P300/CBP inhibition sensitizes mantle cell lymphoma to PI3Kδ inhibitor idelalisib.

Mantle cell lymphoma (MCL) is a lymphoproliferative disorder lacking reliable therapies. PI3K pathway contributes to the pathogenesis of MCL, serving as a potential target. However, idelalisib, an FDA-approved drug targeting PI3Kδ, has shown intrinsic resistance in MCL treatment. Here we report that a p300/CBP inhibitor, A-485, could overcome resistance to idelalisib in MCL cells in vitro and in vivo. A-485 was discovered in a combinational drug screening from an epigenetic compound library containing 45 small molecule modulators. We found that A-485, the highly selective catalytic inhibitor of p300 and CBP, was the most potent compound that enhanced the sensitivity of MCL cell line Z-138 to idelalisib. Combination of A-485 and idelalisib remarkably decreased the viability of three MCL cell lines tested. Co-treatment with A-485 and idelalisib in Maver-1 and Z-138 MCL cell xenograft mice for 3 weeks dramatically suppressed the tumor growth by reversing the unsustained inhibition in PI3K downstream signaling. We further demonstrated that p300/CBP inhibition decreased histone acetylation at RTKs gene promoters and reduced transcriptional upregulation of RTKs, thereby inhibiting the downstream persistent activation of MAPK/ERK signaling, which also contributed to the pathogenesis of MCL. Therefore, additional inhibition of p300/CBP blocked MAPK/ERK signaling, which rendered maintaining activation to PI3K-mTOR downstream signals p-S6 and p-4E-BP1, thus leading to suppression of cell growth and tumor progression and eliminating the intrinsic resistance to idelalisib ultimately. Our results provide a promising combination therapy for MCL and highlight the potential use of epigenetic inhibitors targeting p300/CBP to reverse drug resistance in tumor.

Antidepressant mechanism and active compounds of saffron from network pharmacology study.

Saffron has been applied in depression treatment, but its antidepressant compounds and mechanisms are unclear. In this research, a network pharmacology-based method was proposed to screen the active compounds and the potential mechanisms of saffron for depression treatment. Firstly, the chemical compounds of saffron were collected from literature and filtered by drug-like prediction. Secondly, common targets, by comparing the targets of saffron predicted by Pharm Mapper server with targets associated with depression collected from Genecards, were regarded as the antidepressant targets of saffron. Thirdly, common targets were mapped to KEGG pathways, considered as the pathways related with the antidepressant effects of saffron. Finally, the network of compounds-targets-pathways was constructed and analyzed by cytoscape 3.4.0. Ten compounds including crocetin, picrocrocin, (1R, 5S, 6R)-5-(hydroxymethyl)- 4, 4, 6-trimethyl-7-Oxabicyclo[4.1.0]heptan-2-one and its glycoside were screened as the main antidepressant compounds, some of which were reported for the first time. They might have effective treatment for depression by acting on targets, such as MAP2K1, MAPK1, HRAS, PIK3R1, ALB and AKT1 and pathways related with immune system, signal transduction and so on. This study provided a new insight into the antidepressant mechanism and active compounds of saffron, which also had a guiding effect on later experiments.

Pathophysiology and therapeutic relevance of PI3K(p110α) protein in atrial fibrillation: A non-interventional molecular therapy strategy.

Genetically modified animal studies have revealed specific expression patterns and unequivocal roles of class I PI3K isoenzymes. PI3K(p110α), a catalytic subunit of class I PI3Ks is ubiquitously expressed and is well characterised in the cardiovascular system. Given that genetic inhibition of PI3K(p110α) causes lethal phenotype embryonically, the catalytic subunit is critically important in housekeeping and biological processes. A growing number of studies underpin crucial roles of PI3K(p110α) in cell survival, proliferation, hypertrophy and arrhythmogenesis. While the studies provide great insights, the precise mechanisms involved in PI3K(p110α) hypofunction and atrial fibrillation (AF) are not fully known. AF is a well recognised clinical problem with significant management limitations. In this translational review, we attempted a narration of PI3K(p110α) hypofunction in the molecular basis of AF pathophysiology. We sought to cautiously highlight the relevance of this molecule in the therapeutic approaches for AF management per se (i.e without conditions associate with cell proliferation, like cancer), and in mitigating effects of clinical risk factors in atrial substrate formation leading to AF progression. We also considered PI3K(p110α) in AF gene association, with the aim of identifying mechanistic links between the ever increasingly well-defined genetic loci (regions and genes) and AF. Such mechanisms will aid in identifying new drug targets for arrhythmogenic substrate and AF.