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The Synthesis, Characterization and Reactivity of a Series of Ruthenium N-triphosPh Complexes
Published on: April 10, 2015
Disulfide-Bridged Ru Complex-Mediated Photo-Disulfidptosis for Colorectal Cancer Therapy
Simeng He1, Wendong Jin2, Jiaojiao Pang1
1Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, China.
Abstract:
Despite numerous therapeutic strategies targeting specific programmed cell death pathways, effectively eliminating malignant colorectal cancer (CRC) remains a significant challenge. Disulfidptosis, a newly identified form of cell death, is characterized by rapid NADPH depletion and abnormal disulfide bond formation in cytoskeletal proteins in cells with high SLC7A11 expression under glucose starvation. Given the aberrant expression of SLC7A11 and the hypermetabolic phenotype of CRC cells, targeting the disulfidptosis pathway offers a promising therapeutic approach for CRC treatment. Here, we developed a binuclear ruthenium complex, RuSSRu, bridged by a disulfide bond, to effectively induce the disulfidptosis pathway in CRC cells. Under two-photon excitation, RuSSRu generates reactive oxygen species (ROS), leading to lysosomal damage and initiating cellular escape mechanisms. Crucially, this process triggers a cascade of metabolic disruptions, including an accumulation of disulfide bonds and ROS-induced NADPH depletion, ultimately resulting in cytoskeletal collapse and disulfidptosis. The synergistic interaction between disulfidptosis and lysosomal damage-induced apoptosis amplified tumor cell death, unveiling a novel mechanism and a versatile therapeutic strategy platform for CRC management.
Insights
A novel ruthenium complex, RuSSRu, effectively triggers disulfidptosis, a unique cell death pathway, in colorectal cancer (CRC) cells. This approach combats CRC by inducing metabolic disruptions and synergistic cell death, offering a new therapeutic strategy.
Area of Science:
- Biochemistry
- Oncology
- Materials Science
Background:
- Colorectal cancer (CRC) remains difficult to treat despite various therapeutic strategies.
- Disulfidptosis, a novel cell death pathway, involves NADPH depletion and disulfide bond formation, particularly in high SLC7A11-expressing cells under glucose starvation.
- CRC cells exhibit high SLC7A11 expression and a hypermetabolic phenotype, making disulfidptosis a potential therapeutic target.
Purpose of the Study:
- To develop a novel therapeutic strategy targeting disulfidptosis for colorectal cancer (CRC) treatment.
- To investigate the efficacy of a binuclear ruthenium complex (RuSSRu) in inducing disulfidptosis in CRC cells.
Main Methods:
- Development of a binuclear ruthenium complex, RuSSRu, bridged by a disulfide bond.
- Utilizing two-photon excitation to activate RuSSRu, generating reactive oxygen species (ROS) and inducing lysosomal damage.
- Analyzing metabolic disruptions, including disulfide bond accumulation and NADPH depletion, leading to cytoskeletal collapse and disulfidptosis.
Main Results:
- RuSSRu effectively induced disulfidptosis in CRC cells via ROS generation and lysosomal damage.
- The treatment triggered metabolic cascade: disulfide bond accumulation and NADPH depletion.
- Synergistic cell death was observed through the combined effects of disulfidptosis and lysosomal damage-induced apoptosis.
Conclusions:
- RuSSRu represents a novel therapeutic platform for CRC by effectively inducing disulfidptosis.
- The study unveils a new mechanism for CRC treatment involving synergistic cell death pathways.
- Targeting disulfidptosis offers a promising strategy for managing colorectal cancer.
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