The potential of clusterin inhibiting antisense oligodeoxynucleotide therapy for prostate cancer

This review summarise the authors’ recent experience in the development of antisense (AS) oligodeoxynucleotide (ODN) therapy that targets a cytoprotective gene, clusterin, for the treatment of prostate cancer. The acquisition of resistance to a wide variety of proapototic stimuli was initially demonstrated by introducing the clusterin gene into prostate cancer cells. Furthermore, silencing clusterin expression using AS ODN synergistically enhanced the effects of several conventional therapeutic modalities through the effective induction of apoptosis in prostate cancer xenograft models. Based on these outcomes, Phase I clinical trials were conducted using AS clusterin ODN incorporating 2′-O-(2-methoxy)ethyl-gapmer backbone (OGX-011), and the optimal dose of OGX-011 capable of inducing ≤ 90% suppression of clusterin in human prostate cancer tissue was determined. Collectively, these findings suggest the utility of inactivating clusterin function using AS ODN technology as a novel therapeutic strategy for prostate cancer treatment. There have been four kinds of Phase II studies that have begun to further evaluate the efficacy of OGX-011 in patients with prostate, breast and lung cancers.

[1]  G. Andriole.  A Novel Antisense Oligonucleotide Inhibiting Several Antiapoptotic Bcl-2 Family Members Induces Apoptosis and Enhances Chemosensitivity in Androgen-Independent Human Prostate Cancer PC3 Cells , 2006 .

[2]  M. Gleave,et al.  The inhibition of angiogenesis by antisense oligonucleotides to clusterin , 2005, Angiogenesis.

[3]  M. Gleave,et al.  Enhanced expression of the secreted form of clusterin following neoadjuvant hormonal therapy as a prognostic predictor in patients undergoing radical prostatectomy for prostate cancer. , 2005, Oncology reports.

[4]  M. Gleave,et al.  A novel antisense oligonucleotide inhibiting several antiapoptotic Bcl-2 family members induces apoptosis and enhances chemosensitivity in androgen-independent human prostate cancer PC3 cells , 2005, Molecular Cancer Therapeutics.

[5]  H. Miyake,et al.  Expression of the secreted form of clusterin protein in renal cell carcinoma as a predictor of disease extension , 2005, BJU international.

[6]  G. Giacomelli,et al.  Peptide nucleic acids (PNAs), a chemical overview. , 2005, Current medicinal chemistry.

[7]  M. Gleave,et al.  A phase I pharmacokinetic and pharmacodynamic study of OGX-011, a 2'-methoxyethyl antisense oligonucleotide to clusterin, in patients with localized prostate cancer. , 2005, Journal of the National Cancer Institute.

[8]  M. Gleave,et al.  Antisense oligodeoxynucleotide therapy targeting clusterin gene for prostate cancer: Vancouver experience from discovery to clinic , 2005, International journal of urology : official journal of the Japanese Urological Association.

[9]  T. Aboul-Fadl.  Antisense oligonucleotides: the state of the art. , 2005, Current medicinal chemistry.

[10]  R. Taichman,et al.  Clusterin inhibits apoptosis by interacting with activated Bax , 2005, Nature Cell Biology.

[11]  M. Gleave,et al.  A phase I study of a second generation antisense oligonucleotide to clusterin (OGX-011) in combination with docetaxel: NCIC CTG IND.154 , 2005 .

[12]  M. Gleave,et al.  Efficacy of an intratumoral controlled release formulation of clusterin antisense oligonucleotide complexed with chitosan containing paclitaxel or docetaxel in prostate cancer xenograft models , 2005, Cancer Chemotherapy and Pharmacology.

[13]  M. Gleave,et al.  Enhanced radiosensitivity by inhibition of the anti-apoptotic gene clusterin using antisense oligodeoxynucleotide in a human bladder cancer model. , 2005, Oncology reports.

[14]  M. Gleave,et al.  Synergistic antitumor effect of combined use of adenoviral-mediated p53 gene transfer and antisense oligodeoxynucleotide targeting clusterin gene in an androgen-independent human prostate cancer model. , 2005, Molecular cancer therapeutics.

[15]  M. Gleave,et al.  Therapeutic efficacy of adenoviral-mediated p53 gene transfer is synergistically enhanced by combined use of antisense oligodeoxynucleotide targeting clusterin gene in a human bladder cancer model. , 2005, Neoplasia.

[16]  Colleen Nelson,et al.  Mechanisms of the development of androgen independence in prostate cancer , 2005, World Journal of Urology.

