Reversal of ABCG2-mediated MDR by VEGFR3 inhibitor (S)-SAR131675
Xiang Chen1, Jiaqian Xu2, Ryan Li1,3
1Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, United States.
Abstract:
Multidrug resistance (MDR) remains a major challenge in cancer treatment, as it is a significant factor contributing to chemotherapy failure and cancer recurrence. Among various resistance mechanisms, the overexpression of the breast cancer resistance protein (BCRP/ABCG2) has been identified as a cause of MDR in multiple cancers, including breast cancer, lung cancer, and colon cancer (S)-SAR131675 is the S-enantiomer of SAR131675 (HY-15458), which significantly and selectively suppresses the Vascular Endothelial Growth Factor Receptor 3 (VEGFR3). In this research (S)-SAR131675 shows the ability to overcome the ABCG2-mediated MDR in both the non-small cell lung cancer cell line NCI-H460 and its ABCG2-overexpressing cell line NCI-H460/TPT10, as well as the colorectal cancer cell line S1 and its ABCG2-overexpressing cell line S1-M1-80. Through several experiments, we demonstrate that (S)-SAR131675 targets the efflux function of ABCG2, resulting in an increased intracellular concentration of substrates of ABCG2, including mitoxantrone and topotecan. Additionally, this resensitizing effect did not affect the overall protein expression or subcellular localization of ABCG2 in the ABCG2-overexpressing cell lines. In summary (S)-SAR131675 can overcome ABCG2-mediated MDR by directly suppressing the drug efflux function, providing a promising basis for the further development of cancer treatments associated with MDR in the future.
Insights
The compound (S)-SAR131675 overcomes multidrug resistance (MDR) by inhibiting the drug efflux pump breast cancer resistance protein (BCRP/ABCG2). This restores chemotherapy effectiveness in cancer cells, offering new treatment possibilities.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Multidrug resistance (MDR) is a major obstacle in cancer chemotherapy, leading to treatment failure and recurrence.
- Overexpression of breast cancer resistance protein (BCRP/ABCG2) is a key mechanism driving MDR in various cancers like lung and colorectal cancer.
Purpose of the Study:
- To investigate the efficacy of (S)-SAR131675 in overcoming BCRP/ABCG2-mediated MDR.
- To elucidate the mechanism by which (S)-SAR131675 resensitizes cancer cells to chemotherapy.
Main Methods:
- Utilized non-small cell lung cancer (NCI-H460) and colorectal cancer (S1) cell lines, along with their BCRP/ABCG2-overexpressing counterparts (NCI-H460/TPT10 and S1-M1-80).
- Assessed the effect of (S)-SAR131675 on intracellular drug concentrations of BCRP/ABCG2 substrates (mitoxantrone, topotecan).
- Evaluated BCRP/ABCG2 protein expression and subcellular localization.
Main Results:
- (S)-SAR131675 effectively overcame BCRP/ABCG2-mediated MDR in both lung and colorectal cancer models.
- The compound increased intracellular accumulation of BCRP/ABCG2 substrates, indicating inhibition of efflux.
- (S)-SAR131675 did not alter BCRP/ABCG2 protein levels or localization.
Conclusions:
- (S)-SAR131675 directly suppresses the drug efflux function of BCRP/ABCG2, thereby overcoming MDR.
- This targeted action provides a promising strategy for developing novel cancer therapies against MDR.
