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Targeting sphingosine kinase 1/2 by a novel dual inhibitor SKI-349 suppresses non-small cell lung cancer cell growth.

ABSTRACT: Sphingosine kinase 1 (SphK1) and sphingosine kinase (SphK2) are both important therapeutic targets of non-small cell lung cancer (NSCLC). SKI-349 is a novel, highly efficient and small molecular SphK1/2 dual inhibitor. Here in primary human NSCLC cells and immortalized cell lines, SKI-349 potently inhibited cell proliferation, cell cycle progression, migration and viability. The dual inhibitor induced mitochondrial depolarization and apoptosis activation in NSCLC cells, but it was non-cytotoxic to human lung epithelial cells. SKI-349 inhibited SphK activity and induced ceramide accumulation in primary NSCLC cells, without affecting SphK1/2 expression. 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. Moreover, SKI-349 induced Akt-mTOR inactivation, JNK activation, and oxidative injury in primary NSCLC cells. 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. At last, SKI-349 (10 mg/kg) administration inhibited NSCLC xenograft growth in nude mice. Akt-mTOR inhibition, JNK activation, oxidative injury and BRD4 downregulation were detected in SKI-349-treated NSCLC xenograft tissues. Taken together, targeting SphK1/2 by SKI-349 potently inhibits NSCLC cell growth in vitro and in vivo.

SUBMITTER: Xue Y

PROVIDER: S-EPMC9279331 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundGlioblastoma patients commonly develop resistance to temozolomide chemotherapy. Hypoxia, which supports chemotherapy resistance, favors the expansion of glioblastoma stem cells (GSC), contributing to tumor relapse. Because of a deregulated sphingolipid metabolism, glioblastoma tissues contain high levels of the pro-survival sphingosine-1-phosphate and low levels of the pro-apoptotic ceramide. The latter can be metabolized to sphingosine-1-phosphate by sphingosine kinase (SK) 1 that is overexpressed in glioblastoma. The small molecule SKI-II inhibits SK and dihydroceramide desaturase 1, which converts dihydroceramide to ceramide. We previously reported that SKI-II combined with temozolomide induces caspase-dependent cell death, preceded by dihydrosphingolipids accumulation and autophagy in normoxia. In the present study, we investigated the effects of a low-dose combination of temozolomide and SKI-II under normoxia and hypoxia in glioblastoma cells and patient-derived GCSs.MethodsDrug synergism was analyzed with the Chou-Talalay Combination Index method. Dose-effect curves of each drug were determined with the Sulforhodamine B colorimetric assay. Cell death mechanisms and autophagy were analyzed by immunofluorescence, flow cytometry and western blot; sphingolipid metabolism alterations by mass spectrometry and gene expression analysis. GSCs self-renewal capacity was determined using extreme limiting dilution assays and invasion of glioblastoma cells using a 3D spheroid model.ResultsTemozolomide resistance of glioblastoma cells was increased under hypoxia. However, combination of temozolomide (48 µM) with SKI-II (2.66 µM) synergistically inhibited glioblastoma cell growth and potentiated glioblastoma cell death relative to single treatments under hypoxia. This low-dose combination did not induce dihydrosphingolipids accumulation, but a decrease in ceramide and its metabolites. It induced oxidative and endoplasmic reticulum stress and triggered caspase-independent cell death. It impaired the self-renewal capacity of temozolomide-resistant GSCs, especially under hypoxia. Furthermore, it decreased invasion of glioblastoma cell spheroids.ConclusionsThis in vitro study provides novel insights on the links between sphingolipid metabolism and invasion, a hallmark of cancer, and cancer stem cells, key drivers of cancer. It demonstrates the therapeutic potential of approaches that combine modulation of sphingolipid metabolism with first-line agent temozolomide in overcoming tumor growth and relapse by reducing hypoxia-induced resistance to chemotherapy and by targeting both differentiated and stem glioblastoma cells.

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Targeting sphingosine kinase 1/2 by a novel dual inhibitor SKI-349 suppresses non-small cell lung cancer cell growth.

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