title: 1,1-Bis (3'-indolyl)-1-(p-substitutedphenyl)methane compounds inhibit lung cancer cell and tumor growth in a metastasis model.
abstract: 1,1-Bis(3-indolyl)-1-(p-substitutedphenyl)methane (C-DIM) compounds exhibit remarkable antitumor activity with low toxicity in various cancer cells including lung tumors. Two C-DIM analogs, DIM-C-pPhOCH3 (C-DIM-5) and DIM-C-pPhOH (C-DIM-8) while acting differentially on the orphan nuclear receptor, TR3/Nur77 inhibited cell cycle progression from G0/G1 to S-phase and induced apoptosis in A549 cells. Combinations of docetaxel (doc) with C-DIM-5 or C-DIM-8 showed synergistic anticancer activity in vitro and these results were consistent with their enhanced antitumor activities invivo. Respirable aqueous formulations of C-DIM-5 (mass median aerodynamic diameter of 1.92±0.22μm and geometric standard deviation of 2.31±0.12) and C-DIM-8 (mass median aerodynamic diameter of 1.84±0.31μm and geometric standard deviation of 2.11±0.15) were successfully delivered by inhalation to athymic nude mice bearing A549 cells as metastatic tumors. This resulted in significant (p<0.05) lung tumor regression and an overall reduction in tumor burden. Analysis of lung tumors from mice treated with inhalational formulations of C-DIM-5 and C-DIM-8 showed decreased mRNA and protein expression of mediators of tumor initiation, metastasis, and angiogenesis including MMP2, MMP9, c-Myc, β-catenin, c-Met, c-Myc, and EGFR. Microvessel density assessment of lung tissue sections showed significant reduction (p<0.05) in angiogenesis and metastasis as evidenced by decreased distribution of immunohistochemical staining of VEGF, and CD31. Our studies demonstrate both C-DIM-5 and C-DIM-8 have similar anticancer profiles in treating metastatic lung cancer and possibly work as TR3 inactivators.
authors.affiliation: Department of Pharmaceutics, College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, 1520 South Martin Luther King Jr. Blvd., Tallahassee, FL 32307, USA.
authors.forename: Terrick
authors.initials: T
authors.lastname: Andey
authors.forename: Apurva
authors.initials: A
authors.lastname: Patel
authors.forename: Tanise
authors.initials: T
authors.lastname: Jackson
authors.forename: Stephen
authors.initials: S
authors.lastname: Safe
authors.forename: Mandip
authors.initials: M
authors.lastname: Singh
mesh_terms: D000818:Animals; D000840:Anisoles / Q000008:administration & dosage*; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D000077143:Docetaxel; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage*; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D051379:Mice; D008819:Mice, Nude; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000378:metabolism; D010539:Permeability; D010636:Phenols / Q000008:administration & dosage*; D043823:Taxoids / Q000008:administration & dosage; D047368:Tumor Burden / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C552530:1,1-bis(3'-indolyl)-1-(4-hydroxyphenyl)methane; C545255:1,1-bis(3'-indolyl)-1-(p-anisyl)methane; D000840:Anisoles; D000970:Antineoplastic Agents; D007211:Indoles; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D010636:Phenols; D043823:Taxoids; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D000077143:Docetaxel
keywords: Angiogenesis; Inhalation; Metastatic; Nebulizer; Nur77/TR3
references.citation: Mol Cell Biol. 2003 Dec;23(23):8651-67
references.pmid: 14612408
references.citation: PLoS One. 2011 Mar 15;6(3):e17733
references.pmid: 21423660
references.citation: Carcinogenesis. 2011 Jun;32(6):836-42
references.pmid: 21362629
references.citation: Mol Cancer Ther. 2003 May;2(5):479-88
references.pmid: 12748310
references.citation: J Biomed Biotechnol. 2012;2012:256178
references.pmid: 22187533
references.citation: Clin Cancer Res. 2009 Jan 15;15(2):543-52
references.pmid: 19147759
references.citation: Cancer Res. 2010 Sep 1;70(17):6824-36
references.pmid: 20660371
references.citation: J Cell Biochem. 2012 Oct;113(10):3165-77
references.pmid: 22593008
references.citation: J Biol Chem. 2005 Jul 1;280(26):24903-14
references.pmid: 15871945
references.citation: Prostate. 2011 Sep 15;71(13):1401-12
references.pmid: 21321979
references.citation: Neuron. 1988 May;1(3):183-8
references.pmid: 3272167
references.citation: Cancer Lett. 2008 Oct 8;269(2):326-38
references.pmid: 18501502
references.citation: PLoS One. 2013;8(1):e53070
references.pmid: 23326384
references.citation: BMC Biotechnol. 2005 May 10;5:12
references.pmid: 15885144
references.citation: Nucl Recept Signal. 2006;4:e002
references.pmid: 16604165
references.citation: Cancer Res. 2007 Jan 15;67(2):674-83
references.pmid: 17234778
references.citation: Cancer Chemother Pharmacol. 2010 May;66(1):141-50
references.pmid: 19823826
references.citation: Mol Pharmacol. 2010 Mar;77(3):396-404
references.pmid: 20023005
references.citation: PLoS One. 2012;7(4):e34975
references.pmid: 22514694
references.citation: Clin Cancer Res. 2007 Apr 15;13(8):2414-21
references.pmid: 17438100
references.citation: Br J Cancer. 2005 Jan 17;92(1):94-101
references.pmid: 15558070
references.citation: Biochem Soc Trans. 2011 Apr;39(2):688-93
references.pmid: 21428963
references.citation: Mol Cancer Res. 2009 Jul;7(7):1169-78
references.pmid: 19584258
references.citation: Biomaterials. 2010 Jul;31(21):5598-607
references.pmid: 20413152
references.citation: Carcinogenesis. 2008 Jun;29(6):1139-47
references.pmid: 18460448
references.citation: Oncogene. 2012 Jul 5;31(27):3265-76
references.pmid: 22081070
references.citation: Mol Cancer Ther. 2010 Nov;9(11):3003-14
references.pmid: 20978159
references.citation: Mol Carcinog. 2008 Apr;47(4):252-63
references.pmid: 17957723
references.citation: Clin Cancer Res. 2004 Jan 1;10(1 Pt 1):293-300
references.pmid: 14734482
references.citation: PLoS One. 2012;7(10):e47186
references.pmid: 23056607
references.citation: Mol Cancer Ther. 2008 Oct;7(10):3363-72
references.pmid: 18852139
references.citation: BMC Gastroenterol. 2009 May 29;9:39
references.pmid: 19480695
references.citation: Vet J. 2012 Mar;191(3):323-6
references.pmid: 21324719
references.citation: Pharmacol Rep. 2012;64(3):723-32
references.pmid: 22814025
references.citation: Expert Opin Ther Targets. 2011 Feb;15(2):195-206
references.pmid: 21204731