Synergistic Enhancement of 5-Fluorouracil Chemotherapeutic Efficacy by Taurine in Colon Cancer Rat Model

Abstract

Colorectal cancer (CRC) is one of the top 10 most common cancers worldwide and caused approximately 10 million deaths in 2022. CRC mortality has increased by 10% since 2020 and 52.000 deaths will occur in 2024, highlighting the limitations of current treatments due to ineffectiveness, toxicity, or non-adherence. The widely used chemotherapeutic agent, 5-fluorouracil (5-FU), is associated with several adverse effects, including renal, cardiac, and hepatic toxicity; mucositis; and resistance. Taurine (TAU), an essential β-amino acid with potent antioxidant, antimutagenic, and anti-inflammatory properties, has demonstrated protective effects against tissue toxicity from chemotherapeutic agents like doxorubicin and cisplatin. Taurine deficiency is linked to aging and cancers such as breast and colon cancer. This study hypothesized that TAU may mitigate the adverse effects of 5-fluorouracil (5-FU). Carcinogenesis was chemically induced in rats using 1,2-dimethylhydrazine (DMH). Following five months of cancer progression, taurine (100 mg/kg) was administered orally for 8 days, and colon tissues were analyzed. The results showed 80% of adenocarcinoma (AC) in DMH-induced control animals. Notably, the efficacy of 5-FU showed 70% AC and TAU 50% while, in the 5-FU + TAU group, no adenocarcinoma was observed. No differences were observed in the inflammatory infiltrate or the expression of genes such as K-ras, p53, and Ki-67 among the cancer-induced groups whereas APC/β-catenin expression was increased in the 5FU + TAU-treated group. The mitotic index and dysplasia were increased in the induced 5-FU group and when associated with TAU, the levels returned to normal. These data suggest that 5-FU exhibits a synergic anticancer effect when combined with taurine.

Keywords: 5-fluorouracil; chemotherapy; colon cancer; taurine.

Figure 1

Biosynthesis of taurine.

Figure 2

Experimental protocol design.

Figure 3

Proximal, medial, and distal portion of the colon.

Figure 4

Dysplasia and mitotic index in animals induced with DMH. (-) group without DMH induction; (+) group with DMH induction; * p < 0.5; ** p < 0.01; *** p < 0.001.

Figure 5

Histology of distal colon tissue. (a) Normal tissue: simple columnar epithelium with thin brush border and numerous goblet cells. (b) Dysplastic tissue: regions of dysplastic epithelium are indicated by arrows (H&E 10X).

Figure 6

Distribution of the visible lesions of the colon in animals induced with DMH.

Figure 7

Histopathological image of the positive control with chemical DMH induction. (A,B): Adenocarcinoma of the colon; the arrow points to the invasion area. (C,D): Adenoma of the colon; the arrow points the absence of invasion. Calibration bar: 100 µm.

Figure 8

Immunohistochemical images of β-catenin-reactive cells. (A): C (+); (B): TAU (+); (C): 5FU (+); (D): 5FU + TAU (+) (5× magnification).

Figure 9

Immunohistochemical images of p53-reactive cells. (A): C (+); (B): TAU (+); (C): 5FU (+); (D): 5FU + TAU (+) (5× magnification).

Figure 10

Immunohistochemical image of Ki-67-reactive cells. (A): C (+); (B): TAU (+); (C): 5FU (+); (D): 5FU + TAU (+) (5× magnification).

Figure 11

Immunohistochemical image of K-ras-reactive cells. (A): C (+); (B): TAU (+); (C): 5FU (+); (D): 5FU + TAU (+) (5× magnification).

Figure 12

Mechanism of DMH-induced colon cancer and synergic effect of taurine and 5-FU against cancer growth. DMH is oxidized (a,b) in the liver by phase I enzymes into azoxymethane (AOM) and subsequently into methylazoxymethanol (MAOM). This compound is then glucuronidated by phase II enzymes and excreted through the bile (c). In the intestine, in the presence of beta-glucuronidase from colonocytes or the microbiota (d), MAOM is transformed back and can spontaneously convert into methyldiazonium (e), which is considered the ultimate carcinogen due to its ability to alkylate nitrogenous bases [47] The chromosomal instability generated by DMH can be blocked by TAU since it is able to act as a potent antioxidant, reacting with free radicals and stabilize the chromosome, observed by the decrease in the number of micronucleated reticulocytes caused by mutagenic compounds [29]. The chemotherapeutic antimetabolic agent 5-FU replaces uracil during protein synthesis, inhibiting thymidylate synthase and being mistakenly incorporated into DNA, which triggers cell death [48].