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The intracellular redox environment modulates the cytotoxic efficacy of single and combination chemotherapy in breast cancer cells using photochemical internalisation

Background: Photochemical internalisation (PCI) is a light-triggered and site-specific technique that enhances the delivery of therapeutic agents to their intracellular targets using amphiphilic, photosensitizing agents. Methods: This study investigated the effect that the intracellular redox enviro...

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Autores principales: Adigbli, Derick K., Pye, Hayley, Seebaluck, Jason, Loizidou, Marilena, MacRobert, Alexander J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Royal Society of Chemistry 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9070005/
https://www.ncbi.nlm.nih.gov/pubmed/35530074
http://dx.doi.org/10.1039/c9ra04430b
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author Adigbli, Derick K.
Pye, Hayley
Seebaluck, Jason
Loizidou, Marilena
MacRobert, Alexander J.
author_facet Adigbli, Derick K.
Pye, Hayley
Seebaluck, Jason
Loizidou, Marilena
MacRobert, Alexander J.
author_sort Adigbli, Derick K.
collection PubMed
description Background: Photochemical internalisation (PCI) is a light-triggered and site-specific technique that enhances the delivery of therapeutic agents to their intracellular targets using amphiphilic, photosensitizing agents. Methods: This study investigated the effect that the intracellular redox environment of 4T1 breast cancer cells exerts on PCI-facilitated delivery of the type I ribosome inactivating protein, saporin, and the topoisomerase inhibitor, mitoxantrone, either individually or in combination. Buthionine sulfoximime (BSO), a clinically used inhibitor of glutathione synthesis, and the singlet oxygen scavenger, l-histidine, were used to enhance the oxidative and reductive state of the cells respectively. Results: PCI of saporin at 30 nM was effective in reducing cellular viability, which decreased to 16% compared to “dark” controls (P < 0.01). Addition of BSO enhanced PCI efficacy by a further factor of three (P < 0.01), but addition of l-histidine completely inhibited cytotoxicity induced by PCI. The combination of the two cytotoxic agents, saporin and mitoxantrone, with PCI, elicited 14% and 17% reduction in cell viability (P < 0.01) compared to PCI with saporin alone and mitoxantrone alone respectively. Combination treatment with BSO resulted in a further significant reduction in cell viability by 18% (P < 0.01). Conclusions: Our findings show the efficacy of PCI can be manipulated and potentiated by modifying the intracellular redox environment.
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spelling pubmed-90700052022-05-05 The intracellular redox environment modulates the cytotoxic efficacy of single and combination chemotherapy in breast cancer cells using photochemical internalisation Adigbli, Derick K. Pye, Hayley Seebaluck, Jason Loizidou, Marilena MacRobert, Alexander J. RSC Adv Chemistry Background: Photochemical internalisation (PCI) is a light-triggered and site-specific technique that enhances the delivery of therapeutic agents to their intracellular targets using amphiphilic, photosensitizing agents. Methods: This study investigated the effect that the intracellular redox environment of 4T1 breast cancer cells exerts on PCI-facilitated delivery of the type I ribosome inactivating protein, saporin, and the topoisomerase inhibitor, mitoxantrone, either individually or in combination. Buthionine sulfoximime (BSO), a clinically used inhibitor of glutathione synthesis, and the singlet oxygen scavenger, l-histidine, were used to enhance the oxidative and reductive state of the cells respectively. Results: PCI of saporin at 30 nM was effective in reducing cellular viability, which decreased to 16% compared to “dark” controls (P < 0.01). Addition of BSO enhanced PCI efficacy by a further factor of three (P < 0.01), but addition of l-histidine completely inhibited cytotoxicity induced by PCI. The combination of the two cytotoxic agents, saporin and mitoxantrone, with PCI, elicited 14% and 17% reduction in cell viability (P < 0.01) compared to PCI with saporin alone and mitoxantrone alone respectively. Combination treatment with BSO resulted in a further significant reduction in cell viability by 18% (P < 0.01). Conclusions: Our findings show the efficacy of PCI can be manipulated and potentiated by modifying the intracellular redox environment. The Royal Society of Chemistry 2019-08-19 /pmc/articles/PMC9070005/ /pubmed/35530074 http://dx.doi.org/10.1039/c9ra04430b Text en This journal is © The Royal Society of Chemistry https://creativecommons.org/licenses/by/3.0/
spellingShingle Chemistry
Adigbli, Derick K.
Pye, Hayley
Seebaluck, Jason
Loizidou, Marilena
MacRobert, Alexander J.
The intracellular redox environment modulates the cytotoxic efficacy of single and combination chemotherapy in breast cancer cells using photochemical internalisation
title The intracellular redox environment modulates the cytotoxic efficacy of single and combination chemotherapy in breast cancer cells using photochemical internalisation
title_full The intracellular redox environment modulates the cytotoxic efficacy of single and combination chemotherapy in breast cancer cells using photochemical internalisation
title_fullStr The intracellular redox environment modulates the cytotoxic efficacy of single and combination chemotherapy in breast cancer cells using photochemical internalisation
title_full_unstemmed The intracellular redox environment modulates the cytotoxic efficacy of single and combination chemotherapy in breast cancer cells using photochemical internalisation
title_short The intracellular redox environment modulates the cytotoxic efficacy of single and combination chemotherapy in breast cancer cells using photochemical internalisation
title_sort intracellular redox environment modulates the cytotoxic efficacy of single and combination chemotherapy in breast cancer cells using photochemical internalisation
topic Chemistry
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9070005/
https://www.ncbi.nlm.nih.gov/pubmed/35530074
http://dx.doi.org/10.1039/c9ra04430b
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