Interfering RNAs against the promoter region of P53
View Patent ↗The present invention relates to the inhibition of p53 transcription by interfering with the activity of a p53 promoter using inhibitory double-stranded RNAs. Use of these inhibitory RNAs in the treatment of cancers also is disclosed.
1. A method of inhibiting a cancer cell expressing a dominant-negative P53 comprising contacting said cancer cell with a duplex RNA of 15-25 bases in length that is homologous to bases −200 to −1 of the p53 promoter located 170 bases 5′ relative to DBTSS transcriptional start site, wherein said duplex RNA inhibits expression of a dominant-negative p53 expressed by said cancer cell.
2. The method of claim 1 , wherein said cancer cell is a breast cancer cell, a lung cancer cell, a prostate cancer cell, an ovarian cancer cell, a liver cancer cell, a uterine cancer cell, a stomach cancer cell, a colon cancer cell, a cervical cancer cell, a head & neck cancer cell, an esophageal cancer cell, a brain cancer cell, a pancreatic cancer cell, a testicular cancer cell, a skin cancer cell, a lymphoma cell, a leukemia cell, a sarcoma cell or a carcinoma cell.
3. The method of claim 1 , wherein said duplex RNA comprises a sequence selected from SEQ ID NOS:1-12.
4. The method of claim 1 , wherein said duplex RNA is comprised within a lipid delivery vehicle.
5. The method of claim 1 , wherein said duplex RNA has an IC 50 of 10 −12 .
6. The method of claim 1 , wherein said duplex RNA further increases the expression of a Δp53 expressed by said cancer cell.
7. The method of claim 1 , wherein inhibiting comprises inhibiting cell growth, cell replication, cell survival, metastasis, tissue invasion, or drug resistance.
8. The method of claim 1 , wherein inhibiting comprises inducing cell death.
9. A method of increasing the sensitivity of a cancer cell expressing a dominant-negative p53 to an anti-cancer therapy comprising contacting said cancer cell with a duplex RNA of 15-25 bases in length that is homologous to a transcriptional start bases −200 to −1 of the p53 promoter located 5′ 170 bases relative to DBTSS transcriptional start site, wherein said duplex RNA inhibits expression of a dominant-negative p53 expressed by said cancer cell.
10. The method of claim 9 , wherein said cancer cell is a breast cancer cell, a lung cancer cell, a prostate cancer cell, an ovarian cancer cell, a liver cancer cell, a uterine cancer cell, a colon cancer cell, a stomach cancer cell, a cervical cancer cell, a head & neck cancer cell, an esophageal cancer cell, a brain cancer cell, a pancreatic cancer cell, a testicular cancer cell, a skin cancer cell, a lymphoma cancer cell, a leukemia cell, a sarcoma cell or a carcinoma cell.
11. The method of claim 9 , wherein said duplex RNA comprises a sequence selected from SEQ ID NOS:1-12.
12. The method of claim 9 , wherein said duplex RNA is comprised within a lipid delivery vehicle.
13. The method of claim 9 , wherein said duplex RNA further increases the expression of a Δp53 expressed by said cancer cell.
14. The method of claim 9 , wherein said anticancer therapy is a DNA damaging agent therapy.
15. The method of claim 9 , wherein said anticancer therapy is chemotherapy or radiotherapy.
16. The method of claim 9 , further comprising contacting said cell with said anticancer therapy.
17. A method of altering the expression of p53 isoforms in a cell expressing a dominant-negative p53 comprising contacting said cell with a duplex RNA of 15-25 bases in length that targets bases −200 to −1 of the p53 promoter located 170 bases 5′ relative to DBTSS transcriptional start site.
18. The method of claim 17 , wherein said duplex RNA comprises a sequence selected from SEQ ID NOS:1-12.