DOI: 10.1002/pros.10187. Experimental therapy of human prostate cancer by inhibiting MDM2 expression with novel mixed‐backbone antisense oligonucleotides: In vitro and in vivo activities and mechanisms

Experimental therapy of human prostate cancer by inhibiting MDM2 expression with novel mixed‐backbone antisense oligonucleotides: In vitro and in vivo activities and mechanisms

10.1002/pros.10187

Crossref journal-article

Wiley

The Prostate (311)

Abstract

AbstractBACKGROUNDMDM2 oncogene is overexpressed in many human cancers including prostate cancer and MDM2 levels are associated with poor prognosis. This study was undertaken to investigate the functions of MDM2 oncogene in prostate cancer growth and the value of MDM2 as a drug target for prostate cancer therapy by inhibiting MDM2 expression.METHODSAntisense anti‐human‐MDM2 mixed‐backbone oligonucleotide and its mismatch control were tested in in vitro and in vivo human prostate cancer models (LNCaP, DU 145, and PC‐3) for anti‐tumor activity. Targeted gene products and related proteins were analyzed and the anti‐tumor activity was determined when the oligonucleotides were used alone or in combination with cancer therapeutics.RESULTSThe antisense oligonucleotide specifically inhibited MDM2 expression in a dose‐ and time‐dependent manner, resulting in significant anti‐tumor activity in vitro and in vivo. In LNCaP cells, p53 and p21 levels were elevated. The antisense oligonucleotide also potentiated the effects of p53 activation and p21 induction by chemotherapeutic agents 10‐hydroxycamptothecin, adriamycin, 5‐fluorouracil, and paclitaxel. In DU145 cells, following inhibition of MDM2 expression, p21 levels were elevated although p53 levels remained unchanged. In both cell lines, the antisense oligonucleotide inhibited tumor cell growth and induced apoptosis in vitro. In a dose‐dependent manner, the antisense oligonucleotide showed anti‐tumor activity in nude mice bearing DU145 or PC‐3 xenografts. It significantly increased therapeutic effectiveness of the chemotherapeutic agent irinotecan and slightly improved the effects of paclitaxel and Rituxan.CONCLUSIONSThese results indicate that MDM2 has a role in prostate tumor growth through both p53‐dependent and p53‐independent mechanisms, indicating that MDM2 inhibitors have a broad spectrum of anti‐tumor activities in human prostate cancers regardless of p53 status. Prostate 54: 194–205, 2003. © 2002 Wiley‐Liss, Inc.

Bibliography

Wang, H., Yu, D., Agrawal, S., & Zhang, R. (2002). Experimental therapy of human prostate cancer by inhibiting MDM2 expression with novel mixedâbackbone antisense oligonucleotides: In vitro and in vivo activities and mechanisms. The Prostate, 54(3), 194â205. Portico.

Authors 4

Hui Wang (first)
Dong Yu (additional)
Sudhir Agrawal (additional)
Ruiwen Zhang (additional)

References 50 Referenced 68

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Dates

Type	When
Created	22 years, 7 months ago (Jan. 16, 2003, 4:24 p.m.)
Deposited	1 year, 9 months ago (Nov. 17, 2023, 9:21 p.m.)
Indexed	1 day, 6 hours ago (Aug. 31, 2025, 6:23 a.m.)
Issued	22 years, 8 months ago (Dec. 20, 2002)
Published	22 years, 8 months ago (Dec. 20, 2002)
Published Online	22 years, 8 months ago (Dec. 20, 2002)
Published Print	22 years, 6 months ago (Feb. 15, 2003)

Funders 0

None

BibTeX

@article{Wang_2002, title={Experimental therapy of human prostate cancer by inhibiting MDM2 expression with novel mixed‐backbone antisense oligonucleotides: In vitro and in vivo activities and mechanisms}, volume={54}, ISSN={1097-0045}, url={http://dx.doi.org/10.1002/pros.10187}, DOI={10.1002/pros.10187}, number={3}, journal={The Prostate}, publisher={Wiley}, author={Wang, Hui and Yu, Dong and Agrawal, Sudhir and Zhang, Ruiwen}, year={2002}, month=dec, pages={194–205} }

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  "resource": {
    "primary": {
      "URL": "https://onlinelibrary.wiley.com/doi/10.1002/pros.10187"
    }
  },
  "subtitle": [],
  "short-title": [],
  "issued": {
    "date-parts": [
      [
        2002,
        12,
        20
      ]
    ]
  },
  "references-count": 50,
  "journal-issue": {
    "issue": "3",
    "published-print": {
      "date-parts": [
        [
          2003,
          2,
          15
        ]
      ]
    }
  },
  "alternative-id": [
    "10.1002/pros.10187"
  ],
  "URL": "http://dx.doi.org/10.1002/pros.10187",
  "relation": {},
  "ISSN": [
    "0270-4137",
    "1097-0045"
  ],
  "subject": [],
  "container-title-short": "The Prostate",
  "published": {
    "date-parts": [
      [
        2002,
        12,
        20
      ]
    ]
  }
}