title: Strigolactone analogues induce apoptosis through activation of p38 and the stress response pathway in cancer cell lines and in conditionally reprogrammed primary prostate cancer cells.
abstract: Strigolactones are a novel class of plant hormones produced in roots and regulate shoot and root development. We have previously shown that synthetic strigolactone analogues potently inhibit growth of breast cancer cells and breast cancer stem cells. Here we show that strigolactone analogues inhibit the growth and survival of an array of cancer-derived cell lines representing solid and non-solid cancer cells including: prostate, colon, lung, melanoma, osteosarcoma and leukemic cell lines, while normal cells were minimally affected. Treatment of cancer cells with strigolactone analogues was hallmarked by activation of the stress-related MAPKs: p38 and JNK and induction of stress-related genes; cell cycle arrest and apoptosis evident by increased percentages of cells in the sub-G1 fraction and Annexin V staining. In addition, we tested the response of patient-matched conditionally reprogrammed primary prostate normal and cancer cells. The tumor cells exhibited significantly higher sensitivity to the two most potent SL analogues with increased apoptosis confirmed by PARP1 cleavage compared to their normal counterpart cells. Thus, Strigolactone analogues are promising candidates for anticancer therapy by their ability to specifically induce cell cycle arrest, cellular stress and apoptosis in tumor cells with minimal effects on growth and survival of normal cells.
authors.affiliation: Department of Human Science, Georgetown University Medical Center, NW Washington DC.
authors.forename: Claire B
authors.initials: CB
authors.lastname: Pollock
authors.forename: Sara
authors.initials: S
authors.lastname: McDonough
authors.forename: Victor S
authors.initials: VS
authors.lastname: Wang
authors.forename: Hyojung
authors.initials: H
authors.lastname: Lee
authors.forename: Lymor
authors.initials: L
authors.lastname: Ringer
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.forename: Cristina
authors.initials: C
authors.lastname: Prandi
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Lee
authors.forename: Adam S
authors.initials: AS
authors.lastname: Feldman
authors.forename: Hinanit
authors.initials: H
authors.lastname: Koltai
authors.forename: Yoram
authors.initials: Y
authors.lastname: Kapulnik
authors.forename: Olga C
authors.initials: OC
authors.lastname: Rodriguez
authors.forename: Richard
authors.initials: R
authors.lastname: Schlegel
authors.forename: Christopher
authors.initials: C
authors.lastname: Albanese
authors.forename: Ronit I
authors.initials: RI
authors.lastname: Yarden
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D020869:Gene Expression Profiling; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D007783:Lactones / Q000494:pharmacology*; D008297:Male; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis; D011467:Prostate / Q000187:drug effects / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; C000591191:GR24 strigolactone; D006575:Heterocyclic Compounds, 3-Ring; D007783:Lactones; D012333:RNA, Messenger; C483518:strigol; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases
references.citation: Prostate. 2013 Jun;73(8):835-41
references.pmid: 23255296
references.citation: Nature. 2008 Sep 11;455(7210):195-200
references.pmid: 18690207
references.citation: Proc Natl Acad Sci U S A. 2012 Dec 4;109(49):20035-40
references.pmid: 23169653
references.citation: Biochim Biophys Acta. 2003 Dec 7;1643(1-3):11-24
references.pmid: 14654224
references.citation: Cell Death Dis. 2013 May 23;4:e641
references.pmid: 23703386
references.citation: Curr Med Chem. 2004 Jul;11(13):1693-713
references.pmid: 15279577
references.citation: Clin Cancer Res. 2008 Jul 15;14(14):4408-16
references.pmid: 18628455
references.citation: J Cell Sci. 2006 Jun 15;119(Pt 12):2401-4
references.pmid: 16763193
references.citation: Nature. 2008 Sep 11;455(7210):189-94
references.pmid: 18690209
references.citation: Annu Rev Plant Physiol Plant Mol Biol. 1998 Jun;49:427-451
references.pmid: 15012241
references.citation: Neoplasia. 2008 Nov;10(11):1303-13
references.pmid: 18953440
references.citation: Amino Acids. 2011 Mar;40(3):1003-13
references.pmid: 20821239
references.citation: Cancer. 2003 Jun 15;97(12):3017-26
references.pmid: 12784337
references.citation: J Biol Chem. 2012 Jun 29;287(27):22838-53
references.pmid: 22589537
references.citation: J Pharmacol Exp Ther. 2008 Jun;325(3):841-9
references.pmid: 18337475
references.citation: Nature. 2007 Mar 8;446(7132):153-8
references.pmid: 17344846
references.citation: Clin Cancer Res. 2011 Sep 15;17(18):5850-7
references.pmid: 21673068
references.citation: Oncogene. 2008 Aug 7;27(34):4636-43
references.pmid: 18408762
references.citation: Science. 1965 Apr 23;148(3669):532-3
references.pmid: 17842846
references.citation: Am J Respir Cell Mol Biol. 2002 May;26(5):558-64
references.pmid: 11970907
references.citation: Eur J Endocrinol. 2005 Jul;153(1):123-33
references.pmid: 15994754
references.citation: Nat Genet. 2007 Jun;39(6):741-9
references.pmid: 17468757
references.citation: N Engl J Med. 2012 Sep 27;367(13):1220-7
references.pmid: 23013073
references.citation: Carcinogenesis. 2013 Jun;34(6):1181-8
references.pmid: 23563090
references.citation: Chem Biol Interact. 2010 Dec 5;188(3):487-96
references.pmid: 20833159
references.citation: Cancer Chemother Pharmacol. 2013 Dec;72(6):1315-24
references.pmid: 24121479
references.citation: Plant Physiol. 2012 Apr;158(4):1976-87
references.pmid: 22323776
references.citation: Phytochemistry. 2009 Sep;70(13-14):1600-9
references.pmid: 19660769
references.citation: Cell Mol Biol (Noisy-le-grand). 2012 Oct 10;Suppl.58:OL1780-5
references.pmid: 23046871
references.citation: Am J Pathol. 2012 Feb;180(2):599-607
references.pmid: 22189618
references.citation: Genes Dev. 1994 Feb 15;8(4):453-64
references.pmid: 8125258
references.citation: Mol Cell Biol. 1989 Oct;9(10):4196-203
references.pmid: 2573827
references.citation: Nat Rev Cancer. 2009 Aug;9(8):537-49
references.pmid: 19629069
references.citation: Cell Cycle. 2007 Oct 15;6(20):2429-33
references.pmid: 17957136
references.citation: Cancer Cell. 2007 Jun;11(6):555-69
references.pmid: 17560336
references.citation: Breast Cancer Res Treat. 2012 Aug;134(3):1041-55
references.pmid: 22476848
references.citation: Biochem Biophys Res Commun. 2001 Aug 24;286(3):433-42
references.pmid: 11511077
references.citation: Nat Genet. 2007 Jun;39(6):750-8
references.pmid: 17468755
references.citation: Regen Med. 2010 May;5(3):345-63
references.pmid: 20230312
references.citation: EMBO J. 2004 Dec 8;23(24):4802-12
references.pmid: 15538382
references.citation: Proc Natl Acad Sci U S A. 1998 Jun 23;95(13):7480-4
references.pmid: 9636175
references.citation: Cell. 2007 Sep 21;130(6):986-8
references.pmid: 17889643