mangostin and Pancreatic-Neoplasms

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease exhibiting the poorest prognosis among solid tumors. The efficacy of conventional therapies has been hindered largely due to the insufficient chemotherapeutic delivery to the dense desmoplastic tumor stroma, and the extremely high or toxic dose needed for chemotherapy. Traditional Chinese Medicine (TCM) contains effective components that can effectively regulate tumor microenvironment and kill tumor cells, providing promising alternatives to PDAC chemotherapy. In this study, two active drug monomers of TCM were screened out and a sequentially targeting delivery regimen was developed to realize the optimized combinational therapy. Transforming growth factor-β (TGF-β) plays an indispensable role in promoting cancer-associated fibroblasts (CAFs) activation and proliferation, and CAFs have caused major physical barriers for chemotherapeutic drug delivery. Herein, CAFs-targeting biodegradable polymer nanoparticle (CRE-NP(α-M)) coated with CREKA peptide and loaded with TCM α-mangostin (α-M) was developed to modulate tumor microenvironment by interfering of TGF-β/Smad signaling pathway. Low pH-triggered micelle modified with CRPPR peptide and loaded with another TCM triptolide was constructed to increase the therapeutic effect of triptolide at the tumor sites and reduced its damage to main organs. As expected, CRE-NP(α-M) effectively inactived CAFs, reduced extracellular matrix production, promoted tumor vascular normalization and enhanced blood perfusion at the tumor site. The sequentially targeting drug delivery regimen, CRP-MC(Trip) following CRE-NP(α-M) pretreatment, exhibited strong tumor growth inhibition effect in the orthotopic tumor model. Hence, sequentially targeting delivery of nanoformulated TCM offers an efficient approach to overcome the permeation obstacles and improve the effect of chemotherapy on PDAC, and provides a novel option to treat desmoplastic tumors.

Topics: Carcinoma, Pancreatic Ductal; Diterpenes; Epoxy Compounds; Humans; Pancreatic Neoplasms; Phenanthrenes; Tumor Microenvironment; Xanthones

The current investigation was intended to elucidate the molecular mechanism of α-Mangostin in the regulation of pancreatic cancer stem cell (CSC) characteristics. Here, we demonstrate that α-Mangostin inhibited cell proliferation in pancreatic CSCs and cancer cell lines while it showed no effect on human pancreatic normal ductal epithelial cells. Also, α-Mangostin inhibited colony formation and induced apoptosis in these cells. Further, α-Mangostin inhibited the self-renewal capacity of CSCs isolated from human primary tumours and Kras

Topics: Animals; Antigens, CD; Antineoplastic Agents, Phytogenic; Apoptosis; Cadherins; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cyclin-Dependent Kinase 2; Dose-Response Relationship, Drug; Epithelial-Mesenchymal Transition; Gene Expression Regulation, Neoplastic; Hedgehog Proteins; Humans; Kruppel-Like Factor 4; Mice; Mice, Transgenic; Nanog Homeobox Protein; Neoplastic Stem Cells; Pancreatic Neoplasms; Promoter Regions, Genetic; Protein Binding; Signal Transduction; Snail Family Transcription Factors; Spheroids, Cellular; Xanthones; Zinc Finger Protein GLI1

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.

Topics: Animals; Antigens, CD; Apoptosis; Cadherins; Carcinogenesis; Cell Line, Tumor; Cell Movement; Cell Survival; Drug Carriers; Epithelial-Mesenchymal Transition; Genes, ras; Hedgehog Proteins; Humans; Lactic Acid; Mice; Mice, Transgenic; Nanoparticles; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplastic Stem Cells; Pancreatic Neoplasms; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Proto-Oncogene Proteins p21(ras); Spheroids, Cellular; Xanthones

