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Updated: Jun 28, 2025
SA-β-Galactosidase-Based Screening Assay for the Identification of Senotherapeutic Drugs
Published on: June 28, 2019
Selective Elimination of Senescent Cancer Cells by Galacto-Modified PROTACs
Mengyang Chang1, Feng Gao2, Giri Gnawali2
1Department of Chemistry and Biochemistry, University of Arizona, Tucson, Arizona 85721, United States.
Abstract:
Although the selective and effective clearance of senescent cancer cells can improve cancer treatment, their development is confronted by many challenges. As part of efforts designed to overcome these problems, prodrugs, whose design is based on senescence-associated β-galactosidase (SA-β-gal), have been developed to selectively eliminate senescent cells. However, chemotherapies relying on targeted molecular inhibitors as senolytic drugs can induce drug resistance. In the current investigation, we devised a new strategy for selective degradation of target proteins in senescent cancer cells that utilizes a prodrug composed of the SA-β-gal substrate galactose (galacto) and the proteolysis-targeting chimeras (PROTACs) as senolytic agents. Prodrugs Gal-ARV-771 and Gal-MS99 were found to display senolytic indexes higher than those of ARV-771 and MS99. Significantly, results of in vivo studies utilizing a human lung A549 xenograft mouse model demonstrated that concomitant treatment with etoposide and Gal-ARV-771 leads to a significant inhibition of tumor growth without eliciting significant toxicity.
Insights
Researchers developed novel senolytic prodrugs using galactose and proteolysis-targeting chimeras (PROTACs) to target senescent cancer cells. These prodrugs show enhanced efficacy and reduced toxicity in preclinical models, offering a promising new cancer therapy strategy.
Area of Science:
- Oncology
- Biochemistry
- Molecular Biology
Background:
- Selective elimination of senescent cancer cells is a promising cancer treatment strategy.
- Existing senolytic drugs, often molecular inhibitors, can lead to drug resistance.
- Senescence-associated β-galactosidase (SA-β-gal) is a biomarker for senescent cells.
Purpose of the Study:
- To develop a novel senolytic prodrug strategy for selective degradation of target proteins in senescent cancer cells.
- To evaluate the senolytic efficacy and toxicity of new galactose-based PROTAC prodrugs.
- To assess the in vivo anti-tumor efficacy and toxicity of the developed prodrugs.
Main Methods:
- Design and synthesis of galactose-conjugated proteolysis-targeting chimera (PROTAC) prodrugs (Gal-ARV-771, Gal-MS99).
- Assessment of senolytic activity and senolytic index of prodrugs compared to parent PROTACs.
- In vivo efficacy and toxicity studies using a human lung A549 xenograft mouse model treated with etoposide and Gal-ARV-771.
Main Results:
- Gal-ARV-771 and Gal-MS99 exhibited higher senolytic indexes than their respective parent PROTACs.
- Concomitant treatment with etoposide and Gal-ARV-771 significantly inhibited tumor growth in a human lung A549 xenograft mouse model.
- The combined treatment demonstrated no significant toxicity in the in vivo studies.
Conclusions:
- Galactose-based PROTAC prodrugs represent a novel and effective strategy for targeting senescent cancer cells.
- These prodrugs offer improved senolytic efficacy and reduced toxicity compared to conventional PROTACs.
- The combination of etoposide and Gal-ARV-771 shows potential as a safe and effective cancer therapy.
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