Cancer is among the leading causes of death worldwide and it is estimated that in 2040 more than 29 million people will be diagnosed with some type of cancer. The most prevalent type of cancer in women, worldwide, is breast cancer, a type of cancer associated with a huge death rate. This high mortality is mainly a consequence of the development of drug resistance, which is one of the major challenges to overcome in breast cancer treatment. As a result, research has been focused on finding novel therapeutical weapons, specifically ones that allow for a personalized treatment, based on patients’ characteristics. Although the scientific community has been concerned about guaranteeing the quality of life of cancer patients, researchers are also aware of the increasing costs related to cancer treatment, and efforts have been made to find alternatives to the development of new drugs. The development of new drugs presents some disadvantages as it is a multistep process that is time- and money-consuming, involving clinical trials that commonly fail in the initial phases. A strategy to overcome these disadvantages is drug repurposing. In this review, we focused on describing potential repurposed drugs in the therapy of breast cancer, considering their pharmacogenomic profile, to assess the relationship between patients’ genetic variations and their response to a certain therapy. This review supports the need for the development of further fundamental studies in this area, in order to investigate and expand the knowledge of the currently used and novel potential drugs to treat breast cancer. Future clinical trials should focus on developing strategies to group cancer patients according to their clinical and biological similarities and to discover new potential targets, to enable cancer therapy to be more effective and personalized.

Several central nervous system (CNS) drugs exhibit potent anti-cancer activities. This study aimed to design a novel model of combination that combines different CNS agents and antineoplastic drugs (5-fluorouracil (5-FU) and paclitaxel (PTX)) for colorectal and breast cancer therapy, respectively. Cytotoxic effects of 5-FU and PTX alone and in combination with different CNS agents were evaluated on HT-29 colon and MCF-7 breast cancer cells, respectively. Three antimalarials alone and in combination with 5-FU were also evaluated in HT-29 cells. Different schedules and concentrations in a fixed ratio were added to the cultured cells and incubated for 48 h. Cell viability was evaluated using MTT and SRB assays. Synergism was evaluated using the Chou-Talalay, Bliss Independence and HSA methods. Our results demonstrate that fluphenazine, fluoxetine and benztropine have enhanced anticancer activity when used alone as compared to being used in combination, making them ideal candidates for drug repurposing in colorectal cancer (CRC). Regarding MCF-7 cells, sertraline was the most promising candidate alone for drug repurposing, with the lowest IC₅₀ value. For HT-29 cells, the CNS drugs sertraline and thioridazine in simultaneous combination with 5-FU demonstrated the strongest synergism among all combinations. In MCF-7 breast cancer cells, the combination of fluoxetine, fluphenazine and benztropine with PTX resulted in synergism for all concentrations below IC₅₀. We also found that the antimalarial artesunate administration prior to 5-FU produces better results in reducing HT-29 cell viability than the inverse drug schedule or the simultaneous combination. These results demonstrate that CNS drugs activity differs between the two selected cell lines, both alone and in combination, and support that some CNS agents may be promising candidates for drug repurposing in these types of cancers. Additionally, these results demonstrate that 5-FU or a combination of PTX with CNS drugs should be further evaluated. These results also demonstrate that antimalarial drugs may also be used as antitumor agents in colorectal cancer, besides breast cancer.

The human normal breast cell line MCF-10A is being widely used as a model in toxicity studies due to its structural similarity to the normal human mammary epithelium. Over the years, application of carbon dots (C-dots) in biomedicine has been increasing due to their photoluminescence properties, biocompatibility, biosafety and possible applications in bioimaging and as drug carriers. In this work we prepared three different C-dots from the same set of carbon and nitrogen precursors (citric acid and urea, respectively) via three distinct bottom-up synthetic routes and their safety was tested against the normal breast cell line MCF-10A. The characterization results demonstrated a similar size range and composition for all the C-dots. The MCF-10A cells were treated with different concentrations of C-dots for 24, 48 and 72 h to evaluate the cell viability over time. For the 24 h incubation, there were no significant decreases in the viability of the MCF-10A cells. For the 48 h treatment, there was a significant decrease in the viability of the cells treated with calcination-based C-dots, but without significant cellular viability changes for microwave and hydrothermal-based C-dots. For 72 h, cells treated with hydrothermal-based C-dots have the most promising viability profile. Also, compared with paclitaxel, these C-dots have a safety profile very close to that of an antineoplastic in non-tumor cells. Our results suggest that these new C-dots have potential as imaging candidates or biosensing tools as well as drug carriers, and further investigation in animal models is needed for future application in medicine.

