Splicing factor SF3b as a target of the antitumor natural product pladienolide

Pladienolide is a naturally occurring antitumor macrolide that was discovered by using a cell-based reporter gene expression assay controlled by the human vascular endothelial growth factor promoter. Despite the unique mechanisms of action and prominent antitumor activities of pladienolides B and D in diverse in vitro and in vivo systems, their target protein has remained unclear. We used 3H-labeled, fluorescence-tagged and photoaffinity/biotin (PB)-tagged 'chemical probes' to identify a 140-kDa protein in splicing factor SF3b as the binding target of pladienolide. Immunoblotting of an enhanced green fluorescent protein fusion protein of SF3b subunit 3 (SAP130) revealed direct interaction between the PB probe and SAP130. The binding affinities of pladienolide derivatives to the SF3b complex were highly correlated with their inhibitory activities against reporter gene expression and cell proliferation. Furthermore, pladienolide B impaired in vivo splicing in a dose-dependent manner. Our results demonstrate that the SF3b complex is a pharmacologically relevant protein target of pladienolide and suggest that this splicing factor is a potential antitumor drug target.     

Synthesis and biological evaluation of N-(7-indolyl)-3-pyridinesulfonamide derivatives as potent antitumor agents

We herein report the synthesis and antitumor activity of E7070 analogues containing a 3-pyridinesulfonamide moiety. E7070 was selected from our sulfonamide-based compound collections, currently undergoing Phase II clinical trials because of its tolerable toxicity profile and some antitumor responses in the Phase I setting. Of the analogues examined, ER-35745, a 6-amino-3-pyridinesulfonamide derivative, demonstrated significant oral efficacy against the HCT116 human colon carcinoma xenograft in nude mice.     

Distinctive presence of peritracheal athrocytes in Bombyx mori L. and Bombyx mandarina M. as compared to their absence in several other lepidopteran species

Pericardial cells are present in a wide variety of insects and are thought to constitute the majority of 'athrocytes (nephrocytes)'. In contrast, peritracheal athrocytes have only been observed in Bombyx mori L. Although peritracheal athrocytes have a distinct morphology, it is unknown whether these cells are common to all lepidopterans. We anatomically compared eight lepidopteran species: Bombyx mori L. and Bombyx mandarina M. (Bombycidae); Samia cynthia ricini D. (Saturniidae); Agrius convolvuli L. (Sphingidae); Spodoptera litura F. and Mythimna separata W. (Noctuidae); Pieris rapae L. (Pieridae); and Glyphodes pyloalis W. (Crambidae). Of these species, only Bombyx mori L. and Bombyx mandarina M. possess peritracheal athrocytes.