دورية أكاديمية
أعرض في EDS

5-FU resistant EMT-like pancreatic cancer cells are hypersensitive to photochemical internalization of the novel endoglin-targeting immunotoxin CD105-saporin.

التفاصيل البيبلوغرافية
العنوان: 5-FU resistant EMT-like pancreatic cancer cells are hypersensitive to photochemical internalization of the novel endoglin-targeting immunotoxin CD105-saporin.
المؤلفون: Lund K; Unit for Cell Signaling, Institute of Microbiology, Rikshospitalet, 0372, Oslo, Norway. Kaja.Lund@rr-research.no.; Hybrid Technology Hub - Centre of Excellence, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, PO Box 1112, Blindern, 0317, Oslo, Norway. Kaja.Lund@rr-research.no., Olsen CE; Department of Radiation Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, 0379, Oslo, Norway., Wong JJW; Department of Radiation Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, 0379, Oslo, Norway., Olsen PA; Unit for Cell Signaling, Institute of Microbiology, Rikshospitalet, 0372, Oslo, Norway.; Hybrid Technology Hub - Centre of Excellence, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, PO Box 1112, Blindern, 0317, Oslo, Norway., Solberg NT; Unit for Cell Signaling, Institute of Microbiology, Rikshospitalet, 0372, Oslo, Norway.; Hybrid Technology Hub - Centre of Excellence, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, PO Box 1112, Blindern, 0317, Oslo, Norway., Høgset A; PCI Biotech AS, Ullernchaussèn 64, 0379, Oslo, Norway., Krauss S; Unit for Cell Signaling, Institute of Microbiology, Rikshospitalet, 0372, Oslo, Norway.; Hybrid Technology Hub - Centre of Excellence, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, PO Box 1112, Blindern, 0317, Oslo, Norway., Selbo PK; Department of Radiation Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, 0379, Oslo, Norway. selbo@rr-research.no.
المصدر: Journal of experimental & clinical cancer research : CR [J Exp Clin Cancer Res] 2017 Dec 19; Vol. 36 (1), pp. 187. Date of Electronic Publication: 2017 Dec 19.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: BioMed Central Country of Publication: England NLM ID: 8308647 Publication Model: Electronic Cited Medium: Internet ISSN: 1756-9966 (Electronic) Linking ISSN: 03929078 NLM ISO Abbreviation: J Exp Clin Cancer Res Subsets: MEDLINE
أسماء مطبوعة: Publication: 2009- : London : BioMed Central
Original Publication: [Roma] : APSIT,
مواضيع طبية MeSH: Adenocarcinoma/*pathology , Immunotoxins/*pharmacology , Pancreatic Neoplasms/*pathology , Photosensitizing Agents/*pharmacology , Porphyrins/*pharmacology, Antineoplastic Agents ; Autophagy/drug effects ; Cell Line, Tumor ; Drug Resistance, Neoplasm/drug effects ; Endoglin/antagonists & inhibitors ; Epithelial-Mesenchymal Transition ; Fluorouracil ; Humans ; Phototherapy/methods ; Ribosome Inactivating Proteins, Type 1/pharmacology ; Saporins
مستخلص: Background: Development of resistance to 5-fluorouracil (5-FU) is a major problem in treatment of various cancers including pancreatic cancer. In this study, we reveal important resistance mechanisms and photochemical strategies to overcome 5-FU resistance in pancreatic adenocarcinoma.
Methods: 5-FU resistant (5-FUR), epithelial-to-mesenchymal-like sub-clones of the wild type pancreatic cancer cell line Panc03.27 were previously generated in our lab. We investigated the cytotoxic effect of the endosomal/lysosomal-localizing photosensitizer TPCS 2a (fimaporfin) combined with light (photochemical treatment, PCT) using MTS viability assay, and used fluorescence microscopy to show localization of TPCS 2a and to investigate the effect of photodamage of lysosomes. Flow cytometric analysis was performed to investigate uptake of photosensitizer and to assess intracellular ROS levels. Expression and localization of LAMP1 was assessed using RT-qPCR, western blotting, and structured illumination microscopy. MTS viability assay was used to assess the effect of combinations of 5-FU, chloroquine (CQ), and photochemical treatment. Expression of CD105 was investigated using RT-qPCR, western blotting, flow cytometry, and fluorescence microscopy, and co-localization of TPCS 2a and anti-CD105-saporin was assessed using microscopy. Lastly, the MTS assay was used to investigate cytotoxic effects of photochemical internalization (PCI) of the anti-CD105-immunotoxin.
Results: The 5-FUR cell lines display hypersensitivity to PCT, which was linked to increased uptake of TPCS 2a , altered lysosomal distribution, lysosomal photodamage and increased expression of the lysosomal marker LAMP-1 in the 5-FUR cells. We show that inhibition of autophagy induced by either chloroquine or lysosomal photodamage increases the sensitivity to 5-FU in the resistant cells. The three 5-FUR sub-clones overexpress Endoglin (CD105). Treatment with the immunotoxin anti-CD105-saporin alone significantly reduced the viability of the CD105-expressing 5-FUR cells, whereas little effect was seen in the CD105-negative non-resistant parental cancer cell lines. Strikingly, using the intracellular drug delivery method photochemical internalization (PCI) by combining light-controlled activation of the TPCS 2a with nanomolar levels of CD105-saporin resulted in strong cytotoxic effects in the 5-FUR cell population.
Conclusion: Our findings suggested that autophagy is an important resistance mechanism against the chemotherapeutic drug 5-FU in pancreatic cancer cells, and that inhibition of the autophagy process, either by CQ or lysosomal photodamage, can contribute to increased sensitivity to 5-FU. For the first time, we demonstrate the promise of PCI-based targeting of CD105 in site-specific elimination of 5-FU resistant pancreatic cancer cells in vitro. In conclusion, PCI-based targeting of CD105 may represent a potent anticancer strategy and should be further evaluated in pre-clinical models.
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معلومات مُعتمدة: 33445 Kreftforeningen; 2016023 Helse Sør-Øst RHF; 2017068 Helse Sør-Øst RHF; FU0803 The Norwegian Radium Hospital Research Foundation; SE1603 The Norwegian Radium Hospital Research Foundation
فهرسة مساهمة: Keywords: 5-FU resistance; Autophagy; CD105; Endoglin; Pancreatic cancer; Photochemical internalization
المشرفين على المادة: 0 (Antineoplastic Agents)
0 (ENG protein, human)
0 (Endoglin)
0 (Immunotoxins)
0 (Photosensitizing Agents)
0 (Porphyrins)
0 (Ribosome Inactivating Proteins, Type 1)
0 (meso-tetraphenyl chlorin disulphonate)
EC 3.2.2.22 (Saporins)
U3P01618RT (Fluorouracil)
تواريخ الأحداث: Date Created: 20171221 Date Completed: 20180905 Latest Revision: 20231112
رمز التحديث: 20231215
مُعرف محوري في PubMed: PMC5738190
DOI: 10.1186/s13046-017-0662-6
PMID: 29258566
قاعدة البيانات: MEDLINE
الوصف
تدمد:1756-9966
DOI:10.1186/s13046-017-0662-6