Pancreatic cancer (PC) is the most aggressive malignant disease, ranking as the fourth most leading cause of cancer-related death among men and women in the United States. In this study, we provide evidence of chemotherapeutic effects of α-mangostin, a dietary antioxidant isolated from the pericarp of Garcinia mangostana L. against human PC.. The chemotherapeutic effect of α-mangostin was determined using four human PC cells (PL-45, PANC1, BxPC3, and ASPC1). α-Mangostin resulted in a significant inhibition of PC cells viability without having any effects on normal human pancreatic duct epithelial cells. α-Mangostin showed a dose-dependent increase of apoptosis in PC cells. Also, α-mangostin inhibited the expression levels of pNF-κB/p65Ser552, pStat3Ser727, and pStat3Tyr705. α-Mangostin inhibited DNA binding activity of nuclear factor kappa B (NF-κB) and signal transducer and activator 3 (Stat3). α-Mangostin inhibited the expression levels of matrix metallopeptidase 9 (MMP9), cyclin D1, and gp130; however, increased expression of tissue inhibitor of metalloproteinase 1 (TIMP1) was observed in PC cells. In addition, i.p. administration of α-mangostin (6 mg/kg body weight, 5 days a week) resulted in a significant inhibition of both primary (PL-45) and secondary (ASPC1) human PC cell-derived orthotopic and ectopic xenograft tumors in athymic nude mice. No sign of toxicity was observed in any of the mice administered with α-mangostin. α-Mangostin treatment inhibited the biomarkers of cell proliferation (Ki-67 and proliferating cell nuclear antigen [PCNA]) in the xenograft tumor tissues.. We present, for the first time, that dietary antioxidant α-mangostin inhibits the growth of PC cells in vitro and in vivo.. These results suggest the potential therapeutic efficacy of α-mangostin against human PC.

Topics: Animals; Antineoplastic Agents, Phytogenic; Antioxidants; Cell Line; Cell Proliferation; Disease Models, Animal; Dose-Response Relationship, Drug; Garcinia mangostana; Humans; Injections, Intraperitoneal; Mice; Mice, Nude; Pancreatic Neoplasms; Structure-Activity Relationship; Xanthones; Xenograft Model Antitumor Assays

Recent advances indicating a key role of microenvironment for tumor progression, we investigated the role of PSCs and hypoxia in pancreatic cancer aggressiveness, and examined the potential protective effect of α-mangostin on hypoxia-driven pancreatic cancer progression. Our data indicate that hypoxic PSCs exploit their oxidative stress due to hypoxia to secrete soluble factors favouring pancreatic cancer invasion. α-Mangostin suppresses hypoxia-induced PSC activation and pancreatic cancer cell invasion through the inhibition of HIF-1α stabilization and GLI1 expression. Increased generation of hypoxic ROS is responsible for HIF-1α stabilization and GLI1 upregulation. Therefore, α-mangostin may be beneficial in preventing hypoxia-induced pancreatic cancer progression.

Topics: Cell Hypoxia; Cell Line, Tumor; Cells, Cultured; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Neoplasm Invasiveness; Pancreatic Neoplasms; Pancreatic Stellate Cells; Reactive Oxygen Species; Real-Time Polymerase Chain Reaction; RNA Interference; Transcription Factors; Xanthones; Zinc Finger Protein GLI1

α -Mangostin, a natural product isolated from the pericarp of the mangosteen fruit, has been shown to inhibit the growth of tumor cells in various types of cancers. However, the underlying molecular mechanisms are largely unclear. Here, we report that α -mangostin suppressed the viability and epithelial-mesenchymal transition (EMT) of pancreatic cancer cells through inhibition of the PI3K/Akt pathway. Treatment of pancreatic cancer BxPc-3 and Panc-1 cells with α -mangostin resulted in loss of cell viability, accompanied by enhanced cell apoptosis, cell cycle arrest at G1 phase, and decrease of cyclin-D1. Moreover, Transwell and Matrigel invasion assays showed that α -mangostin significantly reduced the migration and invasion of pancreatic cancer cells. Consistent with these results, α -mangostin decreased the expression of MMP-2, MMP-9, N-cadherin, and vimentin and increased the expression of E-cadherin. Furthermore, we found that α -mangostin suppressed the activity of the PI3K/Akt pathway in pancreatic cancer cells as demonstrated by the reduction of the Akt phosphorylation by α -mangostin. Finally, α -mangostin significantly inhibited the growth of BxPc-3 tumor mouse xenografts. Our results suggest that α -mangostin may be potentially used as a novel adjuvant therapy or complementary alternative medicine for the management of pancreatic cancers.

Topics: Animals; Apoptosis; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Down-Regulation; Epithelial-Mesenchymal Transition; G1 Phase; Gene Expression Regulation, Neoplastic; Male; Mice, Inbred BALB C; Mice, Nude; Neoplasm Invasiveness; Pancreatic Neoplasms; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Resting Phase, Cell Cycle; Signal Transduction; Xanthones