Effects of 1,25 dihydroxyvitamin D3 and its analogues on induction of apoptosis in breast cancer cells

Vitamin D derivatives have been shown both to inhibit the proliferation of cultured breast cancer cells and to cause regression of experimental mammary tumours in vivo. We have investigated the ability of several vitamin D analogues to promote the regression of experimental rat mammary tumours. Our...

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Veröffentlicht in:The Journal of steroid biochemistry and molecular biology 1996-07, Vol.58 (4), p.395-401
Hauptverfasser: JAMES, S. Y, MACKAY, A. G, COLSTON, K. W
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MACKAY, A. G
COLSTON, K. W
description Vitamin D derivatives have been shown both to inhibit the proliferation of cultured breast cancer cells and to cause regression of experimental mammary tumours in vivo. We have investigated the ability of several vitamin D analogues to promote the regression of experimental rat mammary tumours. Our results revealed that one vitamin D compound in particular, EB1089 (1(S),3(R)-dihydroxy-20(R)-5'-ethyl- 5'-hydroxy-hepta-1'(E),3'(E)-dien-1'-yl)-9,10-secopregna-5(Z ),7(E) ,10(19)-triene), was highly effective at inhibiting tumour progression, without causing a significant rise in serum calcium concentration. Tumour regression occurs when the rate of cell death is greater than the rate of cell proliferation. Apoptosis (programmed or active cell death) is an active, energy-dependent process in which a distinct series of biochemical and molecular events leads to the death of cells by specific signals. We have examined effects of 1,25-dihydroxyvitamin D3 (1,25(OH)2(D)3) and the synthetic vitamin D analogue EB1089 on indices of apoptosis in cultured human breast cancer cells. The effects of the vitamin D compounds on the expression of two oncoproteins which may regulate apoptosis, bcl-2 and p53 were examined by Western analysis. In MCF-7 cell cultures treated for six days with 1,25(OH)2(D)3 or EB1089 (1 x 10(-8) M), bcl-2 protein was reduced in comparison to control levels, whereas p53 protein was increased. In addition, the p21 protein, whose gene WAF-1 is induced by wild type p53, was also increased by both vitamin D compounds. Using Northern analysis, it was observed that 24-h treatment of MCF-7 cells with 1 x 10(-8) M 1,25(OH)2(D)3 or EB1089 resulted in an induction of TRPM-2 (clusterin) mRNA, a gene associated with onset of apoptosis in the involuting prostate. Fragmentation of genomic DNA is a characteristic feature of apoptosis. With the terminal deoxynucleotidyl transferase (TdT) assay, 3'-OH DNA breaks indicative of DNA fragmentation were detected histochemically in MCF-7 cells treated with 1 x 10(-8) M 1,25(OH)2(D)3 or EB1089 for four days prior to fixation and TdT reaction. Further evidence of apoptosis was obtained following six days treatment of MCF-7 cell cultures with 5 x 10(-8) M 1,25(OH)2(D)3 or EB1089, utilizing a cell death ELISA assay, which measures the presence of histone-associated oligonucleosome complexes generated from DNA fragmentation. Taken together our findings indicate that vitamin D derivatives may play a role in regulating the expres
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Y ; MACKAY, A. G ; COLSTON, K. W</creator><creatorcontrib>JAMES, S. Y ; MACKAY, A. G ; COLSTON, K. W</creatorcontrib><description>Vitamin D derivatives have been shown both to inhibit the proliferation of cultured breast cancer cells and to cause regression of experimental mammary tumours in vivo. We have investigated the ability of several vitamin D analogues to promote the regression of experimental rat mammary tumours. Our results revealed that one vitamin D compound in particular, EB1089 (1(S),3(R)-dihydroxy-20(R)-5'-ethyl- 5'-hydroxy-hepta-1'(E),3'(E)-dien-1'-yl)-9,10-secopregna-5(Z ),7(E) ,10(19)-triene), was highly effective at inhibiting tumour progression, without causing a significant rise in serum calcium concentration. Tumour regression occurs when the rate of cell death is greater than the rate of cell proliferation. Apoptosis (programmed or active cell death) is an active, energy-dependent process in which a distinct series of biochemical and molecular events leads to the death of cells by specific signals. We have examined effects of 1,25-dihydroxyvitamin D3 (1,25(OH)2(D)3) and the synthetic vitamin D analogue EB1089 on indices of apoptosis in cultured human breast cancer cells. The effects of the vitamin D compounds on the expression of two oncoproteins which may regulate apoptosis, bcl-2 and p53 were examined by Western analysis. In MCF-7 cell cultures treated for six days with 1,25(OH)2(D)3 or EB1089 (1 x 10(-8) M), bcl-2 protein was reduced in comparison to control levels, whereas p53 protein was increased. In addition, the p21 protein, whose gene WAF-1 is induced by wild type p53, was also increased by both vitamin D compounds. Using Northern analysis, it was observed that 24-h treatment of MCF-7 cells with 1 x 10(-8) M 1,25(OH)2(D)3 or EB1089 resulted in an induction of TRPM-2 (clusterin) mRNA, a gene associated with onset of apoptosis in the involuting prostate. Fragmentation of genomic DNA is a characteristic feature of apoptosis. With the terminal deoxynucleotidyl transferase (TdT) assay, 3'-OH DNA breaks indicative of DNA fragmentation were detected histochemically in MCF-7 cells treated with 1 x 10(-8) M 1,25(OH)2(D)3 or EB1089 for four days prior to fixation and TdT reaction. Further evidence of apoptosis was obtained following six days treatment of MCF-7 cell cultures with 5 x 10(-8) M 1,25(OH)2(D)3 or EB1089, utilizing a cell death ELISA assay, which measures the presence of histone-associated oligonucleosome complexes generated from DNA fragmentation. 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Y</creatorcontrib><creatorcontrib>MACKAY, A. G</creatorcontrib><creatorcontrib>COLSTON, K. W</creatorcontrib><title>Effects of 1,25 dihydroxyvitamin D3 and its analogues on induction of apoptosis in breast cancer cells</title><title>The Journal of steroid biochemistry and molecular biology</title><addtitle>J Steroid Biochem Mol Biol</addtitle><description>Vitamin D derivatives have been shown both to inhibit the proliferation of cultured breast cancer cells and to cause regression of experimental mammary tumours in vivo. We have investigated the ability of several vitamin D analogues to promote the regression of experimental rat mammary tumours. Our results revealed that one vitamin D compound in particular, EB1089 (1(S),3(R)-dihydroxy-20(R)-5'-ethyl- 5'-hydroxy-hepta-1'(E),3'(E)-dien-1'-yl)-9,10-secopregna-5(Z ),7(E) ,10(19)-triene), was highly effective at inhibiting tumour progression, without causing a significant rise in serum calcium concentration. Tumour regression occurs when the rate of cell death is greater than the rate of cell proliferation. Apoptosis (programmed or active cell death) is an active, energy-dependent process in which a distinct series of biochemical and molecular events leads to the death of cells by specific signals. We have examined effects of 1,25-dihydroxyvitamin D3 (1,25(OH)2(D)3) and the synthetic vitamin D analogue EB1089 on indices of apoptosis in cultured human breast cancer cells. The effects of the vitamin D compounds on the expression of two oncoproteins which may regulate apoptosis, bcl-2 and p53 were examined by Western analysis. In MCF-7 cell cultures treated for six days with 1,25(OH)2(D)3 or EB1089 (1 x 10(-8) M), bcl-2 protein was reduced in comparison to control levels, whereas p53 protein was increased. In addition, the p21 protein, whose gene WAF-1 is induced by wild type p53, was also increased by both vitamin D