Is there a difference in phenotype between males and females with non-transfusion-dependent thalassemia? A cross-sectional evaluation.

Non-transfusion-dependent thalassemia includes a variety of phenotypes and genotypes that rarely require regular transfusions. However, these patients can experience a wide range of complications. The objective of this retrospective study was to verify whether there is a significant difference in non-transfusion-dependent thalassemia-related complications and treatment among males and females.We performed a re-analysis of samples evaluated in a previously published cross-sectional study, regarding 96 non-transfusion-dependent thalassemia patients followed at the 'UOSD Malattie Rare del Globulo Rosso' Centre of the Cardarelli Hospital in Naples, Italy.We found that females were more anemic than males, but there was no significant difference in prevalence of common complications among genders, except for hypogonadism. Furthermore, the transitory regular transfusions regimen in women who had been pregnant does not seem to have a significant impact on overall prognosis.In non-transfusion-dependent thalassemia patients, the lower levels of hemoglobin found in females do not seem to indicate a higher prevalence of complications.This data should be considered in studies with experimental treatments aiming to correct anemia in patients with non-transfusion-dependent thalassemia. It should probably also be taken into account in order to set up different transfusion regimens among genders in transfusion-dependent patients

Enhanced Antiproliferative and Apoptotic Response of HT-29 Adenocarcinoma Cells to Combination of Photoactivated Hypericin and Farnesyltransferase Inhibitor Manumycin A

Several photodynamically-active substances and farnesyltransferase inhibitors are currently being investigated as promising anticancer drugs. In this study, the combined effect of hypericin (the photodynamically-active pigment from Hypericum perforatum) and selective farnesyltransferase inhibitor manumycin (manumycin A; the selective farnesyltransferase inhibitor from Streptomyces parvulus) on HT-29 adenocarcinoma cells was examined. We found that the combination treatment of cells with photoactivated hypericin and manumycin resulted in enhanced antiproliferative and apoptotic response compared to the effect of single treatments. This was associated with increased suppression of clonogenic growth, S phase cell cycle arrest, elevated caspase-3/7 activity and time-dependent total cleavage of procaspase-3 and lamin B, cleavage of p21Bax into p18Bax and massive PARP cleavage. Moreover, we found that the apoptosis-inducing factor is implicated in signaling events triggered by photoactivated hypericin. Our results showed the relocalization of apoptosis-inducing factor (AIF) to the nuclei after hypericin treatment. In addition, we discovered that not only manumycin but also photoactivated hypericin induced the reduction of total Ras protein level. Manumycin decreased the amount of farnesylated Ras, and the combination treatment decreased the amount of both farnesylated and non-farnesylated Ras protein more dramatically. The present findings indicate that the inhibition of Ras processing may be the determining factor for enhancing the antiproliferative and apoptotic effects of combination treatment on HT-29 cells

N6-isopentenyladenosine arrests tumor cell proliferation by inhibiting farnesyl diphosphate synthase and protein prenylation

The physiological effects of a variety of N6-substituted adenine and adenosine derivatives called cytokinins have been documented in plants, but information on their occurrence and function in other biological system is limited. Here I investigated the anti-proliferative effect of N6-isopentenyladenosine (i6A), an adenosine and isoprenoid derivative, in a thyroid cell system, FRTL-5 wild-type and K-ras transformed KiMol cells. Addition of i6A to FRTL-5 cells caused a dose-dependent arrest of the G0-G1 cell phase transition, associated with a reduction of cells in the S phase that was much more evident in KiMol cells. I6A arrested tumor cell proliferation by inhibiting Farnesyl diphosphate synthase (FPPS) and protein prenylation. Indeed, the addition of farnesol reversed these effects and i6A affected protein prenylation, in particular lamin B processing. I6A effect was not mediated by the adenosine receptor but it was due to a direct modulation of FPPS enzyme activity, as a result of its uptake inside the cells. I6A inhibited FPPS activity more efficaciously in KiMol cells than in normal FRTL-5 cells. Moreover, the i6A anti-proliferative effect was evaluated in vivo in a nude mouse xenograft model, where KiMol cells were implanted subcutaneously. Mice treated with i6A showed a drastic reduction in tumor volume. Our findings indicate that this isoprenoid end product might be used for antineoplastic therapy, an application emulating that of the lovastatin and/or farnesyl-transferase inhibitor