title: Inecalcitol, an analog of 1,25D3, displays enhanced antitumor activity through the induction of apoptosis in a squamous cell carcinoma model system.
abstract: Epidemiological data suggest an important role of vitamin D signaling in cancer development and progression, and experimental studies demonstrate that the active vitamin D metabolite 1α, 25-dihydroxyvitamin D₃ (1,25D₃) has broad spectrum antitumor activity. Hypercalcemia has often been suggested to limit the clinical application of these data. The 14-epi-analog of 1,25D₃, inecalcitol [19-nor-14-epi-23-yne-1,25-(OH)₂D₃; TX522], was developed to have superagonistic antitumor activities but low hypercalcemia potential. We examined the antitumor activity of inecalcitol and the underlying mechanisms in a murine squamous cell carcinoma (SCC) model system. In vitro, compared with 1,25D₃, inecalcitol showed enhanced vitamin D receptor (VDR)-mediated transcriptional activity. Inecalcitol suppressed SCC cell proliferation in a dose-dependent manner with an IC50 value 30 times lower than that of 1,25D₃. Both inecalcitol and 1,25D₃ induced a comparable level of G0/G₁ cell cycle arrest in SCC cells. The level of apoptosis induced by inecalcitol was markedly higher than that of 1,25D₃. Apoptosis was mediated through the activation of the caspase 8/10- caspase 3 pathway. Further, inecalcitol markedly inhibited the mRNA and protein expression of c-IAP1 and XIAP compared with 1,25D₃. In vivo, inecalcitol inhibits SCC tumor growth in a dose-dependent fashion. Notably, inecalcitol induced a significantly higher level of apoptosis in the SCC xenograft model. While in vitro inecalcitol demonstrates apparent enhanced VDR binding and antiproliferative effects compared to 1,25D₃, in vivo these advantages disappear; at doses of inecalcitol that have equivalent antitumor effects, similar hypercalcemia is seen. This may be explained by the pharmacokinetics of 1,25D₃ vs. inecalcitol and attributed to the much shorter serum half-life of inecalcitol.We show that inecalcitol has potent antitumor activity in the SCC model system, and this is associated with a strong induction of apoptosis. These findings support the further development of inecalcitol in cancer treatment.
authors: Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors: Yingyu
authors: Y
authors: Ma
authors: Wei-Dong
authors: WD
authors: Yu
authors: Alejandro A
authors: AA
authors: Hidalgo
authors: Wei
authors: W
authors: Luo
authors: Remi
authors: R
authors: Delansorne
authors: Candace S
authors: CS
authors: Johnson
authors: Donald L
authors: DL
authors: Trump
mesh_terms: D000480:Alkynes / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D020169:Caspases / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002762:Cholecalciferol / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation / Q000187:drug effects; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D051379:Mice; D014158:Transcription, Genetic / Q000187:drug effects; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000494:pharmacology; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism
chemical_list: D000480:Alkynes; D000970:Antineoplastic Agents; D051034:Inhibitor of Apoptosis Proteins; D051636:X-Linked Inhibitor of Apoptosis Protein; C118756:dihydroxy-vitamin D3; C409043:inecalcitol; D014807:Vitamin D; D002762:Cholecalciferol; D020169:Caspases
keywords: 1,25D3; SCC; TX522; apoptosis; inecalcitol
references: J Natl Cancer Inst. 2006 Apr 5;98(7):451-9
references: 16595781
references: J Biol Chem. 2004 Dec 17;279(51):53213-21
references: 15485861
references: Am J Physiol. 1999 Aug;277(2):F157-75
references: 10444570
references: J Bone Miner Res. 2001 Apr;16(4):625-38
references: 11315990
references: J Cell Mol Med. 2005 Jan-Mar;9(1):59-71
references: 15784165
references: Cancer Res. 2000 Apr 15;60(8):2304-12
references: 10786699
references: J Biol Chem. 2002 Aug 23;277(34):30738-45
references: 12072431
references: Am J Public Health. 2006 Feb;96(2):252-61
references: 16380576
references: Cancer Res. 1997 Sep 1;57(17):3759-64
references: 9288784
references: Clin Cancer Res. 2001 Apr;7(4):1043-51
references: 11309356
references: Cancer Res. 1999 Jun 1;59(11):2644-9
references: 10363987
references: Mol Cancer Ther. 2008 Sep;7(9):3047-55
references: 18790784
references: Prostate Cancer Prostatic Dis. 2005;8(2):108-18
references: 15724144
references: Blood. 2003 Apr 1;101(7):2454-60
references: 12446453
references: Endocrinology. 2010 Sep;151(9):4301-12
references: 20591973
references: Oncology. 2004;66(1):62-6
references: 15031600
references: J Biol Chem. 2001 Jul 13;276(28):26365-73
references: 11331275
references: Cancer Res. 2006 Aug 15;66(16):8131-8
references: 16912191
references: Mol Cancer Ther. 2002 Aug;1(10):821-9
references: 12492115
references: Nat Rev Cancer. 2007 Sep;7(9):684-700
references: 17721433
references: Int J Cancer. 2012 May 15;130(10):2464-73
references: 21732345
references: J Biol Chem. 2001 Mar 23;276(12):9101-7
references: 11053435
references: J Steroid Biochem Mol Biol. 2010 Jul;121(1-2):372-5
references: 20398752
references: Mol Cancer Ther. 2002 Jul;1(9):667-77
references: 12479363
references: Mol Pharmacol. 2005 May;67(5):1566-73
references: 15728261
references: Cancer Res. 2000 May 15;60(10):2673-9
references: 10825140
references: J Natl Cancer Inst. 1998 Jan 21;90(2):134-41
references: 9450573
references: J Biol Chem. 2011 Oct 21;286(42):36228-37
references: 21868377
references: Cancer Res. 2010 Jul 15;70(14):5953-62
references: 20587525