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Vandetanib and cabozantinib potentiate mitochondria-targeted agents to suppress medullary thyroid carcinoma cells. Cancer Biol Ther 2017 Jul 03;18(7):473-483

Date

05/06/2017

Pubmed ID

28475408

Pubmed Central ID

PMC5639831

DOI

10.1080/15384047.2017.1323594

Scopus ID

2-s2.0-85020693671   9 Citations

Abstract

Although the FDA-approved receptor tyrosine kinases inhibitors, vandetanib and cabozantinib, are used to treat surgically inoperable progressive medullary thyroid carcinoma (MTC), not all patients are responsive while the disease sometimes progresses after an initial response. To better understand MTC drug resistance at molecular and biochemical levels, we have generated drug-resistant subpopulations of the human MTC cell lines, TT and MZ-CRC-1, via prolonged exposure to vandetanib and cabozantinib. These drug-resistant progenies exhibited substantial cross-resistance to vandetanib and cabozantinib, suggesting that these inhibitors may invoke an overlapping resistance mechanism(s) in MTC cells. Of note, vandetanib and cabozantinib increased mitochondrial membrane potential (Δψm) in drug-naïve as well as drug-resistant cells but only drug-naïve cells exhibited substantially altered oxygen consumption and extracellular acidification rates. Therefore, these inhibitors appear to cause a bioenergetics stress to which drug-resistant MTC cells are more tolerant. Given the ability of vandetanib and cabozantinib to increase Δψm, we hypothesized that these inhibitors can augment growth inhibitory effects of mitochondria-targeted carboxy-proxyl and ubiquinone by increasing their Δψm-dependent uptake/retention in MTC cells. Indeed, our in vitro and mouse xenograft data strongly support this possibility.

Author List

Starenki D, Hong SK, Wu PK, Park JI

Authors

Jong-In Park PhD Professor in the Biochemistry department at Medical College of Wisconsin
Pui Kei Wu PhD Instructor in the Biochemistry department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Anilides
Animals
Carcinoma, Neuroendocrine
Cell Cycle
Cell Line, Tumor
Cell Survival
Disease Models, Animal
Drug Resistance, Neoplasm
Gene Expression Regulation, Neoplastic
Humans
Membrane Potential, Mitochondrial
Mice
Mitochondria
Mitochondrial Dynamics
Piperidines
Protein Kinase Inhibitors
Pyridines
Quinazolines
Thyroid Neoplasms
Xenograft Model Antitumor Assays
jenkins-FCD Prod-482 91ad8a360b6da540234915ea01ff80e38bfdb40a