Induction of autophagy by sphingosine kinase 1 inhibitor PF-543 in head and neck squamous cell carcinoma cells

Hamada, Mareomi; Kameyama, Hiroyasu; Iwai, Shinichi; Yura, Yoshiaki

doi:10.1038/cddiscovery.2017.47

Cited by 28 publications

(20 citation statements)

References 39 publications

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“…SPHK inhibition, either genetically or pharmacologically, inhibited cell viability and proliferation, followed by the induction of LDH and ROS production. These results are supported by findings obtained by Hamada et al, who reported that SPHK1/2 is involved with cell death, proliferation, ROS production [74]. Furthermore, we observed that SPHKs are involved in inhibiting cancer-mediated inflammation.…”

Section: Discussionsupporting

confidence: 93%

A Stilbenoid Isorhapontigenin as a Potential Anti-Cancer Agent against Breast Cancer through Inhibiting Sphingosine Kinases/Tubulin Stabilization

Subedi

Teli

Lee

et al. 2019

Cancers

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Isorhapontigenin (ISO), a tetrahydroxylated stilbenoid, is an analog of resveratrol (Rsv). The various biological activities of Rsv and its derivatives have been previously reported in the context of both cancer and inflammation. However, the anti-cancer effect of ISO against breast cancer has not been well established, despite being an orally bioavailable dietary polyphenol. In this study, we determine the anti-cancer effects of ISO against breast cancer using MCF7, T47D, and MDA-MB-231 cell lines. We observed that ISO induces breast cancer cell death, cell cycle arrest, oxidative stress, and the inhibition of cell proliferation. Additionally, sphingosine kinase inhibition by ISO controlled tubulin polymerization and cancer cell growth by regulating MAPK/PI3K-mediated cell cycle arrest in MCF7 cells. Interestingly, SPHK1/2 gene silencing increased oxidative stress, cell death, and tubulin destabilization in MCF7 cells. This suggests that the anti-cancer effect of ISO can be regulated by SPHK/tubulin destabilization pathways. Overall, ISO successfully induced breast cancer cell death and cell growth arrest, suggesting this phytochemical is a better alternative for breast cancer treatment. Further studies in animal models could confirm the potency and usability of ISO over Rsv for targeting breast cancer, potentially posing an alternative candidate for improved therapy in the near future.

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Section: Discussionsupporting

confidence: 93%

A Stilbenoid Isorhapontigenin as a Potential Anti-Cancer Agent against Breast Cancer through Inhibiting Sphingosine Kinases/Tubulin Stabilization

Subedi

Teli

Lee

et al. 2019

Cancers

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“…Autophagy involves intracellular self‐degradation via double‐membrane organelles (autophagosomes), which transfer cytoplasmic material to lysosomes [26,27]. The pharmacological effects of CBD associated with autophagy have been demonstrated in numerous studies [14,20].…”

Section: Discussionmentioning

confidence: 99%

Cannabidiol alleviates hemorrhagic shock‐induced neural apoptosis in rats by inducing autophagy through activation of the PI3K/AKT pathway

Lin

Gao

et al. 2020

Fundamemntal Clinical Pharma

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Recently, several studies have reported that the pharmacological effects exerted by cannabidiol (CBD) are partially related to the regulation of autophagy. Increasing evidence indicates that autophagy provides protection against ischemia‐induced brain injury. However, the protective effect of CBD against mitochondrial‐dependent apoptosis in hemorrhagic shock (HS)‐induced brain injury has not been studied. In the present study, we observed the protective effects of CBD against neural mitochondrial‐dependent apoptosis in a rat model of HS. In addition, CBD increased Beclin‐1 and LC3II expression and reduced P62 expression, which were indicative of autophagy. CBD treatment attenuated the neural apoptosis induced by HS, as reflected by restoring mitochondrial dysfunction, downregulation of BAX, neuro‐apoptosis ratio and NF‐κB signaling activation, and upregulation of BCL2 in the cerebral cortex. Such protective effects were reversed by 3‐Methyladenine, a specific autophagy inhibitor, indicating that the protective effects of CBD treatment involved autophagy. LY294002, a PI3K inhibitor, significantly inhibited CBD‐induced autophagy, demonstrating that PI3K/AKT signaling is involved in the CBD’s regulation of autophagy. Furthermore, we found that CBD treatment upregulated PI3K/AKT signaling via cannabinoid receptor 1. Therefore, these findings suggested that CBD treatment protects against cerebral injury induced by HS‐mediated mitochondrial‐dependent apoptosis by activating the PI3K/AKT signaling pathway to reinforce autophagy.

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“…In animal studies, intravenous injection of PF543 significantly suppressed HCT-166 xenograft growth while markedly improving mouse survival [ 158 ]. Treatment of oral SCC cells with PF543 at a concentration of 25 μM reduced cell viability, and induced apoptosis, necrosis, and autophagy, although autophagy promoted cell survival [ 159 ]. At higher concentrations, the inhibitory effects of PF543 on cell proliferation and cell survival may be ascribed to its off-target effects on other cellular enzymes, including SphK2.…”

Section: Inhibitors Of Ceramide- and Sphingosine-metabolizing Enzymentioning

confidence: 99%

Inhibitors of Ceramide- and Sphingosine-Metabolizing Enzymes as Sensitizers in Radiotherapy and Chemotherapy for Head and Neck Squamous Cell Carcinoma

Yura

Masui

Hamada

2020

Cancers

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In the treatment of advanced head and neck squamous cell carcinoma (HNSCC), including oral SCC, radiotherapy is a commonly performed therapeutic modality. The combined use of radiotherapy with chemotherapy improves therapeutic effects, but it also increases adverse events. Ceramide, a central molecule in sphingolipid metabolism and signaling pathways, mediates antiproliferative responses, and its level increases in response to radiotherapy and chemotherapy. However, when ceramide is metabolized, prosurvival factors, such as sphingosine-1-phosphate (S1P), ceramide-1-phosphate (C1P), and glucosylceramide, are produced, reducing the antitumor effects of ceramide. The activities of ceramide- and sphingosine-metabolizing enzymes are also associated with radio- and chemo-resistance. Ceramide analogs and low molecular-weight compounds targeting these enzymes exert anticancer effects. Synthetic ceramides and a therapeutic approach using ultrasound have also been developed. Inhibitors of ceramide- and sphingosine-metabolizing enzymes and synthetic ceramides can function as sensitizers of radiotherapy and chemotherapy for HNSCC.

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Induction of autophagy by sphingosine kinase 1 inhibitor PF-543 in head and neck squamous cell carcinoma cells

Cited by 28 publications

References 39 publications

A Stilbenoid Isorhapontigenin as a Potential Anti-Cancer Agent against Breast Cancer through Inhibiting Sphingosine Kinases/Tubulin Stabilization

A Stilbenoid Isorhapontigenin as a Potential Anti-Cancer Agent against Breast Cancer through Inhibiting Sphingosine Kinases/Tubulin Stabilization

Cannabidiol alleviates hemorrhagic shock‐induced neural apoptosis in rats by inducing autophagy through activation of the PI3K/AKT pathway

Inhibitors of Ceramide- and Sphingosine-Metabolizing Enzymes as Sensitizers in Radiotherapy and Chemotherapy for Head and Neck Squamous Cell Carcinoma

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