The Negative Impact of Cancer Cell Nitric Oxide on Photodynamic Therapy
Jonathan M Fahey1, Albert W Girotti2
1Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI, USA.
Abstract:
Numerous studies have shown that low-flux nitric oxide (NO) in tumors produced mainly by inducible nitric oxide synthase (iNOS/NOS2) can signal for angiogenesis, inhibition of apoptosis, and promotion of cell growth, migration, and invasion. Studies in the authors' laboratory have revealed that iNOS-derived NO in various cancer cell types elicits resistance to cytotoxic photodynamic therapy (PDT) and moreover endows PDT-surviving cells with more aggressive proliferation and migration/invasion. In this chapter, we describe how cancer cell iNOS/NO in vitro can be monitored in different PDT model systems (e.g., a targeted cell-bystander cell model) and how pharmacologic interference with basal and PDT-upregulated iNOS/NO can significantly improve PDT outcomes.
Insights
Inducible nitric oxide synthase (iNOS)-derived nitric oxide (NO) promotes cancer growth and resistance to photodynamic therapy (PDT). Targeting iNOS/NO can enhance PDT effectiveness against cancer cells.
Area of Science:
- Oncology
- Biochemistry
- Molecular Biology
Background:
- Low-flux nitric oxide (NO), primarily from inducible nitric oxide synthase (iNOS/NOS2), is implicated in tumor progression, including angiogenesis, apoptosis inhibition, and enhanced cell growth, migration, and invasion.
- iNOS-derived NO in cancer cells contributes to resistance against cytotoxic photodynamic therapy (PDT) and promotes more aggressive phenotypes in surviving cells.
Purpose of the Study:
- To describe methods for monitoring cancer cell iNOS/NO in vitro within PDT model systems.
- To investigate the potential of pharmacologic interference with iNOS/NO to improve PDT outcomes.
Main Methods:
- Utilized various in vitro PDT model systems, including targeted and bystander cell models, to monitor cancer cell iNOS/NO.
- Employed pharmacologic strategies to interfere with both basal and PDT-induced iNOS/NO levels.
Main Results:
- Demonstrated that iNOS-derived NO confers resistance to PDT and enhances the aggressive characteristics of PDT-surviving cancer cells.
- Showcased that modulating iNOS/NO levels significantly improves the efficacy of PDT.
Conclusions:
- Cancer cell iNOS/NO plays a critical role in mediating resistance to PDT and promoting tumor aggressiveness.
- Pharmacologic inhibition of iNOS/NO presents a viable strategy to enhance the therapeutic effectiveness of PDT in cancer treatment.
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