[17]  M. Gleave,et al.  Use of antisense oligonucleotides targeting the cytoprotective gene, clusterin, to enhance androgen- and chemo-sensitivity in prostate cancer , 2005, World Journal of Urology.

[18]  Yusuke Nakamura,et al.  Isolation and characterization of a novel gene CLUAP1 whose expression is frequently upregulated in colon cancer , 2004, Oncogene.

[19]  M. Gleave,et al.  Protection of androgen‐dependent human prostate cancer cells from oxidative stress‐induced DNA damage by overexpression of clusterin and its modulation by androgen , 2004, The Prostate.

[20]  N. Maitland,et al.  Clusterin overexpression in both malignant and nonmalignant prostate epithelial cells induces cell cycle arrest and apoptosis , 2004, British Journal of Cancer.

[21]  T. Yeatman,et al.  Clusterin-Mediated Apoptosis Is Regulated by Adenomatous Polyposis Coli and Is p21 Dependent but p53 Independent , 2004, Cancer Research.

[22]  C. Tangen,et al.  Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. , 2004, The New England journal of medicine.

[23]  I. Tannock,et al.  Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. , 2004, The New England journal of medicine.

[24]  M. Gleave,et al.  Heat Shock Protein 27 Increases after Androgen Ablation and Plays a Cytoprotective Role in Hormone-Refractory Prostate Cancer , 2004, Cancer Research.

[25]  M. Scaltriti,et al.  Intracellular Clusterin Induces G2-M Phase Arrest and Cell Death in PC-3 Prostate Cancer Cells1 , 2004, Cancer Research.

[26]  Ximing J. Yang,et al.  Clusterin as a possible predictor for biochemical recurrence of prostate cancer following radical prostatectomy with intermediate Gleason scores: a preliminary report , 2004, Prostate Cancer and Prostatic Diseases.

[27]  M. Gleave,et al.  Synergistic antitumor activity by combined treatment with gemcitabine and antisense oligodeoxynucleotide targeting clusterin gene in an intravesical administration model against human bladder cancer kotcc-1 cells. , 2004, The Journal of urology.

[28]  F. Pichiorri,et al.  Modulation of different clusterin isoforms in human colon tumorigenesis , 2004, Oncogene.

[29]  M. Gleave,et al.  Nucleotide-based therapies targeting clusterin chemosensitize human lung adenocarcinoma cells both in vitro and in vivo. , 2004, Molecular cancer therapeutics.

[30]  M. Gleave,et al.  Silencing Expression of the Clusterin/Apolipoprotein J Gene in Human Cancer Cells Using Small Interfering RNA Induces Spontaneous Apoptosis, Reduced Growth Ability, and Cell Sensitization to Genotoxic and Oxidative Stress , 2004, Cancer Research.

[31]  E. Jones,et al.  Osteoblast-Derived Factors Induce Androgen-Independent Proliferation and Expression of Prostate-Specific Antigen in Human Prostate Cancer Cells , 2004, Clinical Cancer Research.

[32]  G. Hart,et al.  Glycobiology and Cancer: Meeting Summary and Future Directions , 2004, Cancer biology & therapy.

[33]  B. Aronow,et al.  Essential Requirement of Apolipoprotein J (Clusterin) Signaling for IκB Expression and Regulation of NF-κB Activity* , 2003, Journal of Biological Chemistry.

[34]  M. Gleave,et al.  Overexpression of the cytoprotective protein clusterin decreases radiosensitivity in the human LNCaP prostate tumour model , 2003, BJU international.

[35]  J. O’Sullivan,et al.  Alterations in the post-translational modification and intracellular trafficking of clusterin in MCF-7 cells during apoptosis , 2003, Cell Death and Differentiation.

[36]  M. Gleave,et al.  Castration-induced increases in insulin-like growth factor-binding protein 2 promotes proliferation of androgen-independent human prostate LNCaP tumors. , 2003, Cancer research.

[37]  D. Boothman,et al.  Synthesis and Functional Analyses of Nuclear Clusterin, a Cell Death Protein* , 2003, The Journal of Biological Chemistry.

[38]  D. Boothman,et al.  Repression of IR-Inducible Clusterin Expression by the p53 Tumor Suppressor Protein , 2003, Cancer biology & therapy.

[39]  I. Fidler,et al.  Effects of blocking platelet-derived growth factor-receptor signaling in a mouse model of experimental prostate cancer bone metastases. , 2003, Journal of the National Cancer Institute.

