The antitumor activity of Delta-24-RGD suggests that it has the potential to be an effective agent in the treatment of gliomas.

No abstract

AbstractThe pan-deacetylase inhibitor panobinostat (LBH589) recently has been shown to have significant clinical activity in patients with relapsed Hodgkin lymphoma, but its mechanism of action in Hodgkin lymphoma remains unknown. In this study, we demonstrate that panobinostat has potent antiproliferative activity against Hodgkin lymphoma–derived cell lines. At the molecular level, panobinostat activated the caspase pathway, inhibited STAT5 and STAT6 phosphorylation, and down-regulated hypoxia-inducible factor 1 α and its downstream targets, glucose transporter 1 (GLUT1) and vascular endothelial growth factor. Paradoxically, panobinostat inhibited LKB1 and AMP-activated protein kinase, leading to activation of mammalian target of rapamycin (mTOR) that promotes survival. Combining panobinostat with the mTOR inhibitor everolimus (RAD001) inhibited panobinostat-induced mTOR activation and enhanced panobinostat antiproliferative effects. Collectively, our data demonstrate that panobinostat is a potent deacetylase inhibitor against Hodgkin lymphoma–derived cell lines, and provide a mechanistic rationale for combining panobinostat with mTOR inhibitors for treating Hodgkin lymphoma patients. Furthermore, the effect of panobinostat on GLUT1 expression suggests that panobinostat may modulate the results of clinical diagnostic imaging tests that depend of functional GLUT1, such as fluorodeoxyglucose positron emission tomography.

Chicken spermatozoa may remain in the female oviduct for a prolonged period before induction of the acrosome reaction on contact with the inner perivitelline layer (IPVL). By contrast, the acrosome reaction may be induced very rapidly in vitro in the presence of IPVL and Ca 2C. In the present study, we examined the extent to which the chicken acrosome reaction can be induced in media of various compositions in the presence or absence of IPVL and/or Ca 2C and other factors known to be efficient in mammals. We also compared the efficacy of perivitelline layer (PL) taken at various states of oocyte maturation in initiating the reaction. The acrosome reaction was induced in less than 5 min in the presence of Ca 2C and IPVL. Incubation of spermatozoa in different saline media (Beltsville poultry semen extender (BPSE); Dulbecco's modified eagle medium; NaCl-TES buffer) without IPVL showed a significant induction of acrosome reaction in BPSE supplemented with 5 mM Ca 2C and in the three media after supplementation with Ca 2C and Ca 2C ionophore A23187.By contrast, the acrosome reaction was never induced without Ca 2C. BSA, NaHCO 3 , and progesterone did not stimulate the acrosome reaction. Ca 2C plus PL taken at various physiological states (follicle IPVL, ovulated IPVL, oviposited IPVL, and/or outer perivitelline layer) strongly stimulated the acrosome reaction, the latest states being the most efficient. Although PL induced the acrosome reaction in the presence of extracellular Ca 2C, it was not possible to induce hyperactivation in chicken spermatozoa. Taken together, these results emphasize the central role of Ca 2C in the in vitro initiation of the acrosome reaction in chickens and show specific features of this induction in birds.

Aberrant activation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway has been reported to promote proliferation and survival of Hodgkin and Reed–Sternberg cells of Hodgkin lymphoma (HL). We investigated the activity of the JAK inhibitor AZD1480 in HL-derived cell lines and determined its mechanisms of action. AZD1480 at low doses (0.1–1 μ) potently inhibited STATs phosphorylation, but did not predictably result in antiproliferative effects, as it activated a negative-feedback loop causing phosphorylation of JAK2 and extracellular signal-regulated kinases 1 and 2 (ERK1/2), and increased IP-10, RANTES and interleukin (IL)-8 concentrations in the supernatants. Inhibition of the ERK activity by mitogen-activated extracellular signal regulated kinase (MEK) inhibitors (UO126 and PD98059) enhanced the cytotoxic activity of AZD1480. Interestingly, submicromolar concentrations of AZD1480 demonstrated significant immunoregulatory effects by downregulating T-helper 2 cytokines and chemokines, including IL-13 and thymus- and activation-regulated chemokine, and the surface expression of the immunosuppressive programmed death ligands 1 and 2. Higher concentrations of AZD1480 (5 μ) induced G2/M arrest and cell death by inhibiting Aurora kinases. Our study demonstrates that AZD1480 regulates proliferation and immunity in HL cell lines and provides mechanistic rationale for evaluating AZD1480 alone or in combination with MEK inhibitors in HL.