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Platelet-derived growth factor (PDGF) is one of the most important cytokines associated with pulmonary vascular remodeling in pulmonary arterial hypertension (PAH). PDGF receptor (PDGFR) inhibition exerted therapeutic effects on PAH in clinical trials, but serious side effects warrant the withdrawal of existing drugs. In this study, a novel highly selective PDGFR inhibitor WQ-C-401 was developed, and its effects on PDGFR signaling pathway and pulmonary vascular remodeling in PAH were investigated. Cell proliferation assays and Western blot analysis of PDGFRα/β phosphorylation showed that WQ-C-401 inhibited PDGFR-mediated cell proliferation assay and suppressed PDGFR phosphorylation in a concentration-dependent manner. DiscoverX's KinomeScanTM technology confirmed the good kinome selectivity of WQ-C-401 (S score (1) of PDGFR = (0.01)). In monocrotaline (MCT)-induced PAH rats, intragastric administration of WQ-C-401 (25, 50, 100 mg/kg/d) or imatinib (50 mg/kg/d, positive control) significantly decreased right ventricular systolic pressure (RVSP). Histological analysis demonstrated that WQ-C-401 inhibited pulmonary vascular remodeling by reducing muscularization and fibrosis, as well as alleviated right ventricular hypertrophy in MCT-treated rats. In addition, WQ-C-401 suppressed MCT-induced cell hyperproliferation and CD68 + macrophage infiltration around the pulmonary artery. In vitro, WQ-C-401 inhibited PDGF-BB-induced proliferation and migration of human pulmonary arterial smooth muscle cells (PASMCs). Moreover, Western blot analysis showed that WQ-C-401 concertration-dependently inhibited PDGF-BB-induced phosphorylation of ERK1/2 and PDGFRβ Y751, decreased collagen Ⅰ synthesis and increased alpha smooth muscle actin (α-SMA) expression in PASMCs. Collectively, our results suggest that WQ-C-401 is a selective and potent PDGFR inhibitor which could be a promising drug for the therapeutics of PAH by preventing pulmonary vascular remodeling., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Accumulated pieces of evidence have shown that PI3Kδ plays a critical role in chronic obstructive pulmonary disease (COPD). Using a fragment-hybrid approach, we discovered a potent and selective PI3Kδ inhibitor ( S )-18 . In the biochemical assay, ( S )-18 inhibits PI3Kδ (IC 50 = 14 nM) with high selectivity over other class I PI3Ks (56∼83 fold). ( S )-18 also achieves good selectivity over other protein kinases in the kinome ( S -score (35) = 0.015). In the cell, ( S )-18 selectively and potently inhibits the PI3Kδ-mediated phosphorylation of AKT T308 but not other class I PI3K-mediated signaling. Additionally, ( S )-18 exhibits no apparent inhibitory effect on CYP isoforms except for a moderate effect on CYP2C9. Furthermore, it shows no apparent inhibitory activity against hERG (IC 50 > 10 μM). In vivo, ( S )-18 displays favorable PK properties for inhaled delivery and improves lung function in a rodent model of pulmonary inflammation. These results suggest that ( S )-18 might be a new potential therapeutic candidate for COPD.

