Mouse weights and PAX165 tumor volumes were measured. Tumor volumes in the upamostat, opaganib, and upamostat plus opaganib groups were significantly decreased compared to the control group.

This strong synergistic effect is due to multiple mechanisms of action, i.e., inhibiting MCL-1 through SPHK1 inhibition, leading to ceramide accumulation, activation of protein kinase R, ATF4 upregulation, and NOXA activation, ultimately resulting in MCL-1 degradation. These combination therapies warrant further consideration and investigation in the search for a more comprehensive treatment strategy for AML.

This molecular modeling analysis was carried out by using combined techniques: docking calculations, MD simulations and QTAIM analysis. In this study we also included PF543, as reference compound, in order to better understand the molecular behavior of these ligands at the binding site of SphK1.These results provide useful information for the design of new inhibitors of SphK1 possessing these structural scaffolds.

This is associated with a decrease in overall DNA methylation. These discoveries help to clarify the connection between SPHK2 and the response to DNA damage, as well as its capacity to aid in the resistance against genotoxic agents, including those used in cancer treatment.

Further, the docking and 100 ns MD simulation studies showed that CA, SA, and MF bind with the active site residues of SphK1 with favorable energy and strong non-covalent interactions that might be accountable for inhibiting its kinase activity. Our finding indicates that CA, SA, and MF may be implicated in designing novel anti-cancer therapeutics with an improved affinity and lesser side effects by targeting SphK1.

Taken together, our findings uncover a previously uncharacterized mechanism underlying liver-metastasis of FMC and provide new insights into prognosis and treatment of this feline malignancy.

Our study demonstrated that inhibition of SK2 enhances anti-tumor immunity by promoting CD8 T cell activation likely through IL-36gamma and KLK1B22. These studies provide rationale for clinical trials investigating the combination of opaganib with CAR T therapy or other immunotherapy in cancer treatment.

Overall, our studies demonstrate that SKs are key players in oncogenic, but not in physiological, IL-7/IL-7R-mediated signaling. We uncover the importance of the SK-IL7R signaling crosstalk in ALL and pinpoint the therapeutic potential of SK inhibitors for IL-7R-dependent ALL.

Notably, these selected hit compounds exhibited a higher affinity towards the SK1 binding pocket when compared to the positive control compound (PF-543). Furthermore, these compounds were found to meet the necessary drug like criteria, thus rendering them suitable candidates for further experimental validation as potential anticancer agents.

Inducible deletion of Sphk1 or its pharmacological inhibition drive increased cell death in tumors which is accompanied by selective accumulation of sphingosine levels. These results demonstrate the relevance of SK1 in the growth and maintenance of lymphoma in the absence of p53 function, positioning this enzyme as a potential therapeutic target for the treatment of tumors that lack functional p53.

SphK has been implicated in a variety of liver diseases, such as steatosis, liver fibrosis, hepatocellular carcinoma, and hepatic failure. This study may advance the understanding of the cellular and molecular foundations of liver disease and establish therapeutic approaches via SphK modulation.

Molecular dynamics simulations were carried out to analyze the detailed interactions between the SphK2 and its inhibitors. Moreover, 12e exhibited anti-proliferative activity in various cancer cells, and inhibited the migration of human breast cancer cells MCF-7.

High pSphK1 expression is independently associated with lymphatic invasion and unfavorable prognosis in PDAC patients. Thus, the SphK1-S1P axis may be important in mechanisms of tumor progression, such as lymphatic invasion, in PDAC patients.

The analysis of the time evolution data of structural deviations, compactness, PCA, and free energy landscape (FEL) indicated that the binding of CID:58293960 with SphK1 is relatively stable throughout the simulation. The results of this study provide a platform for the discovery and development of new anticancer therapeutics targeting SphK1.

This 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.

SPHK1 is abnormally overexpressed in human ccRCC. Patients with ccRCC may benefit from treatments that target SPHK1, which may also serve as a prognostic indicator.

