6 research outputs found
Investigation of the Mechanism of Idelalisib Resistance in the Follicular Lymphoma WSU-Fsccl Cell Line
PI3Kδ inhibitor, GS-1101 (CAL-101), attenuates pathway signaling, induces apoptosis, and overcomes signals from the microenvironment in cellular models of Hodgkin lymphoma
GS-1101 (CAL-101) is an oral PI3Kδ-specific inhibitor that has shown preclinical and clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia. To investigate the potential role of PI3Kδ in Hodgkin lymphoma (HL), we screened 5 HL cell lines and primary samples from patients with HL for PI3Kδ isoform expression and constitutive PI3K pathway activation. Inhibition of PI3Kδ by GS-1101 resulted in the inhibition of Akt phosphorylation. Cocultures with stroma cells induced Akt activation in HL cells, and this effect was blocked by GS-1101. Conversely, production of the stroma-stimulating chemokine, CCL5, by HL cells was reduced by GS-1101. GS-1101 also induced dose-dependent apoptosis of HL cells at 48 hours. Reductions in cell viability and apoptosis were enhanced when combining GS-1101 with the mTOR inhibitor everolimus. Our findings suggest that excessive PI3Kδ activity is characteristic in HL and support clinical evaluation of GS-1101, alone and in combination, as targeted therapy for HL
The sarcolemmal calcium pump inhibits the calcineurin/nuclear factor of activated T-cell pathway via interaction with the calcineurin A catalytic subunit.
The calcineurin/nuclear factor of activated T-cell (NFAT) pathway represents a crucial transducer of cellular function. There is increasing evidence placing the sarcolemmal calcium pump, or plasma membrane calcium/calmodulin ATPase pump (PMCA), as a potential modulator of signal transduction pathways. We demonstrate a novel interaction between PMCA and the calcium/calmodulin-dependent phosphatase, calcineurin, in mammalian cells. The interaction domains were located to the catalytic domain of PMCA4b and the catalytic domain of the calcineurin A subunit. Endogenous calcineurin activity, assessed by measuring the transcriptional activity of its best characterized substrate, NFAT, was significantly inhibited by 60% in the presence of ectopic PMCA4b. This inhibition was notably reversed by the co-expression of the PMCA4b interaction domain, demonstrating the functional significance of this interaction. PMCA4b was, however, unable to confer its inhibitory effect in the presence of a calcium/calmodulin-independent constitutively active mutant calcineurin A suggesting a calcium/calmodulin-dependent mechanism. The modulatory function of PMCA4b is further supported by the observation that endogenous calcineurin moves from the cytoplasm to the plasma membrane when PMCA4b is overexpressed. We suggest recruitment by PMCA4b of calcineurin to a low calcium environment as a possible explanation for these findings. In summary, our results offer strong evidence for a novel functional interaction between PMCA and calcineurin, suggesting a role for PMCA as a negative modulator of calcineurin-mediated signaling pathways in mammalian cells. This study reinforces the emerging role of PMCA as a molecular organizer and regulator of signaling transduction pathways
Discovery of a Phosphoinositide 3‑Kinase (PI3K) β/δ Inhibitor for the Treatment of Phosphatase and Tensin Homolog (PTEN) Deficient Tumors: Building PI3Kβ Potency in a PI3Kδ-Selective Template by Targeting Nonconserved Asp856
Phosphoinositide 3-kinase (PI3K)
β signaling is required to sustain cancer cell growth in which
the tumor suppressor phosphatase and tensin homolog (PTEN) has been
deactivated. This manuscript describes the discovery, optimization,
and in vivo evaluation of a novel series of PI3Kβ/δ inhibitors
in which PI3Kβ potency was built in a PI3Kδ-selective
template. This work led to the discovery of a highly selective PI3Kβ/δ
inhibitor displaying excellent pharmacokinetic profile and efficacy
in a human PTEN-deficient LNCaP prostate carcinoma xenograft tumor
model
Discovery of Orally Efficacious Phosphoinositide 3‑Kinase δ Inhibitors with Improved Metabolic Stability
Aberrant signaling of phosphoinositide
3-kinase δ (PI3Kδ)
has been implicated in numerous pathologies including hematological
malignancies and rheumatoid arthritis. Described in this manuscript
are the discovery, optimization, and in vivo evaluation of a novel
series of pyridine-containing PI3Kδ inhibitors. This work led
to the discovery of <b>35</b>, a highly selective inhibitor
of PI3Kδ which displays an excellent pharmacokinetic profile
and is efficacious in a rodent model of rheumatoid arthritis