[40]  M. Gleave,et al.  Resistance to cytotoxic chemotherapy-induced apoptosis in human prostate cancer cells is associated with intracellular clusterin expression. , 2003, Oncology reports.

[41]  Chung Lee,et al.  Response to a lethal dose of heat shock by a transient up‐regulation of clusterin expression followed by down‐regulation and apoptosis in prostate and bladder cancer cells , 2002, The Prostate.

[42]  J. Walczak,et al.  Pharmacological treatments for prostate cancer , 2002, Expert opinion on investigational drugs.

[43]  I. Trougakos,et al.  Clusterin/apolipoprotein J in human aging and cancer. , 2002, The international journal of biochemistry & cell biology.

[44]  M. Gleave,et al.  Enhanced radiation sensitivity in prostate cancer by inhibition of the cell survival protein clusterin. , 2002, Clinical cancer research : an official journal of the American Association for Cancer Research.

[45]  E. Small,et al.  Prostate cancer update , 2002, Current opinion in oncology.

[46]  N. Bruchovsky,et al.  Activation of the Androgen Receptor N-terminal Domain by Interleukin-6 via MAPK and STAT3 Signal Transduction Pathways* , 2002, The Journal of Biological Chemistry.

[47]  M. Gleave,et al.  Clusterin expression is significantly enhanced in prostate cancer cells following androgen withdrawal therapy , 2002, The Prostate.

[48]  H. Miyake,et al.  Over expression of clusterin is an independent prognostic factor for nonpapillary renal cell carcinoma. , 2002, The Journal of urology.

[49]  H. Miyake,et al.  Synergistic chemsensitization and inhibition of tumor growth and metastasis by the antisense oligodeoxynucleotide targeting clusterin gene in a human bladder cancer model. , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[50]  M. Gleave,et al.  Antitumor activity of antisense clusterin oligonucleotides is improved in vitro and in vivo by incorporation of 2'-O-(2-methoxy)ethyl chemistry. , 2001, The Journal of pharmacology and experimental therapeutics.

[51]  A. Partin,et al.  Long-term biochemical disease-free and cancer-specific survival following anatomic radical retropubic prostatectomy. The 15-year Johns Hopkins experience. , 2001, The Urologic clinics of North America.

[52]  D R Schwartz,et al.  Coordinately up-regulated genes in ovarian cancer. , 2001, Cancer research.

[53]  R. Stahel,et al.  Activity of a novel bcl-2/bcl-xL-bispecific antisense oligonucleotide against tumors of diverse histologic origins. , 2001, Journal of the National Cancer Institute.

[54]  M. Gleave,et al.  Synergistic chemosensitization and inhibition of progression to androgen independence by antisense Bcl‐2 oligodeoxynucleotide and paclitaxel in the LNCaP prostate tumor model , 2001, International journal of cancer.

[55]  S. Crooke.  Potential roles of antisense technology in cancer chemotherapy , 2000, Oncogene.

[56]  C. Petito,et al.  Overexpression of clusterin in human breast carcinoma. , 2000, The American journal of pathology.

[57]  B. Calabretta,et al.  Direct Transactivation of the Anti-apoptotic Gene Apolipoprotein J (Clusterin) by B-MYB* , 2000, The Journal of Biological Chemistry.

[58]  M. Gleave,et al.  Inhibition of progression to androgen‐independence by combined adjuvant treatment with antisense BCL‐XL and antisense Bcl‐2 oligonucleotides plus taxol after castration in the Shionogi tumor model , 2000, International journal of cancer.

[59]  M. Gleave,et al.  Overexpression of insulin-like growth factor binding protein-5 helps accelerate progression to androgen-independence in the human prostate LNCaP tumor model through activation of phosphatidylinositol 3'-kinase pathway. , 2000, Endocrinology.

[60]  H. Miyake,et al.  Stress protein GRP78 prevents apoptosis induced by calcium ionophore, ionomycin, but not by glycosylation inhibitor, tunicamycin, in human prostate cancer cells , 2000, Journal of cellular biochemistry.

[61]  F. Natt,et al.  A novel bispecific antisense oligonucleotide inhibiting both bcl-2 and bcl-xL expression efficiently induces apoptosis in tumor cells. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[62]  M. Gleave,et al.  Castration-induced up-regulation of insulin-like growth factor binding protein-5 potentiates insulin-like growth factor-I activity and accelerates progression to androgen independence in prostate cancer models. , 2000, Cancer research.

