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

Abstract

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.