Involvement of the tumour necrosis factor receptor system in glioblastoma cell death induced by palbociclib-heptamethine cyanine dye conjugate

Glioblastoma is the most common and aggressive primary brain tumour in adults. The development of anti-brain cancer agents are challenged by the blood-brain barrier and the resistance conferred by the local tumour microenvironment. Heptamethine cyanine dyes (HMCDs) are a class of near-infrared fluor...

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Published in:	Cell communication and signaling Vol. 22; no. 1; p. 30
Main Authors:	Cooper, Elizabeth, Oyagawa, Caitlin R M, Johnson, Rebecca, Choi, Peter J, Foliaki, Jena Macapagal, Correia, Jason, Schweder, Patrick, Heppner, Peter, Mee, Edward, Turner, Clinton, Faull, Richard, Denny, William A, Dragunow, Mike, Jose, Jiney, Park, Thomas I-H
Format:	Journal Article
Language:	English
Published:	England BioMed Central 11-01-2024 BMC
Subjects:	Antineoplastic Agents - pharmacology Antineoplastic Agents - therapeutic use Apoptosis Blood-brain barrier Brain cancer Brain research Brain tumors Breast cancer Cancer therapies Carbocyanines Caspase-8 Cell cycle Cell death Cell growth Cell Line, Tumor Cell surface Clinical trials Cyclin-dependent kinase Cyclin-dependent kinases Cytostatic Agents - pharmacology Cytostatic Agents - therapeutic use Cytotoxicity DNA damage Drug delivery Dyes Endocytosis FADD protein Fatalities Glioblastoma Glioblastoma - drug therapy Glioblastoma - metabolism Glioblastoma cells Humans Immunotherapy Indoles Inflammation Kinases Medical research NF-κB protein p53 Protein Patients Piperazines Pyridines Radiation Receptors, Tumor Necrosis Factor - physiology Receptors, Tumor Necrosis Factor - therapeutic use Receptors, Tumor Necrosis Factor, Type I - metabolism Signal transduction siRNA Toxicity Tumor Microenvironment Tumor necrosis factor receptors Tumor Necrosis Factor-alpha - pharmacology Tumor necrosis factor-TNF Tumor necrosis factor-α Tumors
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Summary:	Glioblastoma is the most common and aggressive primary brain tumour in adults. The development of anti-brain cancer agents are challenged by the blood-brain barrier and the resistance conferred by the local tumour microenvironment. Heptamethine cyanine dyes (HMCDs) are a class of near-infrared fluorescence compounds that have recently emerged as promising agents for drug delivery. We conjugated palbociclib, a cyclin-dependent kinase (CDK) 4/6 inhibitor, to an HMCD, MHI-148, and conducted drug activity analysis on primary patient-derived glioblastoma cell lines. In addition to the expected cytostatic activity, our in vitro studies revealed that palbociclib-MHI-148 conjugate resulted in an almost 100-fold increase in cytotoxicity compared to palbociclib alone. This shift of palbociclib from cytostatic to cytotoxic when conjugated to MHI-148 was due to increased DNA damage, as indicated by an increase in γH2AX foci, followed by an increased expression of key extrinsic apoptosis genes, including TP53, TNFR1, TRAIL, FADD and caspase 8. In addition, we observed a time-dependent increase in the cell surface expression of TNFR1, consistent with an observed increase in the secretion TNFα, followed by TNFR1 endocytosis at 48 h. The treatment of patient GBM cells with the palbociclib-MHI-148 conjugate prevented TNFα-induced NFκB translocation, suggesting conjugate-induced TNFR1 signalling favoured the TNFR1-mediated apoptotic response rather than the pro-inflammatory response pathway. Notably, pharmacological inhibition of endocytosis of TNFR1, and siRNA-knockdown of TNFR1 reversed the palbociclib-MHI-148-induced cell death. These results show a novel susceptibility of glioblastoma cells to TNFR1-dependent apoptosis, dependent on inhibition of canonical NFκB signalling using our previously reported palbociclib-HMCD conjugate. Video Abstract.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Undefined-1 ObjectType-Feature-3 content type line 23
ISSN:	1478-811X 1478-811X
DOI:	10.1186/s12964-023-01277-z