Honokiol Arrests Cell Cycle, Induces Apoptosis, and Potentiates the Cytotoxic Effect of Gemcitabine in Human Pancreatic Cancer Cells

Survival rates for patients with pancreatic cancer are extremely poor due to its asymptomatic progression to advanced and metastatic stage for which current therapies remain largely ineffective. Therefore, novel therapeutic agents and treatment approaches are desired to improve the clinical outcome. In this study, we determined the effects of honokiol, a biologically active constituent of oriental medicinal herb Magnolia officinalis/grandiflora, on two pancreatic cancer cell lines, MiaPaCa and Panc1, alone and in combination with the standard chemotherapeutic drug, gemcitabine. Honokiol exerted growth inhibitory effects on both the pancreatic cancer cell lines by causing cell cycle arrest at G1 phase and induction of apoptosis. At the molecular level, honokiol markedly decreased the expression of cyclins (D1 and E) and cyclin-dependent kinases (Cdk2 and Cdk4), and caused an increase in Cdk inhibitors, p21 and p27. Furthermore, honokiol treatment led to augmentation of Bax/Bcl-2 and Bax/Bcl-xL ratios to favor apoptosis in pancreatic cancer cells. These changes were accompanied by enhanced cytoplasmic accumulation of NF-κB with a concomitant decrease in nuclear fraction and reduced transcriptional activity of NF-κB responsive promoter. This was associated with decreased phosphorylation of inhibitor of kappa B alpha (IκB-α) causing its stabilization and thus increased cellular levels. Importantly, honokiol also potentiated the cytotoxic effects of gemcitabine, in part, by restricting the gemcitabine-induced nuclear accumulation of NF-κB in the treated pancreatic cancer cell lines. Altogether, these findings demonstrate, for the first time, the growth inhibitory effects of honokiol in pancreatic cancer and indicate its potential usefulness as a novel natural agent in prevention and therapy

Radiation induced segregation and precipitation behavior in self-ion irradiated Ferritic/Martensitic HT9 steel

In this study, Ferritic/Martensitic (F/M) HT9 steel was irradiated to 20 displacements per atom (dpa) at 600 nm depth at 420 and 440˚C, and to 1, 10 and 20 dpa at 600 nm depth at 470˚C using 5 MeV Fe++ ions. The characterization was conducted using ChemiSTEM and Atom Probe Tomography (APT), with a focus on radiation induced segregation and precipitation. Ni and/or Si segregation at defect sinks (grain boundaries, dislocation lines, carbide/matrix interfaces) together with Ni, Si, Mn rich G-phase precipitation were observed in self-ion irradiated HT9 except in very low dose case (1dpa at 470˚C). Some G-phase precipitates were found to nucleate heterogeneously at defect sinks where Ni and/or Si segregated. In contrast to what was previously reported in the literature for neutron irradiated HT9, no Cr-rich α’ phase, χ-phases, η phase and voids were found in self-ion irradiated HT9. The difference of observed microstructures is probably due to the difference of irradiation dose rate between ion irradiation and neutron irradiation. In addition, the average size and number density of G-phase precipitates were found to be sensitive to both irradiation temperature and dose. With the same irradiation dose, the average size of G-phase increased whereas the number density decreased with increasing irradiation temperature. Within the same irradiation temperature, the average size increased with increasing irradiation dose.</p