Establishment and Characterization of 5-Fluorouracil-Resistant Human Colorectal Cancer Stem-Like Cells: Tumor Dynamics under Selection Pressure

Abstract

5-Fluorouracil (5-FU) remains the gold standard of first-line treatment for colorectal cancer (CRC). Although it may initially debulk the tumor mass, relapses frequently occur, indicating the existence of cancer cells that are therapy-resistant and are capable of refueling tumor growth. To identify mechanisms of drug resistance, CRC stem-like cells were subjected to long-term 5-FU selection using either intermittent treatment regimen with the IC50 drug dose or continuous treatment regimen with escalating drug doses. Parental cancer cells were cultivated in parallel. Real-time PCR arrays and bioinformatic tools were used to investigate gene expression changes. We found the first method selected for cancer cells with more aggressive features. We therefore transplanted these cancer cells or parental cells in mice, and again, found that not only did the 5-FU-selected cancer cells generate more aggressive tumors with respect to their parental counterpart, but they also showed a different gene expression pattern as compared to what we had observed in vitro, with ID1 the top upregulated gene. We propose ID1 as a stemness marker pervasively expressed in secondary lesions emerging after completion of chemotherapy.

Effect of co-administration of Bee honey and some chemotherapeutic drugs on dissemination of hepatocellular carcinoma in rats

“…Blocking of thymidylate synthase, the enzyme that catalyzes the de novo synthesis of the DNA precursor thymidylate is one of the most 5-FU mechanisms due to inhibition cell proliferation by forming fluorodeoxyuridine monophosphate. Also, the formation of defective F-RNA, which ultimately interferes with synthesis of protein to form defective, fluorinated DNA, was resulting in the breaking of the single-strand and fragmentation of DNA [[15], [16], [17]]. When 5-FU is taken by the cells it becomes toxic because it metabolized to fluoronucleotides which inserted into nucleic acids or bind to thymidylate synthase.…”

Inhibition of Nadph Oxidase Activity Augments 5-Fluorouracil Mediated Cell Death in Human Colon Carcinoma HCT-116 Cells

“…The NOX enzymes are also known to participate in chemo-resistance in gallbladder cancer (Zhan et al, 2015). Despite 5-FU remains the first-line chemotherapeutic agent for colon cancer,where gaining the against anti-cancer therapy limits its sucessful application in cancer therapy (Francipane et al, 2019). However, the role of NOX activation in 5-FU mediated cell death in colon cancer cells was remaining to elucidate.…”

Inhibitor of Differentiation 1 (Id1) in Cancer and Cancer Therapy

“…Id1-induced pentose phosphate pathway activation confers chemoresistance to oxaliplatin and promotes HCC proliferation [110]. In colorectal cancer, after long time 5-Fu selection, Id1 expression was top upregulated in colorectal cancer cells and more aggressive tumors was generated [111]. Decreasing the expression of Id1 gene was able to restore the sensitivity to 5-Fluorouracil (5-FU) [112,113].…”