compounds. Using Northern analysis, it was observed that 24-h treatment of MCF-7 cells with 1 x 10(-8) M 1,25(OH)2(D)3 or EB1089 resulted in an induction of TRPM-2 (clusterin) mRNA, a gene associated with onset of apoptosis in the involuting prostate. Fragmentation of genomic DNA is a characteristic feature of apoptosis. With the terminal deoxynucleotidyl transferase (TdT) assay, 3'-OH DNA breaks indicative of DNA fragmentation were detected histochemically in MCF-7 cells treated with 1 x 10(-8) M 1,25(OH)2(D)3 or EB1089 for four days prior to fixation and TdT reaction. Further evidence of apoptosis was obtained following six days treatment of MCF-7 cell cultures with 5 x 10(-8) M 1,25(OH)2(D)3 or EB1089, utilizing a cell death ELISA assay, which measures the presence of histone-associated oligonucleosome complexes generated from DNA fragmentation. Taken together our findings indicate that vitamin D derivatives may play a role in regulating the expression of genes and protein products implicated in apoptosis.</description><subject>Animal tumors. Experimental tumors</subject><subject>Animals</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Antineoplastic Agents - therapeutic use</subject><subject>Apoptosis - drug effects</subject><subject>Biological and medical sciences</subject><subject>Breast Neoplasms - chemistry</subject><subject>Breast Neoplasms - pathology</subject><subject>Calcitriol - analogs &amp; derivatives</subject><subject>Calcitriol - pharmacology</subject><subject>Calcitriol - therapeutic use</subject><subject>Carcinoma - chemistry</subject><subject>Carcinoma - pathology</subject><subject>Clusterin</subject><subject>DNA Fragmentation</subject><subject>Experimental genital and mammary tumors</subject><subject>Female</subject><subject>Gene Expression Regulation, Neoplastic - drug effects</subject><subject>Glycoproteins - genetics</subject><subject>Humans</subject><subject>Mammary Neoplasms, Experimental - drug therapy</subject><subject>Medical sciences</subject><subject>Molecular Chaperones</subject><subject>Proto-Oncogene Proteins c-bcl-2 - analysis</subject><subject>Rats</subject><subject>RNA, Messenger - analysis</subject><subject>RNA, Neoplasm - analysis</subject><subject>Tumor Cells, Cultured</subject><subject>Tumor Suppressor Protein p53 - analysis</subject><subject>Tumors</subject><issn>0960-0760</issn><issn>1879-1220</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1996</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9kF1LwzAUhoMoc07_gUIuRBSs5qtpcylzfsDAG70Op2mika6dSSvu35uyMXKRnJznPRwehM4puaOEynuiJMlIIcm1kjeEEFFm6gBNaVmojDJGDtF0jxyjkxi_E8Q5LSZoUirCBeNT5BbOWdNH3DlMb1mOa_-1qUP3t_n1Pax8ix85hrbGPjHQQtN9DjbRLfZtPZjep1eKwrpb9130MX3jKliIPTbQGhuwsU0TT9GRgybas909Qx9Pi_f5S7Z8e36dPywzwxRTmVXOlVYpUdWGEaiUkkCtMZLISoKh6QhbKMd4XZFU16KywComuMyBF4bP0NV27jp0P2nRXq98HDeA1nZD1EWZk7woVALFFjShizFYp9fBryBsNCV61KtHd3p0p1UqRr16jF3s5g_Vytb70M5n6l_u-hANNC4kBz7uMSZKxUXO_wFLk4L7</recordid><startdate>199607</startdate><enddate>199607</enddate><creator>JAMES, S. 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Y</creatorcontrib><creatorcontrib>MACKAY, A. G</creatorcontrib><creatorcontrib>COLSTON, K. W</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>The Journal of steroid biochemistry and molecular biology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>JAMES, S. Y</au><au>MACKAY, A. G</au><au>COLSTON, K. W</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Effects of 1,25 dihydroxyvitamin D3 and its analogues on induction of apoptosis in breast cancer cells</atitle><jtitle>The Journal of steroid biochemistry and molecular biology</jtitle><addtitle>J Steroid Biochem Mol Biol</addtitle><date>1996-07</date><risdate>1996</risdate><volume>58</volume><issue>4</issue><spage>395</spage><epage>401</epage><pages>395-401</pages><issn>0960-0760</issn><eissn>1879-1220</eissn><abstract>Vitamin D