α-Mangostin-encapsulated PLGA nanoparticles inhibit pancreatic carcinogenesis by targeting cancer stem cells in human, and transgenic (Kras(G12D), and Kras(G12D)/tp53R270H) mice.
Activation of sonic hedgehog (Shh) in cancer stem cell (CSC) has been demonstrated with aggressiveness of pancreatic cancer. In order to enhance the biological activity of α-mangostin, we formulated mangostin-encapsulated PLGA nanoparticles (Mang-NPs) and examined the molecular mechanisms by which they inhibit human and KC mice (Pdx(Cre);LSL-Kras(G12D)) pancreatic CSC characteristics in vitro, and pancreatic carcinogenesis in KPC (Pdx(Cre);LSLKras(G12D);LSL-Trp53(R172H)) mice. Mang-NPs inhibited human and Kras(G12D) mice pancreatic CSC characteristics in vitro. Mang-NPs also inhibited EMT by up-regulating E-cadherin and inhibiting N-cadherin and transcription factors Slug, and pluripotency maintaining factors Nanog, c-Myc, and Oct4. Furthermore, Mang-NPs inhibited the components of Shh pathway and Gli targets. In vivo, Mang-NPs inhibited the progression of pancreatic intraneoplasia to pancreatic ductal adenocarcinoma and liver metastasis in KPC mice. The inhibitory effects of Mang-NPs on carcinogenesis in KPC mice were associated with downregulation of pluripotency maintaining factors (c-Myc, Nanog and Oct4), stem cell markers (CD24 and CD133), components of Shh pathway (Gli1, Gli2, Patched1/2, and Smoothened), Gli targets (Bcl-2, XIAP and Cyclin D1), and EMT markers and transcription factors (N-cadherin, Slug, Snail and Zeb1), and upregulation of E-cadherin. Overall, our data suggest that Mang-NPs can inhibit pancreatic cancer growth, development and metastasis by targeting Shh pathway.
Kansas City VA Medical Center, 4801 Linwood Boulevard, Kansas City, MO, 66128, USA.
Raj Kumar
RK
Verma
Kansas City VA Medical Center, 4801 Linwood Boulevard, Kansas City, MO, 66128, USA.
Wei
W
Yu
St. Joseph's Hospital and Medical Center, Phoenix, AZ, 85013, USA.
Anju
A
Shrivastava
Kansas City VA Medical Center, 4801 Linwood Boulevard, Kansas City, MO, 66128, USA.|Department of Pathology and Laboratory Medicine, University of Missouri Kansas City, MO, USA.
Sharmila
S
Shankar
Kansas City VA Medical Center, 4801 Linwood Boulevard, Kansas City, MO, 66128, USA.|Department of Pharmaceutical Sciences, University of Missouri-Kansas City, Kansas City, MO 64108, USA.
Rakesh K
RK
Srivastava
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D017209:Apoptosis; D015820:Cadherins / Q000378:metabolism; D063646:Carcinogenesis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002465:Cell Movement; D002470:Cell Survival; D004337:Drug Carriers / Q000737:chemistry; D058750:Epithelial-Mesenchymal Transition; D011905:Genes, ras; D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D019344:Lactic Acid / Q000737:chemistry; D051379:Mice; D008822:Mice, Transgenic; D053758:Nanoparticles / Q000737:chemistry; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D018874:Spheroids, Cellular; D044004:Xanthones / Q000737:chemistry*
D015703:Antigens, CD; C050361:CDH2 protein, human; D015820:Cadherins; C489083:Cdh2 protein, mouse; D004337:Drug Carriers; D053823:Hedgehog Proteins; C117307:KRAS protein, human; C509239:SHH protein, human; C465570:Shh protein, mouse; D044004:Xanthones; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras); C021053:mangostin