aprepitant and Colonic-Neoplasms

Our knowledge of the major mechanisms underlying the effect of food on drug absorption allows reliable qualitative prediction based on biopharmaceutical properties, which can be assessed during the pre-clinical phase of drug discovery. Furthermore, several recent examples have shown that physiologically based absorption models incorporating biorelevant drug solubility measurements can provide quite accurate quantitative prediction of food effect. However, many molecules currently in development have distinctly sub-optimal biopharmaceutical properties, making the quantitative prediction of food effect for different formulations from in vitro data very challenging. If such drugs reach clinical development and show undesirable variability when dosed with food, improved formulation can help to reduce the food effect and carefully designed in vivo studies in dogs can be a useful guide to clinical formulation development. Even so, such in vivo studies provide limited throughput for screening, and food effects seen in dog cannot always be directly translated to human. This paper describes how physiologically based absorption modeling can play a role in the prediction of food effect by integrating the data generated during pre-clinical and clinical research and development. Such data include physicochemical and in vitro drug properties, biorelevant solubility and dissolution, and in vivo pre-clinical and clinical pharmacokinetic data. Some background to current physiological absorption models of human and dog is given, and refinements to models of in vivo drug solubility and dissolution are described. These are illustrated with examples using GastroPlus to simulate the food effect in dog and human for different formulations of two marketed drugs.

Topics: Adenocarcinoma; Animals; Aprepitant; Cell Line, Tumor; Chemical Precipitation; Chemistry, Pharmaceutical; Colonic Neoplasms; Computer Simulation; Dogs; Eating; Fasting; Female; Food-Drug Interactions; Gastrointestinal Contents; Gastrointestinal Tract; Humans; Hydrogen-Ion Concentration; Intestinal Absorption; Models, Biological; Morpholines; Pharmacokinetics; Solubility; Species Specificity; Theophylline

The substance P (SP)/neurokinin-1 receptor (NK1R) complex and the Wnt cascade are pivotal signaling pathways in the regulation of cell growth and hence, potent targets for future anticancer therapies. However, while the Wnt cascade has long been associated with colon cancer, little is known about the expression of the NK1R complex as a potential target in this tumor and its molecular basis in tumorigenesis in general. We treated the human colon cancer cell lines LiM6 and DLD1 with the NK1R antagonist and the clinical drug aprepitant (AP) and analyzed both growth response and downstream mechanisms using MTT-assay, reverse phase protein array (RPPA), western blot, Super TOP/FOP, confocal microscopy, and sphere formation ability (SFA) assays. Following NK1R blockage, we found significant growth inhibition of both colon cancer cell lines. When analyzing downstream mechanisms, we found a striking inhibition of the canonical Wnt pathway represented by decreased Super TOP/FOP and increased membrane stabilization of β-catenin. This effect was independent from baseline Wnt activity and mutational status of β-catenin. Further, treatment of colon cancer cells grown under cancer stem cell (CSC) conditions reduced sphere formation in both number and size after a single treatment period. We show that the NK1R can be a potent anticancer target in colon cancer and that NK1R antagonists could potentially serve as future anticancer drugs. This effect was seen not only in primary cancer cells but, for the first time, also in CSC-like cells, potentially including these cells in a therapeutic effect. Also, we describe the robust inhibition of canonical Wnt signaling through targeting the SP/NK1R signaling cascade. These findings give important insight into the molecular mechanisms of the SP/NK1R complex as a critical component in tumorigenesis and could help to identify future anticancer therapies for colon and other Wnt-activated cancers.

Topics: Antineoplastic Agents; Aprepitant; Cell Line, Tumor; Cell Proliferation; Colonic Neoplasms; Gene Expression Regulation, Neoplastic; Humans; Molecular Targeted Therapy; Morpholines; Neoplastic Stem Cells; Neurokinin-1 Receptor Antagonists; Receptors, Neurokinin-1; Substance P; Wnt Signaling Pathway