Antisense anti-MDM2 oligonucleotides as a novel therapeutic approach to human breast cancer: in vitro and in vivo activities and mechanisms.
The mouse double minute 2 (MDM2) oncogene has been suggested as a target for cancer therapy. It is amplified or overexpressed in many human cancers, including breast cancer, and MDM2 levels are associated with poor prognosis of several human cancers, including breast cancer, ovarian cancer, osteosarcoma, and lymphoma. In the present study, we investigated the functions of MDM2 oncogene in the growth of breast cancer and the potential value of MDM2 as a drug target for cancer therapy by inhibiting MDM2 expression with a specific antisense antihuman-MDM2 oligonucleotide (oligo). The selected antisense mixed-backbone oligo was evaluated for its in vitro and in vivo antitumor activity in human breast cancer models: MCF-7 cell line containing wild-type p53 and MDA-MB-468 cell line containing mutant p53. In MCF-7 cells, p53 and p21 levels were elevated, resulting from specific inhibition of MDM2 expression by the antisense oligo (AS). In MDA-MB-468 cells, after inhibition of MDM2 expression, p21 levels were elevated, although p53 levels remained unchanged. After i.p. administration of the antisense anti-MDM2 oligo, in vivo antitumor activity occurred in a dose-dependent manner in nude mice bearing MCF-7 or MDA-MB-468 xenografts. In both models, in vivo synergistically or additive therapeutic effects of MDM2 inhibition and the clinically used cancer chemotherapeutic agents irinotecan, 5-fluorouracil, and paclitaxel (Taxol) were observed. These results suggest that MDM2 have a role in tumor growth through both p53-dependent and p53-independent mechanisms. We speculate that MDM2 inhibitors, such as ASs, have a broad spectrum of antitumor activities in human breast cancers, regardless of p53 status. This study should provide a basis for future development of anti-MDM2 ASs as cancer therapeutic agents used alone or in combination with conventional chemotherapeutics.
Wang
H
H
Department of Pharmacology and Toxicology, Division of Clinical Pharmacology, University of Alabama at Birmingham, 1670 University Boulevard, Birmingham, AL 35294, USA.
Nan
L
L
Yu
D
D
Agrawal
S
S
Zhang
R
R
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000187:drug effects / Q000378:metabolism; D016373:DNA, Antisense / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000627:therapeutic use; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D009368:Neoplasm Transplantation; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2; D013997:Time Factors; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D016373:DNA, Antisense; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; C028098:10-hydroxycamptothecin; C497206:MDM2 protein, human; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D005472:Fluorouracil; D002166:Camptothecin