title: Anthothecol-encapsulated PLGA nanoparticles inhibit pancreatic cancer stem cell growth by modulating sonic hedgehog pathway.
abstract: Anthothecol, a limonoid isolated from plant Khaya anthotheca (Meliaceae), is an antimalarial compound. The objectives of this study were to examine the molecular mechanisms by which anthothecol-encapsulated PLGA-nanoparticles (Antho-NPs) regulate the behavior of pancreatic cancer stem cells (CSCs). Antho-NPs inhibited cell proliferation and colony formation, and induced apoptosis in pancreatic CSCs and cancer cell lines, but had no effects on human normal pancreatic ductal epithelial cells. Antho-NPs inhibited self-renewal capacity of pancreatic CSCs isolated from human and Kras(G12D) mice. Furthermore, antho-NPs suppressed cell motility, migration and invasion by up-regulating E-cadherin and inhibiting N-cadherin and Zeb1. In addition, Antho-NPs inhibited pluripotency maintaining factors and stem cell markers, suggesting their inhibitory role on CSC population. Anthothecol disrupted binding of Gli to DNA, and inhibited Gli transcription and Gli target genes. Our studies establish preclinical significance of Antho-NPs for the treatment and/or prevention of pancreatic cancer.
  
  
  BACKGROUND
  Despite medical advances, the prognosis of pancreatic cancer remains poor. The search for an effective treatment has been under intensive research for some time. In this article, the authors investigated the efficacy and mechanism of anthothecol (an antimalarial compound), encapsulated by PLGA nanoparticles (Antho-NPs), against pancreatic cancer cell lines. It was found that Antho-NPs acted via the Sonic hedgehog signaling pathway and inhibited cancer stem cell growth. These results have provided important basis for further clinical trials.
authors.affiliation: Kansas City VA Medical Center, Kansas City, MO, USA.
authors.forename: Raj Kumar
authors.initials: RK
authors.lastname: Verma
authors.affiliation: Kansas City VA Medical Center, Kansas City, MO, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Yu
authors.affiliation: Centre of Bioinformatics (IIDS), University of Allahabad, Allahabad, UP, India.
authors.forename: Surya Pratap
authors.initials: SP
authors.lastname: Singh
authors.affiliation: Kansas City VA Medical Center, Kansas City, MO, USA; Department of Pathology, University of Missouri-School of Medicine, Kansas City, MO, USA.
authors.forename: Sharmila
authors.initials: S
authors.lastname: Shankar
authors.affiliation: Kansas City VA Medical Center, Kansas City, MO, USA. Electronic address: rsrivastava.lab@gmail.com.
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Srivastava
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D019344:Lactic Acid / Q000737:chemistry*; D036701:Limonins / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D029582:Meliaceae / Q000737:chemistry; D051379:Mice; D008958:Models, Molecular; D053758:Nanoparticles / Q000737:chemistry*; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000962:Antimalarials; D000970:Antineoplastic Agents; D053823:Hedgehog Proteins; D036701:Limonins; C530481:anthothecol; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid
keywords: Anthothecol; Cancer stem cell; Nanoparticles; Nanotechnology; PLGA; Pancreatic cancer; Sonic hedgehog