Abstract
BackgroundThe emergence of nonresponse or resistance to traditional chemotherapeutic agents is one of the main challenges of colorectal cancer (CRC) therapies. Thus, novel therapeutic drugs that can improve the clinical outcomes of CRC patients are urgently needed. The purpose of this study was to investigate the effects and mechanisms of pyrimethamine in CRC.Methods and resultsIn this study, we assessed the role of pyrimethamine on CRC cell growth by cell counting kit-8 and colony formation assays. Cell cycle distribution and cellular senescence were determined by flow cytometry and senescence-associated β-galactosidase staining respectively. RNA-seq analysis and western blotting were used to investigate the potential pathways of pyrimethamine in CRC development. Moreover, animal experiments were performed to evaluate the effect of pyrimethamine in vivo. Our results demonstrated that pyrimethamine could inhibit cell growth by inducing S phase arrest followed by cellular senescence in CRC cells, and the p38MAPK-p53 axis was probably involved in that effect. In addition, pyrimethamine could also boost CD8+ T-cell mediated cytotoxicity and exert antitumor activity in vivo.ConclusionThese results indicated that pyrimethamine may be a promising candidate agent for CRC treatment.
Highlights
Colorectal cancer (CRC) is the third most common cancer and accounts for the second leading cause of cancerrelated mortality worldwide [1]
To evaluate whether the pyrimethamine-induced inhibition of cell growth was related to cell cycle arrest, the effect of pyrimethamine on cell cycle distribution was analyzed by flow cytometry
These data revealed that pyrimethamine might inhibit cell growth by inducing S-phase arrest in colorectal cancer (CRC) cells
Summary
Colorectal cancer (CRC) is the third most common cancer and accounts for the second leading cause of cancerrelated mortality worldwide [1]. The effects and mechanisms of pyrimethamine on CRC have not been reported yet. Our results showed that pyrimethamine inhibited the growth of CRC cells both in vitro and in vivo. The p38MAPK-p53 axis might play an important role in pyrimethamine-induced S-phase arrest followed by cellular. The purpose of this study was to investigate the effects and mechanisms of pyrimethamine in CRC. Methods and results In this study, we assessed the role of pyrimethamine on CRC cell growth by cell counting kit-8 and colony formation assays. Our results demonstrated that pyrimethamine could inhibit cell growth by inducing S phase arrest followed by cellular senescence in CRC cells, and the p38MAPK-p53 axis was probably involved in that effect. Conclusion These results indicated that pyrimethamine may be a promising candidate agent for CRC treatment
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