title: Antiproliferative activity of novel imidazopyridine derivatives on castration-resistant human prostate cancer cells.
abstract: Metastatic prostate cancer (mPCa) relapses after a short period of androgen deprivation therapy and becomes the castration-resistant prostate cancer (CR PCa); to which the treatment is limited. Hence, it is imperative to identify novel therapeutic agents towards this patient population. In the present study, antiproliferative activities of novel imidazopyridines were compared. Among three derivatives, PHE, AMD and AMN, examined, AMD showed the highest inhibitory activity on LNCaP C-81 cell proliferation, following dose- and time-dependent manner. Additionally, AMD exhibited significant antiproliferative effect against a panel of PCa cells, but not normal prostate epithelial cells. Further, when compared to AMD, its derivative DME showed higher inhibitory activities on PCa cell proliferation, clonogenic potential and in vitro tumorigenicity. The inhibitory activity was apparently in part due to the induction of apoptosis. Mechanistic studies indicate that AMD and DME treatments inhibited both AR and PI3K/Akt signaling. The results suggest that better understanding of inhibitory mechanisms of AMD and DME could help design novel therapeutic agents for improving the treatment of CR PCa.
authors: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.
authors: Sakthivel
authors: S
authors: Muniyan
authors: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA; Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan, ROC.
authors: Yu-Wei
authors: YW
authors: Chou
authors: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.
authors: Matthew A
authors: MA
authors: Ingersoll
authors: Department of Chemistry, Clark Atlanta University, Atlanta, GA, USA.
authors: Alexus
authors: A
authors: Devine
authors: Department of Biological Sciences, Clark Atlanta University, Atlanta, GA, USA.
authors: Marisha
authors: M
authors: Morris
authors: Department of Biological Sciences, Clark Atlanta University, Atlanta, GA, USA; Center for Cancer Research and Therapeutic Development, Clark Atlanta University, Atlanta, GA, USA.
authors: Valerie A
authors: VA
authors: Odero-Marah
authors: Department of Biological Sciences, Clark Atlanta University, Atlanta, GA, USA; Center for Cancer Research and Therapeutic Development, Clark Atlanta University, Atlanta, GA, USA.
authors: Shafiq A
authors: SA
authors: Khan
authors: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.
authors: William G
authors: WG
authors: Chaney
authors: Department of Chemistry, Clark Atlanta University, Atlanta, GA, USA; Laboratory for Electro-Optical Materials & NASA Center for High Performance Polymers and Composites, Clark Atlanta University, Atlanta, GA, USA.
authors: Xiu R
authors: XR
authors: Bu
authors: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA; Department of Surgery/Urology, University of Nebraska Medical Center, Omaha, NE, USA; School of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, Taiwan, ROC. Electronic address: mlin@unmc.edu.
authors: Ming-Fong
authors: MF
authors: Lin
mesh_terms: D000726:Androgen Antagonists / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D064129:Prostatic Neoplasms, Castration-Resistant / Q000378:metabolism / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D011944:Receptors, Androgen / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
chemical_list: C410798:AR protein, human; D000726:Androgen Antagonists; D000970:Antineoplastic Agents; D007093:Imidazoles; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011944:Receptors, Androgen; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt
keywords: Androgen receptor; Imidazopyridine; PI3K/Akt; Prostate cancer; p66Shc