Novel combination therapy for melanoma induces apoptosis via a gap junction positive feedback mechanism
Archis Bagati1,2, Timothy C Hutcherson3,2, Zethan Koch4,2
1Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA.
Abstract:
Metastatic melanoma cells overexpressing gap junctions were assayed for their ability to propagate cell death by a novel combination therapy that generates reactive oxygen species (ROS) by both 1) non-thermal plasma (NTP) and 2) tirapazamine (TPZ) under hypoxic conditions. Results demonstrate additive-to-synergistic effects of combination therapy compared to each agent individually. NTP induces highly localized cell death in target areas whereas TPZ partially reduces viability over the total surface area. However, when high gap junction expression was induced in melanoma cells, effects of combination NTP+TPZ therapy was augmented, spreading cell death across the entire plate. Similarly, in vivo studies of human metastatic melanoma in a mouse tumor model demonstrate that the combined effect of NTP+TPZ causes a 90% reduction in tumor volume, specifically in the model expressing gap junctions. Treatment with NTP+TPZ increases gene expression in the apoptotic pathway and oxidative stress while decreasing genes related to cell migration. Immune response was also elicited through differential regulation of cytokines and chemokines, suggesting potential for this therapy to induce a cytotoxic immune response with fewer side effects than current therapies. Interestingly, the gap junction protein, Cx26 was upregulated following treatment with NTP+TPZ and these gap junctions were shown to maintain functionality during the onset of treatment. Therefore, we propose that gap junctions both increase the efficacy of NTP+TPZ and perpetuate a positive feedback mechanism of gap junction expression and tumoricidal activity. Our unique approach to ROS induction in tumor cells with NTP+TPZ shows potential as a novel cancer treatment.
Insights
This study shows that combining non-thermal plasma (NTP) and tirapazamine (TPZ) therapy effectively kills metastatic melanoma cells. Overexpressing gap junctions significantly enhances this cancer treatment
Area of Science:
- Oncology
- Biophysics
- Biochemistry
Background:
- Metastatic melanoma poses a significant treatment challenge.
- Gap junctions play a role in intercellular communication and cell death propagation.
- Reactive oxygen species (ROS) generation is a key mechanism in cancer therapy.
Purpose of the Study:
- To investigate the efficacy of a novel combination therapy using non-thermal plasma (NTP) and tirapazamine (TPZ) for metastatic melanoma.
- To determine the role of gap junctions in augmenting the therapeutic effects of NTP+TPZ.
- To explore the underlying mechanisms of action, including ROS generation and immune response.
Main Methods:
- Assaying metastatic melanoma cells overexpressing gap junctions for cell death propagation.
- Utilizing non-thermal plasma (NTP) and tirapazamine (TPZ) under hypoxic conditions to generate reactive oxygen species (ROS).
- Conducting in vivo studies using a human metastatic melanoma mouse tumor model.
Main Results:
- The combination therapy (NTP+TPZ) demonstrated additive-to-synergistic effects compared to individual agents.
- High gap junction expression significantly augmented the cell death propagation of NTP+TPZ therapy.
- In vivo studies showed a 90% reduction in tumor volume in models with gap junction expression.
- Treatment increased apoptotic and oxidative stress markers, decreased cell migration genes, and elicited an immune response.
- Gap junction protein Cx26 was upregulated and functional post-treatment.
Conclusions:
- Gap junctions enhance the efficacy of NTP+TPZ combination therapy against metastatic melanoma.
- A positive feedback loop between gap junction expression and tumoricidal activity is proposed.
- This novel ROS-inducing approach with NTP+TPZ shows potential as an effective cancer treatment with possible reduced side effects.
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