title: Hernandezine, a novel AMPK activator induces autophagic cell death in drug-resistant cancers.
abstract: Drug resistance hinder most cancer chemotherapies and leads to disease recurrence and poor survival of patients. Resistance of cancer cells towards apoptosis is the major cause of these symptomatic behaviours. Here, we showed that isoquinoline alkaloids, including liensinine, isoliensinine, dauricine, cepharanthine and hernandezine, putatively induce cytotoxicity against a repertoire of cancer cell lines (HeLa, A549, MCF-7, PC3, HepG2, Hep3B and H1299). Proven by the use of apoptosis-resistant cellular models and autophagic assays, such isoquinoline alkaloid-induced cytotoxic effect involves energy- and autophagy-related gene 7 (Atg7)-dependent autophagy that resulted from direct activation of AMP activated protein kinase (AMPK). Hernandezine possess the highest efficacy in provoking such cell death when compared with other examined compounds. We confirmed that isoquinoline alkaloid is structurally varied from the existing direct AMPK activators. In conclusion, isoquinoline alkaloid is a new class of compound that induce autophagic cell death in drug-resistant fibroblasts or cancers by exhibiting its direct activation on AMPK.
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China.
authors.forename: Betty Yuen Kwan
authors.initials: BY
authors.lastname: Law
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China.
authors.forename: Simon Wing Fai
authors.initials: SW
authors.lastname: Mok
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China.
authors.forename: Wai Kit
authors.initials: WK
authors.lastname: Chan
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China.
authors.forename: Su Wei
authors.initials: SW
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China.
authors.forename: An Guo
authors.initials: AG
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China.
authors.forename: Xiao Jun
authors.initials: XJ
authors.lastname: Yao
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China.
authors.forename: Jing Rong
authors.initials: JR
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China.
authors.forename: Vincent Kam Wai
authors.initials: VK
authors.lastname: Wong
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects*; D044182:Benzylisoquinolines / Q000494:pharmacology*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004365:Drugs, Chinese Herbal / Q000737:chemistry; D004622:Embryo, Mammalian / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D005434:Flow Cytometry; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D008856:Microscopy, Fluorescence; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D044182:Benzylisoquinolines; D004365:Drugs, Chinese Herbal; C067193:hernandezine; D055372:AMP-Activated Protein Kinases
keywords: AMPK activator; autophagic cell death; autophagy; drug-resistant cancer; hernandezine
references.citation: Nat Cell Biol. 2011 Sep 02;13(9):1016-23
references.pmid: 21892142
references.citation: J Cell Biol. 2005 May 9;169(3):425-34
references.pmid: 15866887
references.citation: Annu Rev Nutr. 2007;27:19-40
references.pmid: 17311494
references.citation: J Biol Chem. 2007 Apr 6;282(14):10341-51
references.pmid: 17287212
references.citation: EMBO Mol Med. 2014 Apr;6(4):519-38
references.pmid: 24497570
references.citation: Metabolism. 1997 Nov;46(11):1270-4
references.pmid: 9361684
references.citation: Br J Pharmacol. 1994 Nov;113(3):767-74
references.pmid: 7858865
references.citation: Diabetes Care. 2012 Feb;35(2):299-304
references.pmid: 22266734
references.citation: Life Sci. 1996;58(25):2327-35
references.pmid: 8649222
references.citation: Oncotarget. 2014 Aug 15;5(15):6087-101
references.pmid: 25026281
references.citation: Oncotarget. 2015 Jun 20;6(17 ):15551-65
references.pmid: 26036632
references.citation: Mol Cancer Ther. 2011 Sep;10(9):1533-41
references.pmid: 21878654
references.citation: Semin Cell Dev Biol. 2010 Sep;21(7):664-70
references.pmid: 20359542
references.citation: J Pharmacol Exp Ther. 2011 Apr;337(1):125-36
references.pmid: 21205922
references.citation: Oncogene. 2011 Mar 10;30(10):1174-82
references.pmid: 21102522
references.citation: Cell. 2000 Jan 7;100(1):57-70
