridine) or two CNS drugs (fluphenazine and sertraline) for 48 h. We found that the use of quetiapine in combined therapies seems to synergistically enhance the anticancer activity of doxorubicin for the management of breast cancer. Both CNS drugs significantly improved the cytotoxic potential of 5-fluorouracil in HT-29 cells, with quetiapine synergistically interacting with the antineoplastic drug in this drug combination. Regarding the combination of repurposed drugs, only found one synergic combination regimen (sertraline IC50 plus variable concentrations of fluphenazine) with anticancer potential against HT-29 colon cancer cells was found. Taken together, these results suggest that quetiapine and edaravone can be used as adjuvant agents in chemotherapy for colon cancer. It was also found that the combination of repurposed drugs, specifically the CNS drugs sertraline and fluphenazine, may have an interesting profile for application in colon cancer novel therapies.

Project description:Conspectus"Drug resistance is an unavoidable consequence of the use of drugs; however, the emergence of multi-drug resistance can be managed by accurate diagnosis and tailor-made regimens."Antimicrobial resistance (AMR), is one of the most paramount health perils that has emerged in the 21st century. The global increase in drug-resistant strains of various bacterial pathogens prompted the World Health Organization (WHO) to develop a priority list of AMR pathogens. Mycobacterium tuberculosis (Mtb), an acid-fast bacillus that causes tuberculosis (TB), merits being one of the highest priority pathogens on this list since drug-resistant TB (DR-TB) accounts for ∼29% of deaths attributable to AMR. In recent years, funded collaborative efforts of researchers from academia, not-for-profit virtual R&D organizations and industry have resulted in the continuous growth of the TB drug discovery and development pipeline. This has so far led to the accelerated regulatory approval of bedaquiline and delamanid for the treatment of DR-TB. However, despite the availability of drug regimes, the current cure rate for multi-drug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) treatment regimens is 50% and 30%, respectively. It is to be noted that these regimens are administered over a long duration and have a serious side effect profile. Coupled with poor patient adherence, this has led to further acquisition of drug resistance and treatment failure. There is therefore an urgent need to develop new TB drugs with novel mechanism of actions (MoAs) and associated regimens.This Account recapitulates drug resistance in TB, existing challenges in addressing DR-TB, new drugs and regimens in development, and potential ways to treat DR-TB. We highlight our research aimed at identifying novel small molecule leads and associated targets against TB toward contributing to the global TB drug discovery and development pipeline. Our work mainly involves screening of various small molecule chemical libraries in phenotypic whole-cell based assays to identify hits for medicinal chemistry optimization, with attendant deconvolution of the MoA. We discuss the identification of small molecule chemotypes active against Mtb and subsequent structure-activity relationships (SAR) and MoA deconvolution studies. This is followed by a discussion on a chemical series identified by whole-cell cross-screening against Mtb, for which MoA deconvolution studies revealed a pathway that explained the lack of in vivo efficacy in a mouse model of TB and reiterated the importance of selecting an appropriate growth medium during phenotypic screening. We also discuss our efforts on drug repositioning toward addressing DR-TB. In the concluding section, we preview some promising future directions and the challenges inherent in advancing the drug pipeline to address DR-TB.

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Study of New Therapeutic Strategies to Combat Breast Cancer Using Drug Combinations.

Publications

Study of New Therapeutic Strategies to Combat Breast Cancer Using Drug Combinations.

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