We previously reported that the sphingosine kinase 1 and 2 (SPHK1/2) inhibitor, SKI-II enhanced the in vitro cell death triggered by fludarabine, bendamustine or ibrutinib and reduced the activation and proliferation of CLL cells [6]...More importantly, SKI-II and opaganib prevented the generation of venetoclax- esistance induced by aaT cells (Figure 1(E)) by reducing the upregulation of BCL-XL and/or MCL-1 on malignant cells (Figure 1(F))... Venetoclax-resistant CLL cells express high levels of SPHK2. Both SPHK inhibitors reduce the activation and proliferation of CLL cells, diminish the generation of venetoclax- resistance and re-sensitize already venetoclax-resistant CLL cells to the drug, suggesting that the inhibition of SHPK2 may be involved in this process. Our results highlight the therapeutic potential of SPHK inhibitors in combination with venetoclax as a promising treatment option for the patients.

The significant antileukemic property of MP-A08-liposomes could be attributed to its enhanced specificity, bioaccessibility, and delivery to the bone marrow, as demonstrated in the pharmacokinetic and biodistribution studies. Our findings indicate that MP-A08-liposomes have potential as a novel treatment for AML.

Adaptive IR recombination reads from exome files have the potential to aid in GBM prognoses and may provide opportunities to detect unproductive immune responses.

We previously reported that the dual SPHK1/2 inhibitor, SKI-II enhanced the in vitro cell death triggered by fludarabine, bendamustine or ibrutinib and reduced the activation and proliferation of chronic lymphocytic leukemia (CLL) cells...To this aim we employed the dual SPHK1/2 inhibitor SKI-II and opaganib, a SPHK2 inhibitor that is being studied in clinical trials...Of note, SPHK inhibitors were able to re-sensitize already resistant CLL cells to a second venetoclax treatment. Our results highlight the therapeutic potential of SPHK inhibitors in combination with venetoclax as a promising treatment option for the patients.

We found that the genetic downregulation of SK2 or treatment with ABC294640, a specific inhibitor of SK2, induced mitophagy and apoptosis in multiple myeloma cell lines...Furthermore, we found that PP2AC and PARK2 form a complex, suggesting that they might regulate mitophagy through protein-protein interactions. Our study demonstrates the important role of SK2 in regulating mitophagy and provides new insights into the mechanism of mitophagy in multiple myeloma.

We found overexpression of C-FLIPS, MCL-1 and survivin by siRNA transfection either alone or in paclitaxel treated cells, as well as elevation in cell apoptosis. Our results showed that SphK2 suppression may be an effective important modality to enhance cell sensitivity to paclitaxel via the induction of apoptosis in colorectal cancers.

In vivo PET imaging showed significantly higher accumulation (2.1 ± 0.3 %ID/g; p = 0.02) of [Ga]Ga-DOTA-PEG-TZ(PEG-Octr)-PEG-Trz-PEG-Val-Cit-pABOC-FTY720 in SSTR2 prostate cancer xenografts than in the SSTR2 xenografts (1.5 ± 0.4 %ID/g) at 13 min post-injection (p.i.) with a rapid excretion through the kidneys. Taken together, these proof-of-concept results validate the design concept of the T-SMPDC, which may hold a great potential for targeted diagnosis and therapy of NEPC.

At the same time, HOXC11 regulated the expression of sphingosine kinase 1 (SPHK1) by directly binding to its promoter region. Therefore, we conclude that HOXC11 impacts the development of LUAD and facilitates lung cancer progression by promoting the expression of SPHK1.

Aberrant lipid metabolism has long been associated with prostate carcinogenesis and progression, but more recently there has been an explosion of preclinical and clinical data which is informing new clinical trials. This review explores the epidemiological links between obesity and metabolic syndrome and PCa, the evidence for altered circulating lipids in PCa and their potential role as biomarkers, as well as novel therapeutic strategies for targeting lipids in men with PCa, including therapies widely used in cardiovascular disease such as statins, metformin and lifestyle modification, as well as novel targeted agents such as sphingosine kinase inhibitors, DES1 inhibitors and agents targeting FASN and beta oxidation.