references.pmid: 10647931
references.citation: J Biol Chem. 2007 Oct 12;282(41):30143-9
references.pmid: 17724029
references.citation: Physiol Rev. 2009 Jul;89(3):1025-78
references.pmid: 19584320
references.citation: Oncogene. 2001 Oct 4;20(45):6570-8
references.pmid: 11641782
references.citation: Cell Res. 2014 Jan;24(1):69-79
references.pmid: 24323045
references.citation: Mol Cancer Ther. 2010 Mar;9(3):718-30
references.pmid: 20197400
references.citation: Proc Natl Acad Sci U S A. 1982 Mar;79(6):1889-92
references.pmid: 6952238
references.citation: Free Radic Biol Med. 2009 Oct 1;47(7):1082-92
references.pmid: 19616619
references.citation: Stem Cells. 1994 Jan;12(1):64-7
references.pmid: 8142921
references.citation: Expert Opin Ther Pat. 2012 Dec;22(12):1467-77
references.pmid: 23136886
references.citation: Nat Cell Biol. 2011 Feb;13(2):132-41
references.pmid: 21258367
references.citation: J Lipid Res. 2011 Sep;52(9):1617-25
references.pmid: 21757781
references.citation: Oncotarget. 2015 Apr 10;6(10):7365-78
references.pmid: 25812084
references.citation: Cell Death Dis. 2013 Jul 11;4:e720
references.pmid: 23846222
references.citation: Proc Natl Acad Sci U S A. 2004 Mar 9;101(10):3329-35
references.pmid: 14985505
references.citation: J Cell Biochem. 2009 May 15;107(2):303-15
references.pmid: 19301261
references.citation: Biochem Pharmacol. 2009 Jul 1;78(1):78-84
references.pmid: 19447226
references.citation: Mol Carcinog. 2015 Oct;54(10 ):1096-109
references.pmid: 24838344
references.citation: Oncotarget. 2015 Apr 10;6(10):8071-88
references.pmid: 25797270
references.citation: Nat Rev Cancer. 2005 Sep;5(9):726-34
references.pmid: 16148885
references.citation: Pol Arch Med Wewn. 2011 Mar;121(3):81-7
references.pmid: 21430609
references.citation: Cell Signal. 2012 Dec;24(12):2329-36
references.pmid: 22885103
references.citation: Curr Opin Cell Biol. 2010 Apr;22(2):132-9
references.pmid: 20056399
references.citation: J Pharmacol Sci. 2013;123(2):102-9
references.pmid: 24048094
references.citation: Oncotarget. 2014 Jan 15;5(1):298-308
references.pmid: 24457597
references.citation: Mol Biol Cell. 2008 Aug;19(8):3283-9
references.pmid: 18508926
references.citation: Biochem Pharmacol. 2008 Apr 1;75(7):1482-91
references.pmid: 18261713
references.citation: Autophagy. 2012 Apr;8(4):445-544
references.pmid: 22966490
references.citation: J Immunol. 2008 Dec 15;181(12):8633-41
references.pmid: 19050283
references.citation: Cell Death Differ. 2004 Sep;11(9):1046-8
references.pmid: 15143348
references.citation: Autophagy. 2012 Aug;8(8):1215-26
references.pmid: 22647982
references.citation: Autophagy. 2007 Sep-Oct;3(5):452-60
references.pmid: 17534139
references.citation: Am J Physiol Endocrinol Metab. 2009 Apr;296(4):E955-64
references.pmid: 19208854
references.citation: Nat Commun. 2013;4:3017
references.pmid: 24352254
references.citation: J Transl Med. 2015 Mar 15;13:92
references.pmid: 25884210
references.citation: Ann Transl Med. 2014 Jun;2(6):57
references.pmid: 25333032
references.citation: Diabetes. 2004 Feb;53(2):330-5
references.pmid: 14747282
references.citation: Cancer Cell Int. 2014 Jun 11;14:49
references.pmid: 24991192
references.citation: Life Sci. 1995;56(5):295-306
references.pmid: 7837929
references.citation: J Nutr Biochem. 2013 Jun;24(6):1053-61
references.pmid: 23313043
references.citation: BMJ. 2005 Jun 4;330(7503):1304-5
references.pmid: 15849206
references.citation: Trends Endocrinol Metab. 2013 Sep;24(9):469-80
references.pmid: 23773243
references.citation: Br J Cancer. 2011 Jan 18;104(2):345-52
references.pmid: 21179032
references.citation: Oncogene. 2002 Sep 5;21(39):6082-90
references.pmid: 12203120
references.citation: J Biol Chem. 2007 Aug 31;282(35):25464-74
references.pmid: 17595159
references.citation: Cancer Cell. 2013 Feb 11;23(2):143-58
references.pmid: 23352126
references.citation: J Biol Chem. 2009 May 1;284(18):12297-305
references.pmid: 19258318
references.citation: Sci Rep. 2014 Jul 01;4:5510
references.pmid: 24981420
references.citation: Nat Rev Mol Cell Biol. 2007 Sep;8(9):741-52
references.pmid: 17717517
references.citation: Mol Cell Biol. 2006 Jul;26(14 ):5336-47
references.pmid: 16809770