derivatives have been shown both to inhibit the proliferation of cultured breast cancer cells and to cause regression of experimental mammary tumours in vivo. We have investigated the ability of several vitamin D analogues to promote the regression of experimental rat mammary tumours. Our results revealed that one vitamin D compound in particular, EB1089 (1(S),3(R)-dihydroxy-20(R)-5'-ethyl- 5'-hydroxy-hepta-1'(E),3'(E)-dien-1'-yl)-9,10-secopregna-5(Z ),7(E) ,10(19)-triene), was highly effective at inhibiting tumour progression, without causing a significant rise in serum calcium concentration. Tumour regression occurs when the rate of cell death is greater than the rate of cell proliferation. Apoptosis (programmed or active cell death) is an active, energy-dependent process in which a distinct series of biochemical and molecular events leads to the death of cells by specific signals. We have examined effects of 1,25-dihydroxyvitamin D3 (1,25(OH)2(D)3) and the synthetic vitamin D analogue EB1089 on indices of apoptosis in cultured human breast cancer cells. The effects of the vitamin D compounds on the expression of two oncoproteins which may regulate apoptosis, bcl-2 and p53 were examined by Western analysis. In MCF-7 cell cultures treated for six days with 1,25(OH)2(D)3 or EB1089 (1 x 10(-8) M), bcl-2 protein was reduced in comparison to control levels, whereas p53 protein was increased. In addition, the p21 protein, whose gene WAF-1 is induced by wild type p53, was also increased by both vitamin D compounds. Using Northern analysis, it was observed that 24-h treatment of MCF-7 cells with 1 x 10(-8) M 1,25(OH)2(D)3 or EB1089 resulted in an induction of TRPM-2 (clusterin) mRNA, a gene associated with onset of apoptosis in the involuting prostate. Fragmentation of genomic DNA is a characteristic feature of apoptosis. With the terminal deoxynucleotidyl transferase (TdT) assay, 3'-OH DNA breaks indicative of DNA fragmentation were detected histochemically in MCF-7 cells treated with 1 x 10(-8) M 1,25(OH)2(D)3 or EB1089 for four days prior to fixation and TdT reaction. Further evidence of apoptosis was obtained following six days treatment of MCF-7 cell cultures with 5 x 10(-8) M 1,25(OH)2(D)3 or EB1089, utilizing a cell death ELISA assay, which measures the presence of histone-associated oligonucleosome complexes generated from DNA fragmentation. Taken together our findings indicate that vitamin D derivatives may play a role in regulating the expression of genes and protein products implicated in apoptosis.</abstract><cop>Oxford</cop><pub>Elsevier Science</pub><pmid>8903423</pmid><doi>10.1016/0960-0760(96)00048-9</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record>
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ispartof The Journal of steroid biochemistry and molecular biology, 1996-07, Vol.58 (4), p.395-401
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subjects Animal tumors. Experimental tumors
Animals
Antineoplastic Agents - pharmacology
Antineoplastic Agents - therapeutic use
Apoptosis - drug effects
Biological and medical sciences
Breast Neoplasms - chemistry
Breast Neoplasms - pathology
Calcitriol - analogs & derivatives
Calcitriol - pharmacology
Calcitriol - therapeutic use
Carcinoma - chemistry
Carcinoma - pathology
Clusterin
DNA Fragmentation
Experimental genital and mammary tumors
Female
Gene Expression Regulation, Neoplastic - drug effects
Glycoproteins - genetics
Humans
Mammary Neoplasms, Experimental - drug therapy
Medical sciences
Molecular Chaperones
Proto-Oncogene Proteins c-bcl-2 - analysis
Rats
RNA, Messenger - analysis
RNA, Neoplasm - analysis
Tumor Cells, Cultured
Tumor Suppressor Protein p53 - analysis
Tumors
title Effects of 1,25 dihydroxyvitamin D3 and its analogues on induction of apoptosis in breast cancer cells
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