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Apoptosis-Inducing Agent for Prostate Cancer Cells

a prostate cancer and apoptosis-inducing technology, which is applied in the direction of peptides, drug compositions, peptides, etc., can solve the problems that most of their functions have not yet been elucidated, and achieve the effects of inhibiting prostate cancer, and reducing the expression level of reic/dkk-3 gen

Inactive Publication Date: 2009-01-01
KUMON HIROMI +3
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0007]The present inventors have conducted intensive studies of the previously reported relationship between the REIC / Dkk-3 gene and cancer cells. It was discovered that the expression level of the REIC / Dkk-3 gene is reduced in human cancer cell lines and cancer tissue. The downregulation of the REIC / Dkk-3 gene was partially caused by promoter hypermethylation. Overexpression of the REIC / Dkk-3 gene with the use of vectors caused growth inhibition in human osteosarcoma cells. These findings indicate that the REIC / Dkk-3 gene could function as an antioncogene and thus that the REIC / Dkk-3 gene could be a new therapeutic target for human cancer.
[0008]In addition, the present inventors have found that the expression level of the REIC / Dkk-3 gene is reduced in highly malignant prostate cancer cells. Thus, they have conducted further intensive studies of the use of the REIC / Dkk-3 gene as a therapeutic agent for prostate cancer. Also, the present inventors have found that it is possible to inhibit prostate cancer by causing REIC / Dkk-3 gene expression in prostate cancer cells so as to induce apoptosis in prostate cancer cells. This has led to the completion of the present invention.
[0010]Furthermore, the present inventors have found that the combined use of the REIC / Dkk-3 gene and hyperthermia results in the improvement in the effects of prostate cancer treatment and prostate cancer metastasis inhibition.

Problems solved by technology

However, most of their functions have not yet been elucidated.

Method used

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  • Apoptosis-Inducing Agent for Prostate Cancer Cells
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  • Apoptosis-Inducing Agent for Prostate Cancer Cells

Examples

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example 1

[0085]Prostate Cancer Cell Apoptosis Induction by REIC / Dkk-3

[0086]Materials used in the Examples of the present invention were obtained as described below. The Examples were carried out by methods described below.

Cells and Culture Method

[0087]Normal prostate epithelial cells (PrEC) and prostate stromal cells (PrSC) were purchased from Cambrex (Baltimore, Md.). The prostate cancer cell lines PC3, DU145, and LNCaP were provided by ATCC (Rockville, Md.). OUMS-24 was provided by Dr. Masayoshi Nanba. An HAM'S F-12 K medium, an RPMI 1640 medium, and modified MEM medium (Nissui) were separately used with a supplement of 10% calf serum for PC3, DU145 and LNCaP, and OUMS-24.

Human Prostate Tissue

[0088]A LandMark™ low-density prostate tissue microarray (Ambion, Austin) was used for immunostaining of the REIC / Dkk-3 gene. Fresh prostate cancer tissue samples were obtained from 40 patients. Of them, 20 samples had a Gleason score of 8 or higher and another 20 samples had a Gleason score of 7 or l...

example 2

[0105]Effects of Prostate Cancer Metastasis Inhibition caused by REIC / Dkk-3 Gene Transfection using Adenovirus Vectors

[0106]Mouse prostate cancer cells RM-9 (5.0×103 cells) were injected into prostates of C57BL / 6 mice. One week later, 1.2×108 pfu of REIC or lacZ (or PBS) was directly injected intratumorally (mean tumor diameter: 60 mm3) with the use of adenovectors. Tumor growth was significantly inhibited in the REIC / Dkk-3 group (treatment group) compared with the control group and the lacZ group (FIGS. 5 and 6). Tumor diameters were measured every 3 days using a transrectal ultrasonography system previously developed by the present inventors. Tumor volumes (V) were calculated by the following formula: ½×(short diameter)2×(long diameter). FIG. 5 shows ultrasound images and images of mouse intraperitoneal cavities taken with the transrectal ultrasonography system. FIG. 6 shows time-dependent changes in tumor volumes. As shown in FIGS. 5 and 6, stronger tumor inhibition effects were ...

example 3

[0112]Relationship between HSP70 and Apoptosis Induction caused by Forced Expression of REIC / Dkk-3

[0113]It was examined whether tumor selectivity in terms of apoptosis expression caused by Ad-REIC would be associated with HSP70 expression in normal cells and cancer cells.

[0114]Normal cells OUMS 24 (human immortalized fibroblast) and prostate cancer cells PC3 were used for comparison. The cells were infected with Ad-REIC at 20 MOI. 24 hours later, an HSP70 inhibitor (heat shock protein inhibitor I, CALBIOCHEM, BIOCHEMICALS) and an HSP70 inducer (Geranyl-Geranyl Acetone) (250 mM each) were separately added to a culture solution. 48 hours later, TUNEL staining was performed to determine influence upon apoptosis. FIGS. 12 and 13 show staining images for OUMS24 and of PC3, respectively. In FIGS. 12 and 13, images on the left side indicate TUNEL-staining results and images on the right side indicate DAPI-staining results. As shown in FIG. 12, among normal cells OUMS24, a large number of T...

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Abstract

According to the present invention, an apoptosis-inducing agent for prostate cancer comprising REIC / Dkk-3 DNA or an REIC / Dkk-3 protein, and a therapeutic agent for prostate cancer and an agent for inhibiting prostate cancer metastasis that comprise such apoptosis-inducing agent are provided.An apoptosis-inducing agent for prostate cancer, comprising, as an active ingredient, an REIC / Dkk-3 protein (a) or (b) or REIC / Dkk-3 DNA (c) or (d):(a) a protein consisting of the amino acid sequence represented by SEQ ID NO: 2;(b) a protein consisting of an amino acid sequence derived from the amino acid sequence represented by SEQ ID NO: 2 by substitution or deletion of 1 or more amino acids;(c) DNA consisting of the nucleotide sequence represented by SEQ ID NO: 1; or(d) DNA that hybridizes under stringent conditions to DNA consisting of a nucleotide sequence complementary to the nucleotide sequence represented by SEQ ID NO: 1 and encodes a protein having apoptosis activity; anda therapeutic agent for prostate cancer comprising such apoptosis-inducing agent are provided

Description

TECHNICAL FIELD [0001]The present invention relates to apoptosis induction in prostate cancer cells with the use of the REIC / Dkk-3 gene, which is a tumor-inhibiting gene, an apoptosis-inducing agent for prostate cancer cells, which comprises the REIC / Dkk-3 gene or an expression product thereof, and a therapeutic agent for prostate cancer and an agent for inhibiting prostate cancer metastasis, which comprise the apoptosis-inducing agent.BACKGROUND ART [0002]Selective elimination of cancer cells is an important key issue in treating cancer. During malignant conversion and progression, various genetic changes occur in cells (Vogelstein, B. et al., Trends Genet 9, 138-41 (1993)). Such mutations could be targets of gene therapies for cancer.[0003]Some types of genes exhibit a selective killing effect on cancer cells when overexpressed. Representative examples of such genes include p 53 (Chen, P. L. et al., Science 250, 1576-80 (1990); Fujiwara, T. et al., J Natl Cancer Inst 86, 1458-62 (...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07K14/00
CPCC07K14/4747A61K38/00A61P35/00A61P35/04
Inventor KUMON, HIROMIHUH, NAM-HOSAKAGUCHI, MASAKIYONASU, YASUTOMO
Owner KUMON HIROMI
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