title: PHY906(KD018), an adjuvant based on a 1800-year-old Chinese medicine, enhanced the anti-tumor activity of Sorafenib by changing the tumor microenvironment.
abstract: PHY906 (KD018) is a four-herb Chinese Medicine Formula. It has been shown to potentially enhance the therapeutic indices of different class anticancer agents in vivo. Here, PHY906 is reported to enhance the anti-tumor activity of Sorafenib in nude mice bearing HepG2 xenografts. Among the four herbal ingredients of PHY906, Scutellaria baicalensis Georgi (S) and Paeonia lactiflora Pall (P) are required; however, S plays a more important role than P in increasing tumor apoptosis induced by Sorafenib with an increase of mouse(m)FasL and human(h)FasR expression. PHY906 may potentiate Sorafenib action by increasing hMCP1 expression and enhancing infiltration of macrophages into tumors with a higher M1/M2 (tumor rejection) signature expression pattern, as well as affect autophagy by increasing AMPKα-P and ULK1-S555-P of tumors. Depletion of macrophage could counteract PHY906 to potentiate the anti-tumor activity of Sorafenib. It was reported that tumor cells with higher levels of ERK1/2-P are more susceptible to Sorafenib, and the S component of PHY906 may increase ERK1/2-P via inhibition of ERK1/2 phosphatase in HepG2 tumors. PHY906 may potentiate the anti-hepatoma activity of Sorafenib by multiple mechanisms targeting on the inflammatory state of microenvironment of tumor tissue through two major ingredients (P and S) of PHY906.
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: Wing
authors.initials: W
authors.lastname: Lam
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: Zaoli
authors.initials: Z
authors.lastname: Jiang
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: Fulan
authors.initials: F
authors.lastname: Guan
authors.affiliation: Department of Computational Biology and Bioinformatics, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: Xiu
authors.initials: X
authors.lastname: Huang
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: Rong
authors.initials: R
authors.lastname: Hu
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Bussom
authors.affiliation: PhytoCeutica Inc. Branford, Connecticut 06405, USA.
authors.forename: Shwu-Huey
authors.initials: SH
authors.lastname: Liu
authors.affiliation: Department of Computational Biology and Bioinformatics, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Department of Molecular Pharmacology. City of Hope, Duarte, California, USA.
authors.forename: Yun
authors.initials: Y
authors.lastname: Yen
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: Yung-Chi
authors.initials: YC
authors.lastname: Cheng
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D004365:Drugs, Chinese Herbal / Q000008:administration & dosage*; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008516:Medicine, Chinese Traditional; D051379:Mice; D008819:Mice, Nude; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives*; D010671:Phenylurea Compounds / Q000008:administration & dosage*; D010936:Plant Extracts / Q000008:administration & dosage / Q000737:chemistry; D031364:Scutellaria baicalensis; D000077157:Sorafenib; D059016:Tumor Microenvironment / Q000187:drug effects
chemical_list: D004365:Drugs, Chinese Herbal; C476037:PHY 906; D010671:Phenylurea Compounds; D010936:Plant Extracts; C499814:Scutellaria baicalensis extract; D009536:Niacinamide; D000077157:Sorafenib
references.citation: Cancer Res. 2004 Oct 1;64(19):7099-109
references.pmid: 15466206
references.citation: Cell Death Dis. 2013;4:e485
references.pmid: 23392173
references.citation: FEBS J. 2010 Jan;277(1):2-21
references.pmid: 19843174
references.citation: Anticancer Res. 2009 Oct;29(10):4083-92
references.pmid: 19846955
references.citation: Cancer Chemother Pharmacol. 2014 Feb;73(2):373-80
references.pmid: 24297682
references.citation: Biochem Biophys Res Commun. 2008 Nov 21;376(3):483-8
references.pmid: 18796294
references.citation: Nat Cell Biol. 2013 Jul;15(7):713-20
references.pmid: 23817233
references.citation: Proc Natl Acad Sci U S A. 2011 Mar 22;108(12):4788-93
references.pmid: 21383122
references.citation: Cancer Metastasis Rev. 2007 Dec;26(3-4):373-400
references.pmid: 17717638
references.citation: N Engl J Med. 2008 Jul 24;359(4):378-90
references.pmid: 18650514
references.citation: Clin Colorectal Cancer. 2011 Jun;10(2):85-96
references.pmid: 21859559
references.citation: J Ethnopharmacol. 2012 Apr 10;140(3):614-23
references.pmid: 22326673
references.citation: BMC Med Genomics. 2011;4:38
references.pmid: 21569348
references.citation: Clin Colorectal Cancer. 2003 Feb;2(4):253-6
references.pmid: 12620148
references.citation: Autophagy. 2013 Sep;9(9):1270-85
references.pmid: 23846383
references.citation: Int J Radiat Biol. 2013 Jan;89(1):16-25
references.pmid: 22856538
references.citation: Phytomedicine. 2010 Mar;17(3-4):161-9
references.pmid: 20092990
references.citation: Biochem J. 2009 Mar 15;418(3):475-89
references.pmid: 19228121
references.citation: J Biol Chem. 2006 Nov 10;281(45):33939-48
references.pmid: 16954213
references.citation: Proc Natl Acad Sci U S A. 1997 Apr 1;94(7):3302-7
references.pmid: 9096388
references.citation: Mol Cancer Ther. 2010 Aug;9(8):2220-31
references.pmid: 20682655
references.citation: Science. 2011 Jan 28;331(6016):456-61
references.pmid: 21205641
references.citation: Hepatology. 2008 Oct;48(4):1312-27
references.pmid: 18821591
references.citation: BMC Med. 2009;7:41
references.pmid: 19698189
references.citation: J Neurochem. 2008 Nov;107(3):616-27
references.pmid: 18710416
references.citation: Mol Pharmacol. 2009 Aug;76(2):342-55
references.pmid: 19483104
references.citation: Apoptosis. 2006 Mar;11(3):337-46
references.pmid: 16538383
references.citation: J Chromatogr A. 2010 Sep 10;1217(37):5785-93
references.pmid: 20696432
references.citation: N Engl J Med. 2011 Sep 22;365(12):1118-27
references.pmid: 21992124
references.citation: J Clin Oncol. 2006 Sep 10;24(26):4293-300
references.pmid: 16908937
references.citation: Chin Med. 2010 Aug 20;5:30
references.pmid: 20727161
references.citation: J Biol Chem. 2000 Dec 15;275(50):39090-5
references.pmid: 10993892
references.citation: Sci Transl Med. 2010 Aug 18;2(45):45ra59
references.pmid: 20720216