P2, N=60, Recruiting, Australian and New Zealand Urogenital and Prostate Cancer Trials Group | Not yet recruiting --> Recruiting

P2, N=60, Not yet recruiting, Australian and New Zealand Urogenital and Prostate Cancer Trials Group

Docking studies supported these findings by showing favorable binding interactions within the SphK2 active site, which were less pronounced in SphK1, correlating with the observed selectivity. This work contributes to the development of novel 1-deoxysphingosine analogues targeting SphK inhibition, as well as to the knowledge of the differential topology of the active sites in SphK1 and SphK2.

Safingol potentiates 2'-nitroflavone apoptotic effect in breast cancer cells. Safingol enhances the 2'-nitroflavone antitumor activity in vivo in breast cancer.

Overexpression of miR-205 in HN12-SK2 cells decreased tumor formation capacity and NOK-SK2 cells abrogated the tumor growth in mice. Our results indicate crosstalk between SK2 and p53 in regulating miR-205 and miR-296, which could be potential targets for HNSCC therapy.

We have also listed available drugs that particularly focus on S1P, S1PRs, SK1, and SK2 for the treatment of pancreatic cancer. Through this review, we would like to suggest that the SK/S1P/S1PR signaling system can be an important target for treating pancreatic cancer, where a new treatment target is desperately warranted.

Intriguingly, knockdown of SphK1 suppressed DLBCL cell viability and increased chemosensitivity to doxorubicin by decreasing cell viability and increasing caspase-3 activity...Collectively, SphK1 knockdown counteracted chemoresistance and immune escape from T cell killing by inhibiting the PI3K/AKT/PD-L1 pathway. Therefore, targeting SphK1 may represent a promising therapeutic strategy for overcoming chemoresistance and immune escape in DLBCL.

Molecular dynamics (MD) simulations showed that among these compounds, 7 compounds have favorable binding energy compared with cocrystal inhibitors. Hence, the study showed that the present lead fragments could act as potential inhibitors against therapeutic target of cancers and neurodegenerative disorders.

CRC cell lines with or without ectopic expression of SNAI1 were used to study the role of S1P signaling as mediators of cancer stemness and 5-fluorouracil (5FU) chemoresistance. SNAI1/SPHK2 signaling mediates cancer stemness and 5FU resistance, implicating S1P as a therapeutic target for CRC. The S1P inhibitor ABC294640 holds potential as a therapeutic agent to target CSCs in therapy refractory CRC.

Our study's findings support the link between SphK1 expression and hematological malignancies. SphK1 gene dysregulation may contribute to various malignancies, suggesting it could be a therapeutic target to improve patient outcomes. Further research is needed to understand SphK1's mechanistic role in hematological malignancies and its therapeutic potential.

We have now investigated the effects of seven commonly used SphK inhibitors (5c, ABC294640 (opaganib), DMS, K145, PF-543, SLM6031434 and SKI-II) on profiles of selected sphingolipids in Chang, HepG2 and HUVEC cells. We found that both compounds affect sphingolipid de novo synthesis, with 3-ketodihydrosphingosine reductase and DEGS as their targets. Our study emphasizes the urgency of monitoring cellular sphingolipid profiles when SphK inhibitors are used in mechanistic investigations, as none of the seven SphK inhibitors tested was free of unexpected on-target and/or off-target effects.

Our findings suggest that 5-FU treatment combined with simultaneous Spkh2 inhibition by ABC294640 has anti-tumor synergistic effects by influencing multiple effects on tumor cells, T cells, and MDSCs, potentially improving the poor prognosis of colorectal cancer patients.