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Romidepsin (FK228) and its analogs directly inhibit phosphatidylinositol 3-kinase activity and potently induce apoptosis as histone deacetylase/phosphatidylinositol 3-kinase dual inhibitors


Page 1994–2001

Phosphatidylinositol 3-kinase (PI3K) is a prominent carginogenic signal transducer and holds promise as an anticancer target. However, a successful PI3K inhibitor has yet to be developed for use in humans. Phosphatidylinositol 3-kinase potentiates cell growth, proliferation, and survival through numerous intracellular signaling molecules. The signal transduction cascade includes AKT, mTOR and the conversion of phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol 3,4,5-trisphosphate (PIP3). Saijo and coworkers took advantage of a property of the yeast Saccharomyces cerevisiae in which cell proliferation was inhibited by the conversion of PIP2 to PIP3. This provided an opportunity to screen potential drugs for their ability to, paradoxically, promote the growth of S. cerevisiae. Their efforts yielded a number of potential PI3K inhibitors, in particular the histone deacetylase inhibitor romidepsin and its analogs. Results from this study reveal that the mechanism by which romidepsin induces apoptosis is through both histone deacetylase activity and inhibition of PI3K.doi: 10.1111/cas.12002

Long-term outcome and prognostic factors of elderly patients with acute promyelocytic leukemia


Page 1974–78

Improved treatments for acute promyelocytic leukemia (APL) have led to overall better outcomes, but data comparing morbidity and mortality benefits between old and young patients is sparse. In their report, Ono et al. provide an analysis of various outcome measures between young and elderly patients with APL. The authors found that the risk of differentiation syndrome, a complication of chemotherapy for APL, was equal for both groups. However, age >60 years was associated with increased risk of death from differentiation syndrome, death from infection, and decreased overall survival. Interestingly, analyses revealed equivalent disease-free survival rates between both sets of patients. By highlighting the causes of early death in patients older than 60 years receiving treatment for APL, results from this study can help guide treatment strategies in this age group.doi: 10.1111/j.1349-7006.2012.02390.x

Chimeric anti-podoplanin antibody suppresses tumor metastasis through neutralization and antibody-dependant cellular toxicity


Page 1913–19

Podoplanin, a platelet-aggregating factor that has been reported to be a marker of tumor-initiating cells, was targeted as a potential mechanism to suppress metastasis in expressing tumors. Podoplanin's expression has been associated with clinical outcome, tumor metastases, malignant progression, and epithelial–mesenchymal transition. In this study, Kaneko et al. produced and tested rat and its chimeric antibody to podoplanin in vivo, NZ-1 and NZ-8, and found them to suppress metastasis of podoplanin-expressing tumors. The mechanism of suppression was shown to be the neutralization of platelet aggregation as well as the promotion of antibody-dependent cellular toxicity and complement-dependent cytoxicity. As NZ-8 seemed to induce antibody-dependent cellular toxicity and complement-dependent cytoxicity more strongly than NZ-1, antibody-based immunotherapy using NZ-8 provides a potential new mechanism by which to target podoplanin-expressing tumors.doi: 10.1111/j.1349-7006.2012.02385.x