5-fluorouracil (5-FU) and doxorubicin (DOX) are potent anti-tumour agents commonly used for colon and breast cancer therapy, respectively. However, their clinical application is limited by their side effects and the development of drug resistance. Honeybee venom is a complex mixture of substances that has been reported to be effective against different cancer cells. Its active compound is melittin, a positively charged amphipathic peptide that interacts with the phospholipids of the cell membrane, forming pores that enable the internalization of small molecules with cytotoxic activities,^. and consequently, causing cell death. Some central nervous system (CNS) drugs have recently demonstrated great anti-cancer potential, both in vitro, in vivo and in clinical trials, being promising candidates for drug repurposing in oncology. The present work evaluated the anti-cancer efficacy of honeybee venom in combination with chemotherapeutic or CNS drugs in HT-29 colon and MCF-7 breast cancer cell lines. The chemical characterization of a Portuguese sample of honeybee venom was done by LC-DAD-ESI/MSn analysis. For single treatments, cells were incubated with increasing concentrations of bee venom. For combination treatments, increasing concentrations of bee venom were first combined with the half-maximal inhibitory concentration (IC₅₀) of 5-FU and DOX, in HT-29 and MCF-7 cells, respectively. Cells were also treated with increasing concentrations of bee venom in combination with the IC₅₀ value of four CNS drugs (fluphenazine, fluoxetine, sertraline and thioridazine). Cytotoxicity was evaluated by MTT and SRB assays. The combination index (CI) value was calculated using CompuSyn software, based on the Chou–Talalay method. Synergy scores of different reference models (HSA, Loewe, ZIP and Bliss) were also calculated using SynergyFinder. The results demonstrate that honeybee venom is active against HT-29 colon and MCF-7 breast cancer cells, having better anti-tumour activity in MCF-7 cells. It was found that bee venom combined with 5-FU and fluphenazine in HT-29 cells resulted in less cytotoxic effects compared to the co-treatment of fluoxetine, sertraline and thioridazine plus bee venom, which resulted in less than 15% of viable cells for the whole range of concentrations. The combination of MCF-7 cells with repurposed drugs plus honeybee venom resulted in better anti-cancer efficacies than with DOX, notably for lower concentrations. A combination of fluoxetine and thioridazine plus honeybee venom resulted in less than 40% of viable cells for all ranges of concentrations. These results support that the combination of honeybee venom with repurposed drugs and chemotherapeutic agents can help improve their anti-cancer activity, especially for lower concentrations, in both cell lines. Overall, the present study corroborates the enormous bioactive potential of honeybee venom for colon and breast cancer treatments, both alone and in combination with chemotherapy or repurposed drugs.

Chemotherapy plays a key role in breast cancer therapy, but drug resistance and unwanted side effects make the treatment less effective. We propose a new combination model that combines antineoplastic drugs and antimalarials for breast cancer therapy. Cytotoxic effects of two antineoplastic agents alone and in combination with several antimalarials on MCF-7 tumor cell line was evaluated. Different concentrations in a fixed ratio were added to the cultured cells and incubated for 48 h. Cell viability was evaluated using MTT and SRB assays. Synergism was evaluated using the Chou-Talalay method. The results indicate doxorubicin (DOX) and paclitaxel (PTX) alone at concentrations of their IC₅₀ and higher are cell growth inhibitors. Mefloquine, artesunate, and chloroquine at concentrations of their IC₅₀ demonstrate anti-cancer activity. In combination, almost all antimalarials demonstrate higher ability than DOX and PTX alone to decrease cell viability at concentrations of IC₅₀ and lower than their IC₅₀. The combination of chloroquine, artesunate and mefloquine with DOX and PTX was synergic (CI < 1). The combination of DOX and mefloquine after 48 h incubation demonstrated the highest cytotoxicity against MCF-7 cells, and the combination of DOX and artesunate was the most synergic. These results suggest antimalarials could act synergistically with DOX/PTX for breast cancer therapy.