![]() ![]() Therefore, uncovering the molecular mechanisms of NSCLC and identifying novel biomarkers could be crucial for early diagnosis and better treatment. Metastatic, recurrent and other advanced NSCLC have very limited clinical treatment options and patients are often with extremely poor prognosis. Among them, NSCLC accounts for over 80–85% of all lung cancer. There are two main subtypes of lung cancer, small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). ![]() Lung cancer is still a common global malignancy and a leading cause of cancer-related human mortalities. Taken together, targeting SphK1/2 by SKI-349 potently inhibits NSCLC cell growth in vitro and in vivo. Akt-mTOR inhibition, JNK activation, oxidative injury and BRD4 downregulation were detected in SKI-349-treated NSCLC xenograft tissues. At last, SKI-349 (10 mg/kg) administration inhibited NSCLC xenograft growth in nude mice. In addition, SKI-349 decreased bromodomain-containing protein 4 (BRD4) expression and downregulated BRD4-dependent genes ( Myc, cyclin D1 and Klf4) in primary NSCLC cells. Moreover, SKI-349 induced Akt-mTOR inactivation, JNK activation, and oxidative injury in primary NSCLC cells. SKI-349-induced NSCLC cell death was attenuated by sphingosine-1-phosphate and by the SphK activator K6PC-5, but was potentiated by the short-chain ceramide C6. SKI-349 inhibited SphK activity and induced ceramide accumulation in primary NSCLC cells, without affecting SphK1/2 expression. The dual inhibitor induced mitochondrial depolarization and apoptosis activation in NSCLC cells, but it was non-cytotoxic to human lung epithelial cells. Here in primary human NSCLC cells and immortalized cell lines, SKI-349 potently inhibited cell proliferation, cell cycle progression, migration and viability. SKI-349 is a novel, highly efficient and small molecular SphK1/2 dual inhibitor. Sphingosine kinase 1 (SphK1) and sphingosine kinase (SphK2) are both important therapeutic targets of non-small cell lung cancer (NSCLC).
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