Photochemically-Induced Release of Lysosomal Sequestered Sunitinib: Obstacles for Therapeutic Efficacy
| العنوان: | Photochemically-Induced Release of Lysosomal Sequestered Sunitinib: Obstacles for Therapeutic Efficacy |
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| المؤلفون: | Sebastian Patzke, Maria E B Berstad, Pål Kristian Selbo, Vigdis Sørensen, Kristian Berg, Judith Jing Wen Wong, Ane Sofie Viset Fremstedal, Qian Peng, Anette Weyergang |
| المصدر: | Cancers, Vol 12, Iss 2, p 417 (2020) Cancers Volume 12 Issue 2 |
| بيانات النشر: | MDPI AG, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | 0301 basic medicine, Cancer Research, Necrosis, Endosome, medicine.medical_treatment, sunitinib, Photodynamic therapy, urologic and male genital diseases, lcsh:RC254-282, Article, 03 medical and health sciences, 0302 clinical medicine, cytosolic release, sunitinib resistance, medicine, Cytotoxic T cell, Photosensitizer, lysosomal sequestration, Chemistry, Sunitinib, photochemical internalization, medicine.disease, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, female genital diseases and pregnancy complications, Cytosol, 030104 developmental biology, photochemical release, Oncology, photodynamic therapy, 030220 oncology & carcinogenesis, Cancer research, medicine.symptom, Infiltration (medical), medicine.drug |
| الوصف: | Lysosomal accumulation of sunitinib has been suggested as an underlying mechanism of resistance. Here, we investigated if photochemical internalization (PCI), a technology for cytosolic release of drugs entrapped in endosomes and lysosomes, would activate lysosomal sequestered sunitinib. By super-resolution fluorescence microscopy, sunitinib was found to accumulate in the membrane of endo/lysosomal compartments together with the photosensitizer disulfonated tetraphenylchlorin (TPCS2a). Furthermore, the treatment effect was potentiated by PCI in the human HT-29 and the mouse CT26.WT colon cancer cell lines. The cytotoxic outcome of sunitinib-PCI was, however, highly dependent on the treatment protocol. Thus, neoadjuvant PCI inhibited lysosomal accumulation of sunitinib. PCI also inhibited lysosomal sequestering of sunitinib in HT29/SR cells with acquired sunitinib resistance, but did not reverse the resistance. The mechanism of acquired sunitinib resistance in HT29/SR cells was therefore not related to lysosomal sequestering. Sunitinib-PCI was further evaluated on HT-29 xenografts in athymic mice, but was found to induce only a minor effect on tumor growth delay. In immunocompetent mice sunitinib-PCI enhanced areas of treatment-induced necrosis compared to the monotherapy groups. However, the tumor growth was not delayed, and decreased infiltration of CD3-positive T cells was indicated as a possible mechanism behind the failed overall response. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 2072-6694 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::0387947bd30dd924c7b6d68f0359fe27 https://www.mdpi.com/2072-6694/12/2/417 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....0387947bd30dd924c7b6d68f0359fe27 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20726694 |
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