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Use of Enzymatically Activated Carbon Monoxide Donors for Sensitizing Drug-Resistant Tumor Cells
Federica Sodano1, Barbara Rolando2, Loretta Lazzarato2
1Department of Pharmacy, "Federico II" University of Naples, 80131 Naples, Italy.
Abstract:
The application of gaseous signaling molecules like NO, H2S or CO to overcome the multidrug resistance in cancer treatment has proven to be a viable therapeutic strategy. The development of CO-releasing molecules (CORMs) in a controlled manner and in targeted tissues remains a challenge in medicinal chemistry. In this paper, we describe the design, synthesis and chemical and enzymatic stability of a novel non-metal CORM (1) able to release intracellularly CO and, simultaneously, facilitate fluorescent degradation of products under the action of esterase. The toxicity of 1 against different human cancer cell lines and their drug-resistant counterparts, as well as the putative mechanism of toxicity were investigated. The drug-resistant cancer cell lines efficiently absorbed 1 and 1 was able to restore their sensitivity vs. chemotherapeutic drugs by causing a CO-dependent mitochondrial oxidative stress that culminated in mitochondrial-dependent apoptosis. These results demonstrate the importance of CORMs in cases where conventional chemotherapy fails and thus open the horizons towards new combinatorial strategies to overcome multidrug resistance.
Insights
This study introduces a novel carbon monoxide-releasing molecule (CORM) that restores chemotherapy sensitivity in drug-resistant cancer cells by inducing CO-dependent oxidative stress and apoptosis.
Area of Science:
- Medicinal Chemistry
- Cancer Biology
- Biochemistry
Background:
- Gaseous signaling molecules like carbon monoxide (CO) show promise in overcoming cancer multidrug resistance.
- Developing controlled and targeted carbon monoxide-releasing molecules (CORMs) is a significant challenge.
Purpose of the Study:
- To design, synthesize, and characterize a novel non-metal CORM.
- To investigate the efficacy of this CORM in restoring sensitivity to chemotherapy in drug-resistant cancer cells.
- To elucidate the mechanism of action of the novel CORM.
Main Methods:
- Synthesis and chemical/enzymatic stability assessment of a novel non-metal CORM (1).
- Evaluation of CORM (1) toxicity against various human cancer cell lines and their drug-resistant counterparts.
- Investigation of the mechanism underlying CORM (1)-induced cancer cell death.
Main Results:
- The novel non-metal CORM (1) was successfully synthesized and demonstrated good stability.
- CORM (1) was efficiently absorbed by drug-resistant cancer cells.
- CORM (1) restored sensitivity to chemotherapeutic drugs by inducing CO-dependent mitochondrial oxidative stress and apoptosis.
Conclusions:
- The developed non-metal CORM (1) offers a promising strategy to overcome multidrug resistance in cancer.
- This CORM induces cancer cell death via a CO-dependent mitochondrial pathway.
- These findings support the development of novel combinatorial therapies for resistant cancers.
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