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Published on: May 10, 2024
TGF-β Receptor Inhibitor SB431542 Enhanced the Sensitivity of Gastric Cancer to 5-Fluorouracil: New Combined Targeted
Sara Bonomo1, Roberto Giovannoni2, Marialuisa Lavitrano1
1School of Medicine and Surgery, University of Milano-Bicocca, Via Cadore 48, 20900 Monza, Italy.
Abstract:
Gastric cancer (GC) continues to be a major cause of cancer-related deaths globally, primarily due to resistance to standard treatments like 5-fluorouracil (5FU). The transforming growth factor-β (TGF-β) signaling pathway is recognized as a key contributor to tumor progression and resistance to therapy. This work investigated the therapeutic potential of targeting TGF-β receptor I (TGFBR1) with the selective inhibitor SB431542 to enhance the effect of 5FU in GC. Analysis of public gene expression datasets revealed that increased levels of TGF-β and TGFBR1 are significantly connected with poor prognosis, particularly in high-grade GC. In vitro experiments using AGS and SNU-1 cell lines demonstrated that co-treatment with SB431542 and 5FU significantly reduced cell viability, making GC cells more sensitive to 5FU. This combination treatment led to a significant activation of caspase-dependent apoptosis, indicating an enhanced pro-apoptotic effect. These findings suggest that TGFBR1 inhibition could provide a strategic approach to reduce the dosage of 5FU, thereby minimizing its severe side effects in gastric cancer patients. Furthermore, these results underscore the potential of TGFBR1 as both a prognostic biomarker and a therapeutic target, warranting further investigation in aggressive forms of gastric cancer.
Insights
Targeting transforming growth factor-β receptor I (TGFBR1) with SB431542 enhances 5-fluorouracil (5FU) efficacy in gastric cancer. This combination therapy increases cancer cell death and improves patient prognosis, potentially reducing 5FU side effects.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Gastric cancer (GC) remains a leading cause of cancer mortality worldwide.
- Resistance to standard chemotherapy, such as 5-fluorouracil (5FU), significantly contributes to poor patient outcomes.
- The transforming growth factor-β (TGF-β) signaling pathway is implicated in GC progression and therapeutic resistance.
Purpose of the Study:
- To investigate the therapeutic potential of inhibiting TGF-β receptor I (TGFBR1) using SB431542 to sensitize gastric cancer cells to 5FU.
- To evaluate TGFBR1 as a prognostic biomarker and therapeutic target in gastric cancer.
Main Methods:
- Analysis of public gene expression datasets to correlate TGF-β and TGFBR1 levels with GC prognosis.
- In vitro studies using AGS and SNU-1 gastric cancer cell lines.
- Co-treatment experiments with SB431542 (TGFBR1 inhibitor) and 5FU.
Main Results:
- Elevated TGF-β and TGFBR1 expression levels are significantly associated with poor prognosis in gastric cancer, especially in high-grade tumors.
- Combined treatment with SB431542 and 5FU markedly reduced gastric cancer cell viability.
- The combination therapy significantly induced caspase-dependent apoptosis, enhancing the anti-cancer effect.
Conclusions:
- Inhibition of TGFBR1 by SB431542 can overcome 5FU resistance in gastric cancer.
- This therapeutic strategy may allow for reduced 5FU dosage, mitigating severe side effects.
- TGFBR1 represents a promising prognostic biomarker and therapeutic target for aggressive gastric cancer.
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