Enhancement of the antitumor effect of 5-fluorouracil with modulation in drug transporters expression using PI3K inhibitors in colorectal cancer cells.

Autor: El-Daly SM; Medical Biochemistry Department, Medicine and Clinical Studies Research Institute, National Research Centre, Dokki, 12622, Cairo, Egypt; Cancer Biology and Genetics Laboratory, Centre of Excellence for Advanced Sciences, National Research Centre, Dokki, 12622, Cairo, Egypt. Electronic address: sm.el-daly@nrc.sci.eg., Abo-Elfadl MT; Cancer Biology and Genetics Laboratory, Centre of Excellence for Advanced Sciences, National Research Centre, Dokki, 12622, Cairo, Egypt; Biochemistry Department, Biotechnology Research Institute, National Research Centre, Dokki, 12622, Cairo, Egypt., Hussein J; Medical Biochemistry Department, Medicine and Clinical Studies Research Institute, National Research Centre, Dokki, 12622, Cairo, Egypt., Abo-Zeid MAM; Cancer Biology and Genetics Laboratory, Centre of Excellence for Advanced Sciences, National Research Centre, Dokki, 12622, Cairo, Egypt; Genetics and Cytology Department, Biotechnology Research Institute, National Research Centre, Dokki, 12622, Cairo, Egypt.
Jazyk: angličtina
Zdroj: Life sciences [Life Sci] 2023 Feb 15; Vol. 315, pp. 121320. Date of Electronic Publication: 2022 Dec 24.
DOI: 10.1016/j.lfs.2022.121320
Abstrakt: Aims: 5-Fluorouracil (5-FU) represents the cornerstone for colorectal cancer therapy. However, resistance to its action is a major hindrance. This study aimed to investigate the effectiveness of suppressing the activity of PI3K/Akt/mTOR signaling pathway on the chemosensitivity of colorectal cancer cells to 5-FU, as well as to delineate the possible underlying cellular mechanisms and the expected modulation in the expression of specific ABC drug transporters.
Main Methods: HCT116 and Caco-2 cells were incubated with 5-FU, LY294002, or PI-103 individually or in combination. Cell viability was monitored using MTT assay. The expression of a panel of drug transporters was evaluated by RT-PCR. Immunofluorescence staining was applied to evaluate the expression pattern of phospho-AKT, phospho-mTOR, and ABGG2. HPLC evaluated the enhancement in the 5-FU cellular uptake. Cell apoptosis was detected by flow cytometry, and cell morphological changes following treatment were inspected under a fluorescence microscope. Additionally, the migration ability of cells following our suggested treatment combination was examined by wound healing assay.
Key Findings: The results reveal a notable enhancement in the cytotoxicity of a low dose of 5-FU when combined with a PI3K inhibitor (LY294002 or PI-103). This enhancement was influenced by the significant reduction in the expression of p-AKT and p-mTOR and was also mediated by a significant suppression in the expression of ABCG2 and ABCC5. Consequently, we detected an increase in the cellular uptake and concentration of 5-FU in cells treated with this combination rather than a single 5-FU treatment. Our Suggested combination treatment also induced cell apoptosis and reduced the migration ability of cells.
Significance: Our data provide evidence that survival signaling pathways represent distinctive targets for the enhancement of chemotherapeutic sensitivity. The antitumor efficacy of 5-FU is enhanced when combined with a PI3K inhibitor, and this effect was mediated by alterations in the expression of specific drug transporters.
Competing Interests: Declaration of competing interest All authors declare that there is no conflict of interest regarding the publication of this paper.
(Copyright © 2022 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: