Molecular and Functional Analysis of Sunitinib-Resistance Induction in Human Renal Cell Carcinoma Cells

Autor: Adriano Rutz, Magdalena Rausch, Mylène Docquier, Jean-Luc Wolfender, Olivier Dormond, Pierre-Marie Allard, Céline Delucinge-Vivier, Patrycja Nowak-Sliwinska
Jazyk: angličtina
Rok vydání: 2021
Předmět:
0301 basic medicine
sunitinib
Cyclin A
Cell
Fluorescent Antibody Technique
Gene Expression
urologic and male genital diseases
isomerization
Cell membrane
acquired drug resistance
0302 clinical medicine
Metabolites
Sunitinib
(clear cell) renal cell carcinoma
drug combination
metabolites
Biology (General)
Drug combination
Spectroscopy
ddc:615
biology
Chemistry
Cell Cycle
General Medicine
Cell cycle
Renal cell carcinoma
Kidney Neoplasms
female genital diseases and pregnancy complications
Computer Science Applications
medicine.anatomical_structure
030220 oncology & carcinogenesis
medicine.drug
Isomerization
QH301-705.5
Antineoplastic Agents
Models
Biological
Catalysis
Article
Inorganic Chemistry
03 medical and health sciences
Downregulation and upregulation
Cell Line
Tumor
medicine
Extracellular
Humans
Physical and Theoretical Chemistry
Carcinoma
Renal Cell
Protein Kinase Inhibitors
QD1-999
Molecular Biology
Gene Expression Profiling
Organic Chemistry
medicine.disease
Clear cell renal cell carcinoma
030104 developmental biology
Drug Resistance
Neoplasm
Cancer research
biology.protein
Acquired drug resistance
Biomarkers
Zdroj: International Journal of Molecular Sciences
International Journal of Molecular Sciences, Vol 22, Iss 6467, p 6467 (2021)
Volume 22
Issue 12
International journal of molecular sciences, vol. 22, no. 12, pp. 6467
International journal of molecular sciences, Vol. 22, No 12 (2021) P. 6467
ISSN: 1422-0067
Popis: Resistance in clear cell renal cell carcinoma (ccRCC) against sunitinib is a multifaceted process encompassing numerous molecular aberrations. This induces clinical complications, reducing the treatment success. Understanding these aberrations helps us to select an adapted treatment strategy that surpasses resistance mechanisms, reverting the treatment insensitivity. In this regard, we investigated the dominant mechanisms of resistance to sunitinib and validated an optimized multidrug combination to overcome this resistance. Human ccRCC cells were exposed to single or chronic treatment with sunitinib to obtain three resistant clones. Upon manifestation of sunitinib resistance, morphometric changes in the cells were observed. At the molecular level, the production of cell membrane and extracellular matrix components, chemotaxis, and cell cycle progression were dysregulated. Molecules enforcing the cell cycle progression, i.e., cyclin A, B1, and E, were upregulated. Mass spectrometry analysis revealed the intra- and extracellular presence of N-desethyl sunitinib, the active metabolite. Lysosomal sequestration of sunitinib was confirmed. After treatment with a synergistic optimized drug combination, the cell metabolic activity in Caki-1-sunitinib-resistant cells and 3D heterotypic co-cultures was reduced by >
80%, remaining inactive in non-cancerous cells. These results demonstrate geno- and phenotypic changes in response to sunitinib treatment upon resistance induction. Mimicking resistance in the laboratory served as a platform to study drug responses.
Databáze: OpenAIRE
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