Combination Nanopreparations of a Novel Proapoptotic Drug - NCL-240, TRAIL and siRNA.

Purpose: To develop a multifunctional nanoparticle system carrying a combination of pro-apoptotic drug, NCL-240, TRAIL [tumor necrosis factor-α (TNF-α)-related apoptosis-inducing ligand] and anti-survivin siRNA and to test the combination preparation for anti-cancer effects in different cancer cells.

Methods: Polyethylene glycol-phosphoethanolamine (PEG-PE) - based polymeric micelles were prepared carrying NCL-240. These micelles were used in combination with TRAIL-conjugated micelles and anti-survivin siRNA-S-S-PE containing micelles.

Optimization of the anti-cancer activity of phosphatidylinositol-3 kinase pathway inhibitor PITENIN-1: switching a thiourea with 1,2,3-triazole.

We previously reported encouraging and anti-cancer activity of -((3-chloro-2-hydroxy-5-nitrophenyl)carbamothioyl)benzamide (termed PITENIN-1). In the current work, we describe the structure-activity relationship study of PIT-1 series, based on the replacement of central thiourea unit with a 1,2,3-triazole, which leads to increased liver microsomal stability, drug likeness and toxicity towards cancer cells.

Role of phosphatidylinositol 3,4,5-trisphosphate in cell signaling.

Many lipids present in cellular membranes are phosphorylated as part of signaling cascades and participate in the recruitment, localization, and activation of downstream protein effectors. Phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)P3) is one of the most important second messengers and is capable of interacting with a variety of proteins through specific PtdIns(3,4,5)P3 binding domains. Localization and activation of these effector proteins controls a myriad of cellular functions including cell survival, proliferation, cytoskeletal rearrangement, and gene expression.

Micellar formulations of pro-apoptotic DM-PIT-1 analogs and TRAIL in vitro and in vivo.

We have developed and characterized micellar formulations of analogs to the recently developed inhibitor of the phosphatidylinositol-3-kinase (PI3K) pathway (N-[(2-hydroxy-5-nitrophenyl)amino]carbonothioyl-3,5-dimethylbenzamide (DM-PIT-1)) for their physicochemical, loading and cytotoxic properties. The first generation inhibitor DM-PIT-1 is a non-lipid, small molecule inhibitor of phosphatidylinositol-3,4,5-triphosphate/Pleckstrin homology (PIP3/PH) binding capable of inhibiting the growth of tumor cells both in vitro and in vivo. A second generation of improved and druggable analogs has been developed.