Microcystin-LR (MC-LR), a heptapeptide produced by blue-green algae, is shown to induce cytotoxicity by inhibiting protein phosphatase 2A (PP2A) activity. Our previous study revealed that MC-LR promoted cell proliferation in vitro by activating the Akt/mTORC1/S6K1 pathway. This study aims to further investigate the effects of MC-LR on cell proliferation and the correlated mechanisms in vivo. Mice were injected intraperitoneally with 20-80 μg/kg/d MC-LR from 2 h (hours) to 4 d (days). The results showed that the associations of MC-LR with PP2A/C (PP2A C subunit) were concentration-dependent but not time-dependent in the liver, whereas the total PP2A activity was inhibited in both concentration and time dependent manners. The PP2A regulator α4 was found to release its associated PP2A/C as MC-LR bound to PP2A/C. Importantly, 80 μg/kg MC-LR promoted liver cell proliferation beginning at 1 d post exposure, and hyperproliferation also occurred in the 40 μg/kg group at 4 d after exposure. Meanwhile, the Akt/mTORC1/S6K1 and Akt/β-catenin signaling pathways were activated as early as at 2 h post exposure. Furthermore, MC-LR also activated ERK/p38/JNK MAPKs as early as at 2 h post exposure, which was supported by the hyperphosphorylation of their substrates, ATF-2, c-Jun and c-Myc. Interestingly, the total c-Jun and c-Myc levels also increased after MC-LR exposure. These findings indicate that MC-LR can also promote cell proliferation in vivo, and the activation of Akt and MAPK signaling pathways due to PP2A inhibition is proposed to participate in this process., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

BCR gene fused ABL kinase is the critical driving force for the Philadelphia Chromosome positive (Ph+) Chronic Myeloid Leukemia (CML) and has been extensively explored as a drug target. With a structure-based drug design approach we have discovered a novel inhibitor CHMFL-074, that potently inhibits both the native and a variety of clinically emerged mutants of BCR-ABL kinase. The X-ray crystal structure of CHMFL-074 in complex with ABL1 kinase (PDB ID: 5HU9) revealed a typical type II binding mode (DFG-out) but relatively rare hinge binding. Kinome wide selectivity profiling demonstrated that CHMFL-074 bore a high selectivity (S score(1) = 0.03) and potently inhibited ABL1 kinase (IC50: 24 nM) and PDGFR α/β (IC50: 71 nM and 88 nM). CHMFL-074 displayed strong anti-proliferative efficacy against BCR-ABL-driven CML cell lines such as K562 (GI50: 56 nM), MEG-01 (GI50: 18 nM) and KU812 (GI50: 57 nM). CHMFL-074 arrested cell cycle into the G0/G1 phase and induced apoptosis in the Ph+ CML cell lines. In addition, it potently inhibited the CML patient primary cell's proliferation but did not affect the normal bone marrow cells. In the CML cell K562 inoculated xenograft mouse model, oral administration of 100 mg/kg/d of CHMFL-074 achieved a tumor growth inhibition (TGI) of 65% without exhibiting apparent toxicity. As a potential drug candidate for fighting CML, CHMFL-074 is under extensive preclinical safety evaluation now., Competing Interests: Dr. Shanchun Zhang is a shareholder of Hefei Cosource Inc. Dr. Qingsong Liu is a shareholder of PreceDo pharmaceutical Inc.

Our previous studies had shown that MC-LR inhibited PP2A activity and hyperphosphorylated PP2A substrates at 24 h exposure in HL7702 cells. Although the cytoskeleton was rearranged, the cellular effects were not observed. The purpose of the present study with HL7702 cell exposed to MC-LR for 1-72 h was to further uncover the adverse effects of MC-LR comprehensively. The results showed that there were no obvious difference in apoptosis rate and cell-cycle distribution but the cell proliferation was changed since 36 h exposure while the uptake of MC-LR and its binding to PP2A/C kept unchanged since 1h exposure. PP2A activity had not manifested continued decline compare to 24h exposure and PP2A regulator α4 was found to release its associated PP2A/C since 1h exposure. The increasing of p-Akt-T308, p-Akt-S473, p-S6K1, p-S6, and p-4E-BP1 since 1h MC-LR exposure indicated that Akt/S6K1 cascade had been activated as early as 1h MC-LR treatment. And, PI3K/Akt inhibitor (LY294002) blocked MC-LR-induced Akt/S6K1 activation and proliferation. Besides, MC-LR also led to hyperphosphorylation of c-Myc, c-Jun, Bcl-2 and Bad and activation of Cdk1. Our study indicated that MC-LR exposure promoted HL7702 cell proliferation and the main mechanism was the activation of Akt/S6K1 cascade. Meanwhile, hyperphosphorylation of Bcl-2, Bad, c-Myc and c-Jun