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Changes in intracellular redox status influence multidrug resistance in gastric adenocarcinoma cells
DE-Jun Tai1, Wen-Sen Jin, Cheng-Si Wu
1Department of General Surgery, The First Affiliated Hospital.
Abstract:
Multidrug resistance (MDR) to chemotherapeutic agents is a major obstacle for the treatment of various types of cancers. The exact mechanism of MDR has not yet been fully clarified, although it has been frequently associated with the variation of intracellular redox status. The levels of intracellular glutathione (GSH) are considered to play a vital role in the regulation of the intracellular redox status. In our study, we investigated the effects of buthionine sulfoximine (BSO), an inhibitor of GSH biosynthesis, and NAC, a cysteine source for GSH synthesis, on sensitive gastric adenocarcinoma cells (SGC7901) and cisplatin-resistant SGC7901/DDP cells using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The two cell lines were pretreated with various non-toxic concentrations of BSO for 24 h and combined with fluorouracil (5-FU) or mitomycin (MMC) in the presence or absence of NAC before culturing further. After various treatments, the IC(50) values of MMC and 5-FU were calculated and intracellular GSH levels were measured using the glutathione reductase/5,5'-dithiobis-(2-nitrobenzoic acid) (DTNB) recycling assay without anticancer drug stimulation under the same microenvironments. The study demonstrated that BSO increased the sensitivity of the cells to chemotherapeutics while NAC exhibited the reverse effect, particularly in drug-resistant cells. It is, therefore, possible that changes in intracellular GSH levels affect the chemosensitivity of the resistant cells to a greater extent than that of their parent cells. This study indicates that variation in the intracellular redox status may be closely correlated with MDR and may provide a valuable basic strategy for anticancer therapy.
Insights
Buthionine sulfoximine (BSO) enhances chemotherapy effectiveness by lowering glutathione (GSH) levels, while N-acetylcysteine (NAC) reverses this effect, impacting multidrug resistance (MDR) in cancer cells.
Area of Science:
- Biochemistry
- Oncology
- Cell Biology
Background:
- Multidrug resistance (MDR) is a significant challenge in cancer treatment, often linked to altered intracellular redox status.
- Intracellular glutathione (GSH) levels are crucial regulators of cellular redox balance and are implicated in MDR.
- Understanding the role of GSH in MDR can reveal new therapeutic strategies.
Purpose of the Study:
- To investigate the impact of modulating intracellular GSH levels on the chemosensitivity of gastric adenocarcinoma cells.
- To evaluate the effects of buthionine sulfoximine (BSO), a GSH synthesis inhibitor, and N-acetylcysteine (NAC), a GSH precursor, on drug-resistant and sensitive cancer cells.
- To explore the correlation between intracellular GSH levels, redox status, and MDR.
Main Methods:
- Utilized sensitive (SGC7901) and cisplatin-resistant (SGC7901/DDP) gastric adenocarcinoma cell lines.
- Treated cells with BSO and/or NAC in combination with chemotherapeutic agents (5-fluorouracil and mitomycin C).
- Assessed cell viability using the MTT assay and quantified intracellular GSH levels via a DTNB recycling assay.
Main Results:
- BSO pretreatment significantly increased cancer cell sensitivity to chemotherapeutic agents.
- NAC pretreatment demonstrated an inverse effect, reducing chemosensitivity, particularly in drug-resistant cells.
- Modifications in intracellular GSH levels showed a more pronounced effect on the chemosensitivity of resistant cells compared to sensitive cells.
Conclusions:
- Intracellular GSH levels and the associated redox status are closely correlated with multidrug resistance in cancer.
- Targeting GSH biosynthesis or levels may offer a viable strategy to overcome MDR.
- This study provides a foundational understanding for developing novel anticancer therapies aimed at reversing drug resistance.
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