Baglo Yan, Hagen Lars, Høgset Anders, Drabløs Finn, Otterlei Marit, Gederaas Odrun A
Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology, P.O. Box 8905, 7491 Trondheim, Norway.
PCI Biotech AS, Strandveien 55, 1366 Lysaker, Norway.
Biomed Res Int. 2014;2014:921296. doi: 10.1155/2014/921296. Epub 2014 Jun 30.
Bleomycin is a cytotoxic chemotherapeutic agent widely used in cancer treatment. However, its efficacy in different cancers is low, possibly due to limited cellular internalization. In this study, a novel approach known as photochemical internalization (PCI) was explored to enhance bleomycin delivery in bladder cancer cells (human T24 and rat AY-27), as bladder cancer is a potential indication for use of PCI with bleomycin. The PCI technique was mediated by the amphiphilic photosensitizer disulfonated tetraphenyl chlorin (TPCS(2a)) and blue light (435 nm). Two additional strategies were explored to further enhance the cytotoxicity of bleomycin; a novel peptide drug ATX-101 which is known to impair DNA damage responses, and the protease inhibitor E-64 which may reduce bleomycin degradation by inhibition of bleomycin hydrolase. Our results demonstrate that the PCI technique enhances the bleomycin effect under appropriate conditions, and importantly we show that PCI-bleomycin treatment leads to increased levels of DNA damage supporting that the observed effect is due to increased bleomycin uptake. Impairing the DNA damage responses by ATX-101 further enhances the efficacy of the PCI-bleomycin treatment, while inhibiting the bleomycin hydrolase does not.
博来霉素是一种细胞毒性化疗药物，广泛应用于癌症治疗。然而，其在不同癌症中的疗效较低，可能是由于细胞内化有限。在本研究中，探索了一种称为光化学内化（PCI）的新方法，以增强博来霉素在膀胱癌细胞（人T24和大鼠AY-27）中的递送，因为膀胱癌是使用PCI联合博来霉素的潜在适应症。PCI技术由两亲性光敏剂二磺化四苯基卟啉（TPCS(2a)）和蓝光（435nm）介导。还探索了另外两种策略来进一步增强博来霉素的细胞毒性；一种已知会损害DNA损伤反应的新型肽药物ATX-101，以及可能通过抑制博来霉素水解酶来减少博来霉素降解的蛋白酶抑制剂E-64。我们的结果表明，PCI技术在适当条件下增强了博来霉素的作用，重要的是我们表明PCI-博来霉素治疗导致DNA损伤水平增加，支持观察到的效果是由于博来霉素摄取增加。ATX-101损害DNA损伤反应进一步增强了PCI-博来霉素治疗的疗效，而抑制博来霉素水解酶则没有。
