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Published on: September 17, 2020
Selective targeting of cancer and senescence via shared metabolic shifts extends lifespan of old mice
Zachery R Robinson1, Sabrina C Fong1, Daniella Y Choi1
1Department of Bioengineering and QB3 Institute, UC Berkeley, Berkeley, CA 94720-3220, USA.
Abstract:
Eliminating both senescent and cancer cells through pharmacological intervention presents a powerful therapeutic strategy against aging and tumor progression. Navitoclax has emerged as a promising candidate with both senolytic and antitumor activity, but its clinical application remains limited due to dose-dependent thrombocytopenia and tumor-specific resistance. To overcome these limitations, we combined dichloroacetate and metformin with a 10-fold reduced dose of Navitoclax (ABT-263) and show that this pharmacology, termed, DMA, selectively targets the metabolic vulnerabilities underlying senescent and malignant cells. We demonstrate that DMA effectively ablates different types of senescent and cancer cells in vitro by exacerbating their defects in ATP production. Notably, the treatment is well tolerated by healthy human cells and in mice in vivo, and in fact improves the functional performance of aged mice after acute administration and extends lifespan after prolonged dosing. While the in vivo effects of DMA are yet to be fully explored, our findings suggest that it might represent a new, clinically viable way to combat cancer and senescence without toxicity to healthy cells and tissues.
Insights
A new drug combination, DMA, effectively eliminates senescent and cancer cells by targeting their energy production. This approach shows promise for treating aging and cancer with reduced toxicity to healthy cells.
Area of Science:
- Biomedical Sciences
- Cell Biology
- Gerontology
Background:
- Pharmacological elimination of senescent and cancer cells offers therapeutic potential for aging and cancer.
- Navitoclax (ABT-263) exhibits senolytic and antitumor activity but faces limitations like thrombocytopenia and resistance.
- Targeting metabolic vulnerabilities is a strategy to overcome drug resistance and toxicity.
Purpose of the Study:
- To develop a novel pharmacological approach combining dichloroacetate and metformin with a reduced dose of Navitoclax (ABT-263), termed DMA.
- To investigate the efficacy and safety of DMA in selectively targeting senescent and cancer cells.
- To assess the impact of DMA on cellular ATP production and its therapeutic potential in aging and cancer models.
Main Methods:
- Combination therapy using dichloroacetate, metformin, and a reduced dose of Navitoclax (ABT-263).
- In vitro assessment of DMA's effect on various senescent and cancer cell types.
- In vivo studies in mice to evaluate DMA's tolerability, impact on aged mice's performance, and lifespan extension.
Main Results:
- DMA effectively ablates senescent and cancer cells in vitro by exacerbating ATP production defects.
- The DMA treatment is well tolerated by healthy human cells and in mice.
- Acute DMA administration improved functional performance in aged mice, and prolonged dosing extended lifespan.
Conclusions:
- DMA represents a novel, clinically viable strategy for combating cancer and senescence.
- This combination therapy selectively targets metabolic vulnerabilities of senescent and malignant cells.
- DMA demonstrates potential for treating age-related diseases and cancer with reduced toxicity to healthy tissues.
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