Targeting this novel ISR pathway in combination with the Bcl-2 inhibitor venetoclax synergistically killed primary AML blasts, including those with venetoclax-resistant mutations, as well as leukemia-initiating cells, and reduced leukemic burden in patient-derived AML xenografts. Collectively, these findings provide mechanistic insight into the anti-cancer effects of ceramide and pre-clinical evidence for new approaches to augment Bcl-2 inhibition in the therapy of AML and other cancers with high Mcl-1 dependency.

S1P/S1PR initiated the feedback loops, whereby S1P-S1PR1/S1PR3-YAP signaling mediated lymphomagenesis contributing to tumor aggressive growth, while S1P-ALOX15 signaling mediated TAMs contributing to immunosuppressive microenvironment in obesity-lymphoma. S1P-targeted therapy could be potentially effective and immune-enhancive against obesity-lymphomagenesis.

Inhibition of SPHK1 by the inhibitor, PF543, also decreased tumorigenesis in the U87-MG and U251-MG SPHK1 orthotopic mouse models. In summary, we have characterized the role and molecular mechanisms by which SPHK1 promotes GBM, which may provide opportunities for SPHK1-targeted therapy.

Together, we identified novel rapamycin-insensitive sphingosine metabolic signatures in TSC2-null LAM cells. Therapeutic targeting of aberrant SPHK1/S1P/S1PR3 signaling may have potent therapeutic benefit for patients with TSC/LAM or other hyperactive mTOR neoplasms with autophagy inhibition.

The phosphorylation of focal adhesion kinase (FAK), a transcription factor that regulates migration, was inhibited by MBZ, so it was found that the effect of MBZ regulates the migration of cancer cells through the S1P/FAK/vimentin pathway. In conclusion, our study suggests that the anthelmintic MBZ can be used as a potential therapeutic agent for treating PDAC and for structural synthesis studies of its analogs.

Studies on the effect of quercetin and fingolimod on the two proteins associated with apoptotic events, AKT and Bcl-2, showed that only quercetin, alone or in combination, down-regulated the activity of the two proteins. The reported observations provide information which can be useful in the search of novel anti-tumor approaches, aiming at optimization of the therapeutic effect and maximal preservation of healthy tissues.

Importantly, SphK1 modulates adipocyte-induced E/N-cadherin switch through Twist1, a key process in EOC metastasis. Our study reveals a previously unrecognized role of SphK1 in modulating the metastatic tropism of EOC to the adipocyte-rich niche, suggesting a new target for EOC therapy.

Herein, we demonstrate that ABT-263 and AZD-5991, inhibitors of Bcl-2/Bcl-X and Mcl-1, respectively, induce the production of ectoCRT, indicative of ICD. While ceramide, produced by the inhibition of SphK1 is required for production of the cell surface marker of ICD, ectoCRT. Thus, inhibition of SphK1 represents a means to enhance the therapeutic efficacy of ICD-inducing agents.

Targeting SPHK1 with PF-543 significantly inhibited the cell cycle and tumor growth in preclinical xenograft tumor models of NSCLC. Taken together, our findings exhibit the vital role of the SPHK1/S1PR3/PBX1 axis in regulating the cell cycle of NSCLC, and targeting SPHK1 may develop a therapeutic effect in tumor treatment.

In both tumor models, the optimal suppression of tumor growth was attained by the combination of opaganib with IR (± cisplatin). Overall, opaganib substantially protects normal tissue from radiation damage that may occur through unintended exposure or cancer radiotherapy.

Three S1PR inhibitors (W146 for S1PR1, CAY10444 for S1PR3, and FTY720 for S1PR1-5) were selected to confirm the hypothesis that S1P signaling could mediate the HIPPO pathway in lymphoma cells...These results indicated that blockage of S1PR1 and/or S1PR3 significantly attenuated the S1P-induced decreases of YAP phosphorylation in both HH cells and SU-DHL-4 cells.(D) In conclusion, the NHL patients with obesity have a poor PFS and OS, which is associated with the elevated S1P-SPHK1 signaling. S1P-S1PR1/S1PR3-YAP signaling mediates lymphomagenesis contributing to tumor aggressive growth.