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3D-Shaped Binders of Unfolded Proteins Inducing Cancer Cell-Specific Endoplasmic Reticulum Stress In Vitro and In
Insa Klemt1, Oleg Varzatskii2,3, Roman Selin1
1Department of Chemistry and Pharmacy, Organic Chemistry II, Friedrich-Alexander-University of Erlangen-Nürnberg (FAU), 91058 Erlangen, Germany.
Journal of the American Chemical Society
|September 29, 2023
Summary
A novel compound, FeC2, targets unfolded proteins to induce endoplasmic reticulum (ER) stress selectively in cancer cells. This targeted approach offers a promising, less toxic alternative for cancer therapy by suppressing tumor growth and metastasis.
Area of Science:
- Biochemistry
- Oncology
- Drug Discovery
Background:
- Cancer cells accumulate unfolded proteins, leading to endoplasmic reticulum (ER) stress.
- Existing ER stress inducers like bortezomib have dose-limiting side effects.
- There is a need for more cancer-specific ER stress-inducing drugs.
Purpose of the Study:
- To investigate the potential of FeC2 as a novel cancer-specific ER stress inducer.
- To evaluate the efficacy and safety of FeC2 in preclinical cancer models.
Main Methods:
- FeC2 was synthesized and tested for its ability to bind unfolded proteins.
- Cell viability assays were performed on various human and murine cancer cell lines.
- In vivo studies were conducted using murine lymphoma and lung cancer models to assess tumor growth and metastasis suppression.
Main Results:
- FeC2 selectively induces ER stress and reactive oxygen species (ROS) increase in cancer cells, not normal cells.
- FeC2 demonstrated low micromolar toxicity against multiple cancer cell lines (HL-60, BL-2, Jurkat, A2780, SK-MES-1, LLC1).
- FeC2 showed no in vivo toxicity up to 147 mg/kg and did not affect normal blood or bone marrow cells at therapeutic doses.
Conclusions:
- FeC2 represents a promising new therapeutic agent that selectively targets cancer cells by inducing ER stress.
- FeC2 effectively suppresses primary tumor growth and metastasis in preclinical models.
- The cancer-specific mechanism of FeC2 suggests a favorable therapeutic window with reduced side effects compared to existing treatments.
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