might also be involved. And, the inhibition of PP2A was the major reason for these molecular changes., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Cationic monofunctional platinum(II)-based anticancer agents with a general formula of cis-[Pt(NH3)2(N-donor)Cl](+) have recently drawn significant attention due to their unique mode of action, distinctive anticancer spectrum, and promising antitumor activity both in vitro and in vivo. Understanding the mechanism of action of novel monofunctional platinum compounds through rational drug design will aid in the further development of active agents. In this study, we synthesized and evaluated a monofunctional platinum-based anticancer agent SA-Pt containing a bulky salicylanilide moiety. The antiproliferative activity of SA-Pt was close to that of cisplatin. Mechanism studies revealed that SA-Pt entered HeLa cells more efficiently than cisplatin, blocked the cell cycle at the S-phase, and induced apoptosis. The compound bound to DNA as effectively as cisplatin, but did not block RNA polymerase II-mediated transcription as strongly as cisplatin, indicating that once the compound formed Pt-DNA lesions, the salicylanilide group was more easily recognized and removed. This study not only enriches the family of monofunctional platinum-based anticancer agents but also guides the design of more potent monofunctional platinum complexes., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Wound healing is a complex biological process, and current research finds that jellyfish have a great capacity for promoting growth and healing. However, the underlying mechanisms remain unclear. Thus, this study was conducted to investigate the molecular mechanisms and effects of a tentacle extract (TE) from the jellyfish Cyanea capillata (C. capillata) on cell proliferation and migration in human umbilical vein endothelial cells (HUVECs). First, our results showed that TE at the concentration of 1 μg/ml could promote cell proliferation over various durations, induce a transition of the cells from the G1-phase to the S/G2-phase of the cell cycle, and increase the expression of cell cycle proteins (CyclinB1 and CyclinD1). Second, we found that TE could activate the PI3K/Akt, ERK1/2 and JNK MAPK signaling pathways but not the NF-κB signaling pathway or the apoptosis signaling cascade. Finally, we demonstrated that the TE-induced expression of cell cycle proteins was decreased by ERK1/2 inhibitor PD98059 but not by PI3K inhibitor LY294002 or JNK inhibitor SP600125. Similarly, the TE-enhanced migration ability of HUVECs was also markedly attenuated by PD98059. Taken together, our findings indicate that TE-induced proliferation and migration in HUVECs mainly occurred through the ERK1/2 MAPK signaling pathway. These results are instructively important for further research on the isolation and purification of growth-promoting factors from C. capillata and are hopeful as a means to improve human wound repair in unfavorable conditions. [ABSTRACT FROM AUTHOR]

Objective To investigate the combination effect using iron chelators deferasirox and cisplatin on A549 cell proliferation and apoptosis and to provide evidences to explore an effective way to treat lung cancer. Methods Lung adenocarcinoma cells were cultured by conventional way, with administration of different concentrations of deferasirox and cisplatin. Cell growth inhibition was observed under an inverted microscope. Proliferation inhibition was evaluated by MTT assay. Morphological changes of cell apoptosis was detected using DAPI, AO/EB straning and flow cytometry. Results After a certain time of incubation with different concentrations of the combined drugs, the cell number reduce significantly, which was counted under invert microscope. Cells were dispersed with each other and adherent cells appear shrunken and poor in refractivity. MTT assay showed that inhibition of cell proliferation was in a concentration-time-dependent manner. Chromatin condensation, nuclear condensation and other typical apoptotic morphology were detected after DAPI and AO/EB straining. Flow cytometry showed that apoptosis increased with rising drug concentration. So combination therapy was significantly pro-apoptotic. Conclusion Deferasirox has the ability to inhibit proliferation of A549 cells and can promote tumor cell apoptosis and enhances cancer cell tolerance when combined with cisplatin. It can also reduce the amount and toxicity of cisplatin. It provides a basis for finding an effective way to treat lung cancer. [ABSTRACT FROM AUTHOR]