[63]  D. Boothman,et al.  Nuclear clusterin/XIP8, an x-ray-induced Ku70-binding protein that signals cell death. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[64]  J. Kurie,et al.  Antisense approaches enter the clinic. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[65]  H. Miyake,et al.  Antisense TRPM-2 oligodeoxynucleotides chemosensitize human androgen-independent PC-3 prostate cancer cells both in vitro and in vivo. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[66]  H. Miyake,et al.  Acquisition of chemoresistant phenotype by overexpression of the antiapoptotic gene testosterone-repressed prostate message-2 in prostate cancer xenograft models. , 2000, Cancer research.

[67]  Y. Kondo,et al.  Treatment of prostate cancer in vitro and in vivo with 2-5A-anti-telomerase RNA component , 2000, Oncogene.

[68]  M. Gleave,et al.  Chemosensitization and delayed androgen-independent recurrence of prostate cancer with the use of antisense Bcl-2 oligodeoxynucleotides. , 2000, Journal of the National Cancer Institute.

[69]  B. Sikic,et al.  Phase I study of an antisense oligonucleotide to protein kinase C-alpha (ISIS 3521/CGP 64128A) in patients with cancer. , 1999, Clinical cancer research : an official journal of the American Association for Cancer Research.

[70]  E Mahlamäki,et al.  Hormone therapy failure in human prostate cancer: analysis by complementary DNA and tissue microarrays. , 1999, Journal of the National Cancer Institute.

[71]  A. Belldegrun,et al.  Evidence for clonal outgrowth of androgen-independent prostate cancer cells from androgen-dependent tumors through a two-step process. , 1999, Cancer research.

[72]  M. Gleave,et al.  Progression to androgen independence is delayed by adjuvant treatment with antisense Bcl-2 oligodeoxynucleotides after castration in the LNCaP prostate tumor model. , 1999, Clinical cancer research : an official journal of the American Association for Cancer Research.

[73]  M. Gleave,et al.  Antisense Bcl-2 oligodeoxynucleotides inhibit progression to androgen-independence after castration in the Shionogi tumor model. , 1999, Cancer research.

[74]  M. Gleave,et al.  Castration-induced apoptosis of androgen-dependent shionogi carcinoma is associated with increased expression of genes encoding insulin-like growth factor-binding proteins. , 1999, Cancer research.

[75]  J. Carver,et al.  Clusterin Has Chaperone-like Activity Similar to That of Small Heat Shock Proteins* , 1999, The Journal of Biological Chemistry.

[76]  Noah Craft,et al.  A mechanism for hormone-independent prostate cancer through modulation of androgen receptor signaling by the HER-2/neu tyrosine kinase , 1999, Nature Medicine.

[77]  C. Bennett,et al.  Antisense oligonucleotide therapeutics. , 1999, Expert opinion on investigational drugs.

[78]  K. Nath,et al.  Clusterin protects against oxidative stress in vitro through aggregative and nonaggregative properties. , 1998, Kidney international.

[79]  S. North,et al.  Stress-induced transcription of the clusterin/apoJ gene. , 1997, The Biochemical journal.

[80]  A. Rademaker,et al.  Intracellular levels of SGP-2 (Clusterin) correlate with tumor grade in prostate cancer. , 1997, Clinical cancer research : an official journal of the American Association for Cancer Research.

[81]  A. Porter,et al.  Target to apoptosis: A hopeful weapon for prostate cancer , 1997, The Prostate.

[82]  M. Gleave,et al.  Androgenic Induction of Prostate-specific Antigen Gene Is Repressed by Protein-Protein Interaction between the Androgen Receptor and AP-1/c-Jun in the Human Prostate Cancer Cell Line LNCaP* , 1997, The Journal of Biological Chemistry.

[83]  Guy S. Salvesen,et al.  X-linked IAP is a direct inhibitor of cell-death proteases , 1997, Nature.

[84]  M. Matteucci.  Structural modifications toward improved antisense oligonucleotides , 1996 .

[85]  Doriano Fabbro,et al.  Antitumor activity of a phosphorothioate antisense oligodeoxynucleotide targeted against C-raf kinase , 1996, Nature Medicine.

[86]  P. Howe,et al.  Transforming Growth Factor β (TGFβ)-Induced Nuclear Localization of Apolipoprotein J/Clusterin in Epithelial Cells† , 1996 .

[87]  E. Lesnik,et al.  Enhanced activity of an antisense oligonucleotide targeting murine protein kinase C-alpha by the incorporation of 2'-O-propyl modifications. , 1996, Nucleic acids research.

