PPARα ligand, AVE8134, and cyclooxygenase inhibitor therapy synergistically suppress lung cancer growth and metastasis

Autor: Meiyan Dai, Huihui Li, Lujin Wu, Wei Wang, Dao Wen Wang, Chen Chen
Jazyk: angličtina
Rok vydání: 2019
Předmět:
0301 basic medicine
MAPK/ERK pathway
Cancer Research
Lung Neoplasms
Angiogenesis
Indomethacin
Drug Evaluation
Preclinical
Benzoates
11-HETE
Metastasis
Mice
0302 clinical medicine
Cell Movement
Neoplasm Metastasis
Oxazoles
Mice
Knockout
biology
Neovascularization
Pathologic
Chemistry
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Treatment Outcome
Oncology
030220 oncology & carcinogenesis
Drug Therapy
Combination
EETs
Lung cancer
medicine.drug
Research Article
Antineoplastic Agents
lcsh:RC254-282
AVE8134
03 medical and health sciences
In vivo
Cell Line
Tumor
Genetics
medicine
Animals
Cyclooxygenase Inhibitors
PPAR alpha
Cytochrome P450 Family 2
Protein kinase B
Cell Proliferation
Bezafibrate
PPARα agonist
medicine.disease
Xenograft Model Antitumor Assays
Mice
Inbred C57BL
030104 developmental biology
Pyrimidines
Eicosanoid
biology.protein
Cancer research
Eicosanoids
Cyclooxygenase
Zdroj: BMC Cancer
BMC Cancer, Vol 19, Iss 1, Pp 1-16 (2019)
ISSN: 1471-2407
Popis: BackgroundLung cancer (LC) is one of the leading causes of death worldwide, which highlights the urgent need for better therapies. Peroxisome proliferator-activated nuclear receptor alpha (PPARα), known as a key nuclear transcription factor involved in glucose and lipid metabolism, has been also implicated in endothelial proliferation and angiogenesis. However, the effects and potential mechanisms of the novel PPARα ligand, AVE8134, on LC growth and progression remain unclear.MethodsA subcutaneous tumour was established in mice by injecting TC-1 lung tumour cells (~ 1 × 106cells) into their shaved left flank. These mice were treated with three different PPARα ligands: AVE8134 (0.025% in drinking water), Wyeth-14,643 (0.025%), or Bezafibrate (0.3%). Tumour sizes and metastasis between treated and untreated mice were then compared by morphology and histology, and the metabolites of arachidonic acid (AA) were detected by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Inhibition of either Cyp2c44 expression by genetic disruption or cyclooxygenase (COX) activity by indomethacin was used to test the mechanisms by which AVE8134 affects tumour growth.ResultsThe pharmacodynamics effects of AVE8134, Wyeth-14,643, and Bezafibrate on lipids control were similar. However, their effects on tumour suppression were different. Eicosanoid profile analysis showed that all PPARα ligands reduced the production of AA-derived epoxyeicosatrienoic acids (EETs) and increased the hydroxyl product, 11-hydroxyeicosatetraenoic acids (11-HETE). Moreover, increased 11-HETE promoted endothelial proliferation, angiogenesis, and subsequent tumour deterioration in a dose-dependent manner possibly via activating the AKT/extracellular signal-regulated kinase (ERK) pathway. The increased 11-HETE partly neutralized the benefits provided by the Cyp2c44-EETs system inhibited by PPARα ligands in tumour-bearing mice. AVE8134 treatment worsened the tumour phenotype in Cyp2c44 knockout mice, indicating that AVE8134 has contradictory effects on tumour growth. The COX inhibitor indomethacin strengthened the inhibitory actions of AVE8134 on tumour growth and metastasis by inhibiting the 11-HETE production in vivo and in vitro.ConclusionIn this study, we found that the degrees of inhibition on LC growth and metastasis by PPARα ligands depended on their bidirectional regulation on EETs and 11-HETE. Considering their safety and efficacy, the novel PPARα ligand, AVE8134, is a potentially ideal anti-angiogenesis drug for cancer treatment when jointly applied with the COX inhibitor indomethacin.
Databáze: OpenAIRE
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