Colorectal cancer (CRC) is the third most common malignancy worldwide and the second most deadly cancer. Scientists have projected that by 2040, the prevalence will reach up to 3.2 million new cases annually due to population aging, disadvantageous diet transformations, and elevated exposure to risk factors. In the past decades, the five-year survival rate in colorectal cancer has significantly increased to 65% due to the development of an early endoscopic diagnosis and new chemotherapeutic approaches. Fluoropyrimidines, such as 5-fluorouracil or capecitabine, are commonly used to treat CRC. One of the most fundamental mechanisms of 5-FU is based on the inhibition of thymidylate synthase. This action is responsible for the therapeutic, but also toxic, effects of the drug. In this short review, we discuss the possible effects of vitamin D activity on colorectal cancer cells in relation to fluoropyrimidines. PubMed, Embase, and Web of Science databases were searched up to January 2022 for studies on vitamin D and 5-fluorouracil interaction mechanisms. Original studies, case reports, and review articles were included.
Vitamin D or its analogs target multiple biochemical pathways and modulate numerous pathophysiolo-gical mechanisms in the course of colon cancer, including those related to the pharmacological sites of fluoropyrimidines. However, the available data concerning vitamin D–fluoropyrimidine pharmacological interactions are limited, especially regarding patients suffering from colon cancer and being treated with fluoropyrimidines.

5-fluorouracil (5-FU), which is a commonly used chemotherapy agent exerts undesired cardiac toxicity. Mitochondrial dysfunction is thought to be one of potentially important mechanisms of 5-FU- induced cardiotoxicity. α-ketoglutarate dehydrogenase (α-KGDHC) is the key regulatory enzyme of TCA cycle. The complex consists of multiple copies of three catalytic subunits: α-ketoglutarate dehydrogenase (E1), dihydrolipoamide succinyltransferase (E2) and dihydrolipoamide dehydrogenase (E3). α-KGDHC together with branched chain α-ketoacid dehydrogenase (BCKDHC) and pyruvate dehydrogenase (PDHC), are the members of 2-oxoacid dehydrogenases family that share some structural and functional similarities. Recently, it has been found that 5-FU stimulates BCKDHC in rat’s cardiac muscle. Therefore, we hypothesize that 5-FU modifies α-KGDHC activity and affects cardiac muscle metabolism. The aim of this study was to determine the effect of 5-FU on α-KGDHC activity and protein levels of E1 and E2 subunits of the complex in rat’s cardiac muscle. Wistar male rats were administered with 4 doses of 5-FU, 150 mg/kg b.wt. each (study group) or 0.3% methylcellulose (control group). α-KGDHC activity was assayed spectrophotometrically. The E1 and E2 proteins levels were quantified by Western blot. 5-FU administration resulted in stimulation of myocardial α-KGDHC activity in rats. In addition, E2 protein level increased in response to 5-FU treatment, while the E1 protein level remained unchanged. Up- regulation of α-KGDHC appears to result from change in E2 subunit protein level. However, the effect of 5-FU on factors modifying α-KGDHC activity at post-translational level cannot be excluded.

Undisturbed branched-chain amino acids (BCAA) catabolism is necessary for normal heart function. The key enzyme in BCAA catabolism is a multienzyme branched-chain α-keto acid dehydro-genase complex (BCKDH). BCKDH activity is regulated mainly by reversible dephosphorylation (activa-tion)/phosphorylation (inactivation) cycle catalyzed by regulatory enzymes, a specific phosphatase (PPM1K) and kinase (BDK). 5-fluorouracil (5-FU) is widely used in the treatment of different types of cancer. 5-FU has the potential to cause a wide spectrum of cardiotoxicity, ranging from asymptomatic electrocardiographic changes to cardiomyopathy and subsequent cardiac failure. We hypothesize that 5-FU modifies BCKDH activity and affects cardiac muscle metabolism. The current study was aimed at the investigation of the in vivo effect of 5-FU on BCKDH activity and mRNA levels for E1, PPM1K and BDK. Wistar male rats were administered with 4 doses of 5-FU, 150 mg/kg b.wt. each (study group) or 0.3% methylcellulose (control group). BCKDH activity was assayed spectrophotometrically. The mRNA levels were quantified by real-time PCR. 5-FU treatment caused an increase in BCKDH activity that appears to result mainly from increased dephosphorylation of the complex and is associated with an increase of PPM1K mRNA level and reduction of BDK and E1 mRNA levels. It is conceivable that 5-FU stimulation of BCKDH is an adaptive reaction with the purpose of enhancing the BCAA catabolism and protecting from toxic effect caused by excessive accumulation of these amino acids in heart.