Abstract
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.
Highlights
Cancer represents a major health problem worldwide and is the second leading cause of death in the United States of America (USA)
We found that the combination of 5-FU with sertraline and thioridazine induces a greater anti-tumour effect compared to each drug alone in these cells
Cells were treated with 5-FU in concentrations ranging 0.1–100 μM for 48 h and cell survival was evaluated by MTT, a viability assay that measures mitochondrial activity
Summary
Cancer represents a major health problem worldwide and is the second leading cause of death in the United States of America (USA). In 2021, there were an estimated 1,898,160 new cancer cases and 608,570 cancer deaths in the USA. Colorectal cancer (CRC) represents the second leading cause of death by cancer in the USA, and in 2021, there were an estimated 149,500 newly diagnosed cases and 52,980 deaths caused by this type of cancer. Breast cancer represents the second leading cause of death by cancer among women, with an estimated 281,550 new cases and 43,600 deaths in 2021 in the USA [1]. The development of new drugs for cancer therapy is, urgent, but this process is time-consuming, costly and has low approval rates [2]. The majority of the new chemotherapeutics have problems related to toxicity, leading to side effects [3]
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