Targeting the Sphingosine Kinase/Sphingosine-1-Phosphate Signaling Axis in Drug Discovery for Cancer Therapy

Gupta, Preeti; Taiyab, Aaliya; Hussain, Afzal; Alajmi, Mohamed F.; Islam, Asimul; Hassan, Md. Imtaiyaz

doi:10.3390/cancers13081898

Cited by 48 publications

(38 citation statements)

References 233 publications

(180 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These inhibitors of de novo ceramide synthesis are potent, with IC 50 = 1–100 nM, , and have been used extensively to downregulate ceramide production (Table S1). We also used D-PPMP, GW4869, DPTIP, and NVP-231 to target the production of downstream sphingolipid-related enzymes, glucosylceramide synthase, neutral sphingomyelinase, and ceramide kinase, respectively. − Finally, D-NMAPPD, dimethylsphingosine, PF-543, ABC294640, and FTY720P were used to inhibit acid ceramidase, sphingosine kinase 1 and 2, and a sphingosine-1-phosphate receptor, respectively. − …”

Section: Resultsmentioning

confidence: 99%

Ceramide-1-Phosphate Is Involved in Therapy-Induced Senescence

et al. 2022

View full text Add to dashboard Cite

Sphingolipids are key signaling lipids and their dysregulation has been associated with various cellular processes. We have previously shown significant changes in sphingolipids in therapy-induced senescence, a state of cell cycle arrest as a response to chemotherapy, including the accumulation of ceramides, and provided evidence suggesting that ceramide processing is important for this process. Herein, we conducted a focused small molecule inhibitor screen targeting the sphingolipid pathway, which highlighted a new lipid regulator of therapy-induced senescence. Among the inhibitors tested, the inhibition of ceramide kinase by NVP-231 reduced the levels of senescent cells. Ceramide kinase knockdown exhibited similar effects, strongly supporting the involvement of ceramide kinase during this process. We showed that ceramide-1-phosphate was upregulated in therapy-induced senescence and that NVP-231 reduced ceramide-1-phosphate levels in different cell line models of therapy-induced senescence. Finally, ceramide-1-phosphate addition to NVP-231-treated cells reversed the effects of NVP-231 during senescence. Overall, our results identify a previously unknown lipid player in therapy-induced senescence and highlight a potential targetable enzyme to reduce the levels of therapy-induced senescent cells.

show abstract

Section: Resultsmentioning

confidence: 99%

Ceramide-1-Phosphate Is Involved in Therapy-Induced Senescence

et al. 2022

View full text Add to dashboard Cite

show abstract

“…S1P is a sphingolipid metabolite produced by the sphingosine kinases (SphKs) 1 and 2 that is increased in TME and was considered as a promising therapeutic target in the control of cancer growth [110]. S1P is secreted by tumor cells and was found in high concentrations in TME [111].…”

Section: Bioactive Lipids As Key Molecules Involved In Mc-tumor Interactionsmentioning

confidence: 99%

Mast Cell–Tumor Interactions: Molecular Mechanisms of Recruitment, Intratumoral Communication and Potential Therapeutic Targets for Tumor Growth

Segura-Villalobos

Ramírez-Moreno

Martínez-Aguilar

et al. 2022

Cells

View full text Add to dashboard Cite

Mast cells (MCs) are tissue-resident immune cells that are important players in diseases associated with chronic inflammation such as cancer. Since MCs can infiltrate solid tumors and promote or limit tumor growth, a possible polarization of MCs to pro-tumoral or anti-tumoral phenotypes has been proposed and remains as a challenging research field. Here, we review the recent evidence regarding the complex relationship between MCs and tumor cells. In particular, we consider: (1) the multifaceted role of MCs on tumor growth suggested by histological analysis of tumor biopsies and studies performed in MC-deficient animal models; (2) the signaling pathways triggered by tumor-derived chemotactic mediators and bioactive lipids that promote MC migration and modulate their function inside tumors; (3) the possible phenotypic changes on MCs triggered by prevalent conditions in the tumor microenvironment (TME) such as hypoxia; (4) the signaling pathways that specifically lead to the production of angiogenic factors, mainly VEGF; and (5) the possible role of MCs on tumor fibrosis and metastasis. Finally, we discuss the novel literature on the molecular mechanisms potentially related to phenotypic changes that MCs undergo into the TME and some therapeutic strategies targeting MC activation to limit tumor growth.

show abstract

“…More recently, C6-ceramide was reported to reduce the cell viability of cutaneous T-cell lymphomas [21]. In this review, we focus mainly on another important bioactive sphingolipid, S1P, its role in immune homeostasis and its involvement in homeostatic dysregulation of the GI immune system, GALT, in inflammation [22][23][24][25][26][27][28][29]. S1P action in acute and persistent low-grade inflammation of the digestive system, from top to bottom, is discussed, with reference to a recent review by Sukocheva et al [22].…”

Section: Cancer Typementioning

confidence: 99%

Targeting Chronic Inflammation of the Digestive System in Cancer Prevention: Modulators of the Bioactive Sphingolipid Sphingosine-1-Phosphate Pathway

McGowan

Lin

Chen

2022

Cancers

View full text Add to dashboard Cite

Incidence of gastrointestinal (GI) cancers is increasing, and late-stage diagnosis makes these cancers difficult to treat. Chronic and low-grade inflammation are recognized risks for most GI cancers. The GI mucosal immune system maintains healthy homeostasis and signalling molecules made from saturated fats, bioactive sphingolipids, play essential roles in healthy GI immunity. Sphingosine-1-phosphate (S1P), a bioactive sphingolipid, is a key mediator in a balanced GI immune response. Disruption in the S1P pathway underlies systemic chronic metabolic inflammatory disorders, including diabetes and GI cancers, providing a strong rationale for using modulators of the S1P pathway to treat pathological inflammation. Here, we discuss the effects of bioactive sphingolipids in immune homeostasis with a focus on S1P in chronic low-grade inflammation associated with increased risk of GI carcinogenesis. Contemporary information on S1P signalling involvement in cancers of the digestive system, from top to bottom, is reviewed. Further, we discuss the use of novel S1P receptor modulators currently in clinical trials and their potential as first-line drugs in the clinic for chronic inflammatory diseases. Recently, ozanimod (ZeposiaTM) and etrasimod have been approved for clinical use to treat ulcerative colitis and eosinophilic oesophagitis, respectively, which may have longer term benefits in reducing risk of GI cancers.

show abstract

Targeting the Sphingosine Kinase/Sphingosine-1-Phosphate Signaling Axis in Drug Discovery for Cancer Therapy

Cited by 48 publications

References 233 publications

Ceramide-1-Phosphate Is Involved in Therapy-Induced Senescence

Ceramide-1-Phosphate Is Involved in Therapy-Induced Senescence

Mast Cell–Tumor Interactions: Molecular Mechanisms of Recruitment, Intratumoral Communication and Potential Therapeutic Targets for Tumor Growth

Targeting Chronic Inflammation of the Digestive System in Cancer Prevention: Modulators of the Bioactive Sphingolipid Sphingosine-1-Phosphate Pathway

Contact Info

Product

Resources

About