Effects of 5-Fluorouracil in Nuclear and Cellular Morphology, Proliferation, Cell Cycle, Apoptosis, Cytoskeletal and Caveolar Distribution in Primary Cultures of Smooth Muscle Cells

Abstract

Colon cancer is one of the most prevalent types of cancer in the world and is one of the leading causes of cancer death. The anti-metabolite 5- fluorouracil (5-FU) is widely used in the treatment of patients with colon cancer and other cancer types. 5-FU-based chemotherapy has been shown to be very efficient in the improvement of overall survival of the patients and for the eradication of the disease. Unfortunately, common side effects of 5-FU include severe alterations in the motility of the gastrointestinal tissues. Nevertheless, the molecular and cellular effects of 5-FU in smooth muscle cells are poorly understood. Primary smooth muscle cell cultures are an important tool for studies of the biological consequences of 5-FU at the cellular level. The avian gizzard is one of the most robust organs of smooth muscle cells. Here we studied the molecular and cellular effects of the chemotherapic drug 5-FU in a primary culture of chick gizzard smooth muscle cells. We found that treatment of smooth muscle cells with 5-FU inhibits cell proliferation by the arrest of cells in the G1 phase of cell cycle and induce apoptosis. 5-FU induced a decrease in the percentage of histone H3-positive cells. Treatment of cells with 5-FU induced changes in cellular and nuclear morphology, a decrease in the number of stress fibers and a major decrease in the number of caveolin-3 positive cells. Our results suggest that the disorganization of the actin cytoskeleton and the reduction of caveolin-3 expression could explain the alterations in contractility observed in patients treated with 5-FU. These findings might have an impact in the understanding of the cellular effects of 5-FU in smooth muscle tissues and might help the improvement of new therapeutic protocols for the treatment of colon cancer.

May cannabinoids prevent the development of chemotherapy‐induced diarrhea and intestinal mucositis? Experimental study in the rat

“…Vacuolization and neutrophil infiltration might have contributed to an increased thickness of the muscle layers in the small intestine (present study). In addition to inflammation‐related effects on the muscle (and maybe other motor components), direct actions of 5‐FU on the smooth muscle cells could also contribute to accelerated transit and small intestinal hypercontractility (present study).…”

“…48,49 On experimental day 4 (2 days after the second 5-FU administration), delayed gastric emptying was more apparent, although this did promoted changes in the cellular and nuclear morphology. 50 Possibly other components of the gastric wall, which was damaged by 5-FU treatment both in fundus and body (see Fig. S4), or its extrinsic innervation, may also be altered, as has been shown for isolated gastric preparations from cisplatin-treated patients.…”

“…Their in vitro assays revealed hypercontractility of the deep muscle of the stomach and duodenum 3 and 15 days after a single dose of 5‐FU (150 mg kg −1 ), corresponding to the inflammatory and postinflammatory phases of mucositis respectively. In addition, in cultured smooth muscle cells, 5‐FU inhibited cell proliferation, induced apoptosis, and promoted changes in the cellular and nuclear morphology . Possibly other components of the gastric wall, which was damaged by 5‐FU treatment both in fundus and body (see Fig.…”

The Clinical Significance of miR-34a in Pancreatic Ductal Carcinoma and Associated Molecular and Cellular Mechanisms

“…Cells were transfected with miR-34a mimic (5′-UGGCAGUGUCUUAGCUGGUUGU-3′), miR-150 mimic (5′-UCUCCCAACCCUUGUACCAGUG-3′) and control miRNA (5′-AAUUCUCCGAACGUGUCACGU-3′), using Lipfectin-2000 (Invitrogen) according to the user manual. Six hours later, the Opti-MEM medium was completely replaced with RPMI 1640 medium and cells were continually cultured for 24 h, followed by incubation with or without 0.1 m M of 5-FU as previously reported [15]. …”

Global trends in nanomedicine research on triple negative breast cancer: a bibliometric analysis

“…10 However, the majority of the drugs used in chemotherapy are mutagenic and cause damage to DNA from the tumor and non-tumor cells, leading to the death of rapidly dividing cells, which is associated with the collateral effects observed in patients. 11 Aiming to improve the efficacy to decrease toxicity and increase the bioavailability of chemotherapy medication, nanotechnology has emerged as an important option. 12,13 Nanoparticles accumulate preferentially in the tumors due to the presence of well defined characteristics in tumors mass, such as the defective vasculature and poor lymphatic drainage, resulting in an increase in permeation and retention effect.…”