Arenobufagin Inhibits the Phosphatidylinositol 3-kinase/Protein Kinase B/Mammalian Target of Rapamycin Pathway and Induces Apoptosis and Autophagy in Pancreatic Cancer Cells.
Animals
Apoptosis
/ drug effects
Autophagy
/ drug effects
Bufanolides
/ pharmacology
Cell Cycle
/ drug effects
Cell Line
Cell Line, Tumor
Cell Survival
/ drug effects
Humans
Membrane Potential, Mitochondrial
/ drug effects
Mice, Inbred BALB C
Mice, Nude
Microscopy, Electron, Transmission
Pancreatic Neoplasms
/ drug therapy
Phosphatidylinositol 3-Kinase
/ metabolism
Proto-Oncogene Proteins c-akt
/ metabolism
Signal Transduction
/ drug effects
TOR Serine-Threonine Kinases
/ metabolism
Xenograft Model Antitumor Assays
/ methods
Journal
Pancreas
ISSN: 1536-4828
Titre abrégé: Pancreas
Pays: United States
ID NLM: 8608542
Informations de publication
Date de publication:
02 2020
02 2020
Historique:
pubmed:
6
2
2020
medline:
26
1
2021
entrez:
4
2
2020
Statut:
ppublish
Résumé
The aim of the study was to investigate the effects of arenobufagin on pancreatic carcinoma in vitro and in vivo and its molecular mechanism. The proliferation of pancreatic cancer cells was detected by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Transmission electron microscopy was used to observe the formation of autophagic vacuoles after arenobufagin treatment. Hoechst 33258 and monodansylcadaverine fluorescence staining were performed to evaluate cell apoptosis and autophagy. Annexin V-fluorescein isothiocyanate/propidium iodide double-staining and JC-1 staining assays were used to evaluate apoptosis-related changes. Reverse-transcription polymerase chain reaction and western blotting were carried out to examine the expression of apoptosis- and autophagy-related markers after arenobufagin treatment. A tumor xenograft nude mouse model was established to evaluate arenobufagin efficacy in vivo. Arenobufagin effectively inhibited the proliferation of SW1990 and BxPC3 cells and induced cell arrest, apoptosis, and autophagy. Arenobufagin upregulated the expression of apoptotic- and autophagy-related proteins while downregulated the expression of phosphatidylinositol 3-kinase family proteins. Furthermore, arenobufagin also exerted inhibitory effects on tumor growth in xenograft nude mice. Arenobufagin inhibits tumor growth in vivo and in vitro. The mechanism underlying arenobufagin action may involve induction of autophagy and apoptosis through the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin pathway.
Identifiants
pubmed: 32011523
doi: 10.1097/MPA.0000000000001471
pii: 00006676-202002000-00016
doi:
Substances chimiques
Bufanolides
0
arenobufagin
464-74-4
Phosphatidylinositol 3-Kinase
EC 2.7.1.137
AKT1 protein, human
EC 2.7.11.1
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
TOR Serine-Threonine Kinases
EC 2.7.11.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
261-272Références
Schnelldorfer T, Gansauge S, Gansauge F, et al. Glutathione depletion causes cell growth inhibition and enhanced apoptosis in pancreatic cancer cells. Cancer. 2015;89:1440–1447.
Hidalgo M, O'Reilly EM, Ko YJ, et al. Improved 6-month survival rate in subjects with prostate stem cell antigen positive tumors in a global, randomized phase 2 trial comparing gemcitabine vs. gemcitabine + Ags-1c4d4 (Asp6182) in metastatic pancreatic cancer. In: Oral presentations. Ann Oncol. 2011;22(suppl 5):v12.abstract O-0007.
Adiseshaiah PP, Crist RM, Hook SS, et al. Nanomedicine strategies to overcome the pathophysiological barriers of pancreatic cancer. Nat Rev Clin Oncol. 2016;13:750–765.
Capasso M, Franceschi M, Rodriguez-Castro KI, et al. Epidemiology and risk factors of pancreatic cancer. Acta Biomed. 2018;89(9-S):141–146.
Stathis A, Moore MJ. Advanced pancreatic carcinoma: current treatment and future challenges. Nat Rev Clin Oncol. 2010;7:163–172.
Hartel M, di Mola FF, Selvaggi F, et al. Vanilloids in pancreatic cancer: potential for chemotherapy and pain management. Gut. 2006;55:519–528.