[88]  A. Bitonti,et al.  A ribonucleotide reductase inhibitor, MDL 101,731, induces apoptosis and elevates TRPM-2 mRNA levels in human prostate tumor xenografts. , 1996, Experimental cell research.

[89]  M E Rosenberg,et al.  Clusterin: physiologic and pathophysiologic considerations. , 1995, The international journal of biochemistry & cell biology.

[90]  M. Griswold,et al.  Prevention of cell death induced by tumor necrosis factor alpha in LNCaP cells by overexpression of sulfated glycoprotein-2 (clusterin). , 1995, Cancer research.

[91]  D. Clemmons,et al.  Insulin-like growth factors and their binding proteins: biological actions. , 1995, Endocrine reviews.

[92]  R. Wagner.  Gene inhibition using antisense oligodeoxynucleotides , 1994, Nature.

[93]  L. French,et al.  Human clusterin gene expression is confined to surviving cells during in vitro programmed cell death. , 1994, The Journal of clinical investigation.

[94]  Z. Dominski,et al.  Restoration of correct splicing in thalassemic pre-mRNA by antisense oligonucleotides. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[95]  P. D. Cook,et al.  Evaluation of 2'-modified oligonucleotides containing 2'-deoxy gaps as antisense inhibitors of gene expression. , 1993, The Journal of biological chemistry.

[96]  M. Campbell,et al.  Expression of the protooncogene bcl-2 in the prostate and its association with emergence of androgen-independent prostate cancer. , 1992, Cancer research.

[97]  L. French,et al.  Distinct sites of production and deposition of the putative cell death marker clusterin in the human thymus. , 1992, The Journal of clinical investigation.

[98]  L. Miraglia,et al.  Modulation of eucaryotic initiation factor-4E binding to 5'-capped oligoribonucleotides by modified anti-sense oligonucleotides. , 1992, The Journal of biological chemistry.

[99]  C. Olsson,et al.  SGP-2 expression as a genetic marker of progressive cellular pathology in experimental hydronephrosis. , 1991, Kidney international.

[100]  S. Dudek,et al.  Prostatic ductal system in rats: regional variation in localization of an androgen-repressed gene product, sulfated glycoprotein-2. , 1991, Endocrinology.

[101]  N. Kyprianou,et al.  Programmed cell death during regression of PC-82 human prostate cancer following androgen ablation. , 1990, Cancer research.

[102]  A. Coldman,et al.  Effects of androgen withdrawal on the stem cell composition of the Shionogi carcinoma. , 1990, Cancer research.

[103]  B. Shiramizu,et al.  Tumour-specific inhibition of lymphoma growth by an antisense oligodeoxynucleotide , 1990, The Lancet.

[104]  E R Kandel,et al.  Selective elimination of mRNAs in vivo: complementary oligodeoxynucleotides promote RNA degradation by an RNase H-like activity. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[105]  W. Stec,et al.  Reversed-phase high-performance liquid chromatographic separation of diastereomeric phosphorothioate analogues of oligodeoxyribonucleotides and other backbone-modified congeners of DNA. , 1985, Journal of chromatography.

[106]  M. Gleave,et al.  Overexpression of clusterin in transitional cell carcinoma of the bladder is related to disease progression and recurrence. , 2002, Urology.

[107]  I Lebedeva,et al.  Antisense oligonucleotides: promise and reality. , 2001, Annual review of pharmacology and toxicology.

[108]  M. Gleave,et al.  Chemosensitization of human renal cell cancer using antisense oligonucleotides targeting the antiapoptotic gene clusterin. , 2001, Neoplasia.

[109]  H. Miyake,et al.  Testosterone-repressed prostate message-2 is an antiapoptotic gene involved in progression to androgen independence in prostate cancer. , 2000, Cancer research.

[110]  C. F. Bennett,et al.  Progress in antisense oligonucleotide therapeutics. , 1996, Annual review of pharmacology and toxicology.

[111]  T. Mukhopadhyay,et al.  Antisense therapy for cancer. , 1995, The cancer journal from Scientific American.

[112]  N. Davidson,et al.  Programmed cell death during regression of the MCF-7 human breast cancer following estrogen ablation. , 1991, Cancer research.

[113]  B. Gross,et al.  Inhibition of expression of SV40 virus large T-antigen by antisense oligodeoxyribonucleotides. , 1989, Biomedica biochimica acta.

[114]  M. Tenniswood,et al.  Androgen‐repressed messages in the rat ventral prostate , 1986, The Prostate.