title: Evaluation of the potential therapeutic role of a new generation of vitamin D analog, MART-10, in human pancreatic cancer cells in vitro and in vivo.
abstract: Pancreatic cancer is a lethal disease with no known effective chemotherapy and radiotherapy, and most patients are diagnosed in the late stage, making them unsuitable for surgery. Therefore, new therapeutic strategies are urgently needed. 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3] is known to possess antitumor actions in many cancer cells in vitro and in vivo models. However, its clinical use is hampered by hypercalcemia. In this study, we investigated the effectiveness and safety of a new generation, less calcemic analog of 1α,25(OH)2D3, 19-nor-2α-(3-hydroxypropyl)-1α,25-dihydroxyvitamin D3 (MART-10), in BxPC-3 human pancreatic carcinoma cells in vitro and in vivo. We demonstrate that MART-10 is at least 100-fold more potent than 1α,25(OH)2D3 in inhibiting BxPC-3 cell proliferation in a time- and dose-dependent manner, accompanied by a greater upregulation of cyclin-dependent kinase inhibitors p21 and p27 and a greater downregulation of cyclin D3 and cyclin-dependent kinases 4 and 5, leading to a greater increase in the fraction of cells in G0/G1 phase. No induction of apoptosis and no effect on Cdc25 phosphatases A and C were observed in the presence of either MART-10 or 1α,25(OH)2D3. In a xenograft mouse model, treatment with 0.3 µg/kg body weight of MART-10 twice/week for 3 weeks caused a greater suppression of BxPC-3 tumor growth than the same dose of 1α,25(OH)2D3 without inducing hypercalcemia and weight loss. In conclusion, MART-10 is a promising agent against pancreatic cancer growth. Further clinical trial is warranted.
authors.affiliation: General Surgery Department, Chang Gung Memorial Hospital, Keelung, Taiwan ROC.
authors.forename: Kun-Chun
authors.initials: KC
authors.lastname: Chiang
authors.forename: Chun-Nan
authors.initials: CN
authors.lastname: Yeh
authors.forename: Jun-Te
authors.initials: JT
authors.lastname: Hsu
authors.forename: Ta-sen
authors.initials: TS
authors.lastname: Yeh
authors.forename: Yi-yin
authors.initials: YY
authors.lastname: Jan
authors.forename: Chun-Te
authors.initials: CT
authors.lastname: Wu
authors.forename: Huang-Yang
authors.initials: HY
authors.lastname: Chen
authors.forename: Shyh-Chuan
authors.initials: SC
authors.lastname: Jwo
authors.forename: Masashi
authors.initials: M
authors.lastname: Takano
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kittaka
authors.forename: Horng-Heng
authors.initials: HH
authors.lastname: Juang
authors.forename: Tai C
authors.initials: TC
authors.lastname: Chen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002762:Cholecalciferol / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D056743:Cyclin D3 / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D018709:Statistics, Nonparametric; D013997:Time Factors; D014183:Transplantation, Heterologous
chemical_list: C569618:19-nor-2-(3-hydroxypropyl)-1,25-dihydroxyvitamin D3; D056743:Cyclin D3; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D002762:Cholecalciferol; D051360:Cyclin-Dependent Kinase 5; D051358:Cyclin-Dependent Kinase 4
keywords: BxPC-3; MART-10; cell cycle; chemotherapy; pancreatic cancer; vitamin D analog; xenograft
references.citation: Anticancer Agents Med Chem. 2013 Jan;13(1):126-39
references.pmid: 23094926
references.citation: Biochem Pharmacol. 1997 Dec 1;54(11):1173-9
references.pmid: 9416968
references.citation: Trends Endocrinol Metab. 2003 Nov;14(9):423-30
references.pmid: 14580762
references.citation: Annu Rev Pharmacol Toxicol. 2001;41:421-42
references.pmid: 11264464
references.citation: Br J Cancer. 1996 Jun;73(11):1341-6
references.pmid: 8645577
references.citation: Anticancer Res. 2009 Sep;29(9):3547-53
references.pmid: 19667147
references.citation: Ann Surg. 1995 Jan;221(1):59-66
references.pmid: 7826162
references.citation: Invest New Drugs. 2009 Aug;27(4):374-8
references.pmid: 18843448
references.citation: J Org Chem. 2001 Dec 28;66(26):8760-71
references.pmid: 11749604
references.citation: J Invest Dermatol. 1995 Jan;104(1):113-7
references.pmid: 7798628
references.citation: CA Cancer J Clin. 2013 Jan;63(1):11-30
references.pmid: 23335087