Andersson R, Aho U, Nilsson BI, et al. Gemcitabine chemoresistance in pancreatic cancer: molecular mechanisms and potential solutions. Scand J Gastroenterol. 2009;44:782–786.
Vernerey D, Huguet F, Vienot A, et al. Prognostic nomogram and score to predict overall survival in locally advanced untreated pancreatic cancer (PROLAP). Br J Cancer. 2016;115:281–289.
Cao HH, Zhang DM, Liu JS, et al. Inhibitory effect of arenobufagin on the adhesion, invasion and migration of human hepatoma carcinoma cells. Chinese Pharmacol Bull. 2011;27:19–23.
Dang L, Ren QW, Wei MH. The effect and mechanism of apoptosis induced by Arenobufagin in human hepatocellular carcinoma cells SMMC-7721. J Emerg Trad Chin Med. 2013;22:1845–1847, 1883.
Cunha-Filho GA, Resck IS, Cavalcanti BC, et al. Cytotoxic profile of natural and some modified bufadienolides from toad Rhinella schneideri parotoid gland secretion. Toxicon. 2010;56:339–348.
Wang XD, Yan ZP, Zhang L, et al. Survey on the study of extraction and separation of the effective components from the skin of Bufo bufo gargarizans cantor. Acta Academiae Medicinae CPAF. 2011;20:1009–1011, 1016.
Li M, Wu S, Liu Z, et al. Arenobufagin, a bufadienolide compound from toad venom, inhibits VEGF-mediated angiogenesis through suppression of VEGFR-2 signaling pathway. Biochem Pharmacol. 2012;83:1251–1260.
Zhang DM, Liu JS, Deng LJ, et al. Arenobufagin, a natural bufadienolide from toad venom, induces apoptosis and autophagy in human hepatocellular carcinoma cells through inhibition of PI3K/Akt/mTOR pathway. Carcinogenesis. 2013;34:1331–1342.
Wang T, Zhuang Z, Zhang P, et al. Effect of arenobufagin on human pancreatic carcinoma cells. Oncol Lett. 2017;14:4971–4976.
Wang T, Yuan Y. Arenobufagin targets K-Ras downstream to enhance the efficiency of gemcitabine in human pancreatic carcinoma cells. Cancer Res. 2015;75(suppl):abstract 2696.
Dai ZJ, Gao J, Ma XB, et al. Up-regulation of hypoxia inducible factor-1α by cobalt chloride correlates with proliferation and apoptosis in PC-2 cells. J Exp Clin Cancer Res. 2012;31:28.
Chen X, Deng L, Jiang X, et al. Chinese herbal medicine for oesophageal cancer. Cochrane Db Syst Rev. 2016;1:CD004520.
Zhang JQ, Li YM, Liu T. Antitumor effect of matrine in human hepatoma G2 cells by inducing apoptosis and autophagy. World J Gastroenterol. 2010;16:4281–4290.
Ye J, Cai X, Yang J, et al. Bacillus as a potential diagnostic marker for yellow tongue coating. Sci Rep. 2016;6:32496.
Dai ZJ, Gao J, Ma XB, et al. Antitumor effects of rapamycin in pancreatic cancer cells by inducing apoptosis and autophagy. Int J Mol Sci. 2013;14:273–285.
Biederbick A, Kern HF, Elsässer HP. Monodansylcadaverine (MDC) is a specific in vivo marker for autophagic vacuoles. Euro J Cell Biol. 1995;66:3–14.
Han L, Xia X, Xiang X, et al. Protective effects of canolol against hydrogen peroxide-induced oxidative stress in AGS cells. RSC Adv. 2017;7:42826–42832.
Yang X, Hao J, Zhu CH, et al. Survival benefits of Western and traditional Chinese medicine treatment for patients with pancreatic cancer. Medicine (Baltimore). 2015;94:e1008.
Chen L, Mai W, Chen M, et al. Arenobufagin inhibits prostate cancer epithelial-mesenchymal transition and metastasis by down-regulating β-catenin. Pharmacol Res. 2017;123:130–142.
Deng LJ, Peng QL, Wang LH, et al. Arenobufagin intercalates with DNA leading to G2 cell cycle arrest via ATM/ATR pathway. Oncotarget. 2015;6:34258–34275.
Ma L, Zhu Y, Fang S, et al. Arenobufagin induces apoptotic cell death in human non-small-cell lung cancer cells via the NOXA-related pathway. Molecules. 2017;22:pii: E1525.
