Vandetanib and cabozantinib potentiate mitochondria-targeted agents to suppress medullary thyroid carcinoma cells
| Autor: | Jong-In Park, Pui Kei Wu, Dmytro Starenki, Seung-Keun Hong |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Cancer Research medicine.medical_specialty Cabozantinib Mitochondrion Vandetanib Receptor tyrosine kinase Thyroid carcinoma 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Internal medicine medicine Pharmacology biology Cell cycle In vitro 030104 developmental biology Endocrinology Oncology chemistry Cell culture 030220 oncology & carcinogenesis biology.protein Cancer research Molecular Medicine medicine.drug |
| Zdroj: | Cancer Biology & Therapy. 18:473-483 |
| ISSN: | 1555-8576 1538-4047 |
| Popis: | 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-naive as well as drug-resistant cells but only drug-naive 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. |
| Databáze: | OpenAIRE |
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