references.citation: Br J Cancer. 1998 Jul;78(1):6-13
references.pmid: 9662243
references.citation: Clin Cancer Res. 2000 Mar;6(3):901-8
references.pmid: 10741714
references.citation: J Steroid Biochem Mol Biol. 2007 Mar;103(3-5):717-20
references.pmid: 17207993
references.citation: Biochem Pharmacol. 1995 Aug 25;50(5):577-83
references.pmid: 7669059
references.citation: Cancer Res. 2005 Oct 15;65(20):9287-93
references.pmid: 16230390
references.citation: J Gastroenterol Hepatol. 2011 Nov;26(11):1597-603
references.pmid: 21880026
references.citation: Curr Top Med Chem. 2006;6(12):1273-88
references.pmid: 16848741
references.citation: J Endocrinol. 1999 Feb;160(2):223-9
references.pmid: 9924191
references.citation: Nucleic Acids Res. 2011 Nov;39(21):9181-93
references.pmid: 21846776
references.citation: J Steroid Biochem Mol Biol. 2011 Nov;127(3-5):269-75
references.pmid: 21911059
references.citation: Cancer Invest. 1995;13(3):280-6
references.pmid: 7743381
references.citation: Oncogene. 1998 Nov 5;17(18):2295-304
references.pmid: 9811460
references.citation: Genes Dev. 1999 Jun 15;13(12):1501-12
references.pmid: 10385618
references.citation: J Steroid Biochem Mol Biol. 1993 Sep;46(3):365-71
references.pmid: 9831485
references.citation: Ann Surg. 1990 Apr;211(4):447-58
references.pmid: 2322039
references.citation: Mol Cancer Res. 2004 Apr;2(4):203-14
references.pmid: 15140942
references.citation: Nat Rev Cancer. 2007 Sep;7(9):684-700
references.pmid: 17721433
references.citation: Br J Pharmacol. 1998 Nov;125(5):953-62
references.pmid: 9846632
references.citation: Evid Based Complement Alternat Med. 2012;2012:310872
references.pmid: 23304196
references.citation: Curr Opin Genet Dev. 1996 Feb;6(1):56-64
references.pmid: 8791491
references.citation: Br J Cancer. 2000 Jul;83(2):239-45
references.pmid: 10901377
references.citation: Front Biosci. 2008 Jan 01;13:2191-202
references.pmid: 17981702
references.citation: Br J Cancer. 2002 Mar 4;86(5):680-5
references.pmid: 11875725
references.citation: Mol Endocrinol. 2001 Aug;15(8):1370-80
references.pmid: 11463860
references.citation: FEBS Lett. 1998 Aug 21;433(3):287-93
references.pmid: 9744813
references.citation: J Clin Endocrinol Metab. 2010 Feb;95(2):471-8
references.pmid: 20133466
references.citation: Semin Oncol. 2003 Aug;30(4 Suppl 11):3-10
references.pmid: 14506598
references.citation: Breast Cancer Res Treat. 1994;31(2-3):191-202
references.pmid: 7881099
references.citation: Int J Pancreatol. 1991 Oct;10(2):103-4
references.pmid: 1748825
references.citation: Steroids. 2011 Dec 11;76(13):1513-9
references.pmid: 21888924
references.citation: J Med Chem. 2006 Aug 24;49(17):5199-205
references.pmid: 16913708
references.citation: J Cell Biochem. 1997 Sep 15;66(4):552-62
references.pmid: 9282333
references.citation: J Immunol Methods. 2000 Sep 21;243(1-2):167-90
references.pmid: 10986414
references.citation: Pancreatology. 2003;3(1):41-6
references.pmid: 12649563
references.citation: J Org Chem. 2003 Sep 19;68(19):7407-15
references.pmid: 12968893
references.citation: Ann Surg. 1997 Sep;226(3):248-57; discussion 257-60
references.pmid: 9339931
references.citation: Cancer Biol Ther. 2008 Mar;7(3):430-6
references.pmid: 18094617
references.citation: World J Surg Oncol. 2012 May 04;10:77
references.pmid: 22559838
references.citation: Biochem Pharmacol. 1992 Dec 15;44(12):2273-80
references.pmid: 1472092
references.citation: Arch Biochem Biophys. 2012 Jul 1;523(1):107-14
references.pmid: 22085499
references.citation: Gastroenterology. 1996 May;110(5):1605-13
references.pmid: 8613068
references.citation: Cancer Epidemiol Biomarkers Prev. 1999 Mar;8(3):241-8
references.pmid: 10090302
references.citation: Br J Cancer. 1997;76(8):1017-20
references.pmid: 9376260
references.citation: Future Oncol. 2009 May;5(4):493-507
references.pmid: 19450178
references.citation: World J Gastroenterol. 2009 Jul 21;15(27):3349-54
references.pmid: 19610135
references.citation: Cancer Res. 1994 Nov 1;54(21):5711-7
references.pmid: 7923220
references.citation: J Mol Biol. 2010 Feb 19;396(2):441-51
references.pmid: 19961857
references.citation: Annu Rev Pharmacol Toxicol. 2011;51:311-36
references.pmid: 20936945
references.citation: Br J Cancer. 1997;76(7):884-9
references.pmid: 9328147