Baehrecke EH. How death shapes life during development. Nat Rev Mol Cell Bio. 2002;3:779–787.
Loos B, Engelbrecht AM, Lockshin RA, et al. The variability of autophagy and cell death susceptibility: unanswered questions. Autophagy. 2013;9:1270–1285.
Maycotte P, Thorburn A. Autophagy and cancer therapy. Cancer Biol Ther. 2013;11:127–137.
Yang C, Kaushal V, Shah SV, et al. Autophagy is associated with apoptosis in cisplatin injury to renal tubular epithelial cells. Am J Physiol-Renal. 2008;294:F777–F787.
Morselli E, Galluzzi L, Kepp O. Anti- and pro-tumor functions of autophagy. Biochim Biophys Acta. 2009;1793:1524–1532.
Liang XH, Jackson S, Seaman M, et al. Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature. 1999;402:672–676.
Yue Z, Jin S, Yang C, et al. Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proc Natl Acad Sci U S A. 2003;100:15077–15082.
Mundi PS, Sachdev J, McCourt C, et al. AKT in cancer: new molecular insights and advances in drug development. Brit J Clin Pharmacol. 2016;82:943–956.
Gao Y, Gartenhaus RB, Lapidus RG, et al. Differential IKK/NF-κB activity is mediated by TSC2 through mTORC1 in PTEN-null prostate cancer and tuberous sclerosis complex tumor cells. Mol Cancer Res. 2015;13:1602–1614.
Cheng Y, Kim J, Li XX, et al. Promotion of ovarian follicle growth following mTOR activation: synergistic effects of AKT stimulators. PLoS One. 2015;10:e0117769.
Wang G, Zhang T, Sun W, et al. Arsenic Sulfide induces apoptosis and autophagy through the activation of ROS/JNK and suppression of Akt/mTOR signaling pathways in osteosarcoma. Free Radic Biol Med. 2017;106:24–37.
Zhou G, Myers R, Li Y, et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest. 2001;108:1167–1174.
Hu J, Cui W, Ding W, et al. Globular adiponectin attenuated H2O2-induced apoptosis in rat chondrocytes by inducing autophagy through the AMPK/mTOR pathway. Cell Physiol Biochem. 2017;43:367–382.
Hahn SA, Schutte M, Hoque AT, et al. DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science. 1996;271:350–353.
Fullerton PT Jr, Creighton CJ, Matzuk MM. Insights into SMAD4 loss in pancreatic cancer from inducible restoration of TGF-β signaling. Mol Endocrinol. 2015;29:1440–1453.
Komarova EA, Gudkov AV. Suppression of p53: a new approach to overcome side effects of antitumor therapy. Biochemistry (Mosc). 2000;65:41–48.
Mathew R, Karp CM, Beaudoin B, et al. Autophagy suppresses tumorigenesis through elimination of p62. Cell. 2009;137:1062–1075.
Tomek M, Akiyama T, Dass CR. Role of Bcl-2 in tumour cell survival and implications for pharmacotherapy. J Pharm Pharmacol. 2012;64:1695–1702.
Mao Y, Xi L, Li Q, et al. Regulation of cell apoptosis and proliferation in pancreatic cancer through PI3K/Akt pathway via Polo-like kinase 1. Oncol Rep. 2016;36:49–56.
Fujimoto K, Hanson PT, Tran H, et al. Autophagy regulates pancreatic beta cell death in response to Pdx1 deficiency and nutrient deprivation. J Biol Chem. 2009;284:27664–27673.
Yoshioka A, Miyata H, Doki Y, et al. LC3, an autophagosome marker, is highly expressed in gastrointestinal cancers. Int J Oncol. 2008;33:461–468.
Kung CP, Budina A, Balaburski G, et al. Autophagy in tumor suppression and cancer therapy. Crit Rev Eukaryotic Gene Expression. 2011;21:71–100.
Mei Y, Glover K, Su M, et al. Conformational flexibility of BECN1: essential to its key role in autophagy and beyond. Protein Sci. 2016;25:1767–1785.
Bu HQ, Liu DL, Wei WT, et al. Oridonin induces apoptosis in SW1990 pancreatic cancer cells via p53-and caspase-dependent induction of p38 MAPK. Oncol Rep. 2014;31:975–982.
Lv J, Lin S, Peng P, et al. Arenobufagin activates p53 to trigger esophageal squamous cell carcinoma cell apoptosis in vitro and in vivo. Onco Targets Ther. 2017;10:1261–1267.