Identification of a novel PAK1 inhibitor to treat pancreatic cancer

Pancreatic cancer is one of the most aggressive cancers with poor prognosis and a low 5-year survival rate.The family of P21-activated kinases(PAKs)appears to modulate many signaling pathways that contribute to pancreatic carcinogenesis.In this work,we demonstrated that PAK1 is a critical regulator in pancreatic cancer cell growth.PAK1-targeted inhibition is therefore a new potential therapeutic strategy for pancreatic cancer.Our small molecule screening identified a relatively specific PAK1-targeted inhibitor,CP734.Pharmacological and biochemical studies indicated that CP734 targets residue V342 of PAK1 to inhibit its ATPase activity.Further in vitro and in vivo studies elucidated that CP734 suppresses pancreatic tumor growth through depleting PAK1 kinase activity and its downstream signaling pathways.Little toxicity of CP734 was observed in murine models.Combined with gemcitabine or 5-fluorouracil,CP734 also showed synergistic effects on the anti-proliferation of pancreatic cancer cells.All these favorable results indicated that CP734 is a new potential therapeutic candidate for pancreatic cancer.

Mailuoning prevents high-glucose-mediated human umbilical vein endothelial cells apoptosis

OBJECTIVE： To investigated the role of Mailuoning in the prevention of highglucosemediated cell apoptosis in human umbilical vein endothelial cells （HUVEC） and the mechanisms involved. METHODS： MTT assay was used to investigate cell viability, western blot was used to investigate pro tein expression, and flow cytometric detection technology was used to detect cell apoptosis. RESULTS： Exposure of HUVEC to high glucose （50 mM） significantly suppressed cell viability and increased cell apoptosis compared with normal glu cose （11 mM） （all P〈0.05）. However, Mailuoning pre vented highglucoseinduced HUVEC apoptosis in dosedependent manner. Further studies indicated that Mailuoning suppressed highglucoseinduced p38 mitogenactivated protein kinase phosphoryla tion, but had no effect on extracellular signalregu lated kinase 1/2 and Akt phosphorylation. CONCLUSION： Mailuoning can prevent highglu coseinduced HUVEC apoptosis by suppressing p38 activation.

IL-6R blockade by chikusetsusaponin IVa butyl ester inhibits Th17 cell differentiation and ameliorates collagen-induced arthritis

Interleukin(IL)-6 is central to the pathogenesis of rheumatoid arthritis(RA).1 IL-6 receptor(IL-6R)blockade is an effective treatment strategy for RA based on the clinical efficacy of tocilizumab.However,serious infections are the most frequent adverse events associated with long-term monotherapy with tocilizumab,an exogenous biomacromolecule.2 Novel small-molecule IL-6R inhibitors with fewer deleterious side effects could therefore have potential as RA treatments.We previously identified chikusetsusaponin IVa butyl ester(CS)as a natural small-molecule IL-6R antagonist.3 Here,we assessed the effects of CS on a mouse model of collagen-induced arthritis(CIA)to evaluate its therapeutic potential against RA.The results showed that CS ameliorated arthritis in CIA mice by inhibiting T-helper 17(Th17)cell differentiation and could serve as a novel agent for treating RA.