A recombinant adenovirus expressing wild type p53 induces apoptosis in drug-resistant human breast cancer cells: A gene therapy approach for drug-resistant cancers

Prem Seth, Dai Katayose, Zhuangwu Li, Min Kim, Robert Wersto, Caroline Craig, Naga Shanmugam, Ekta Ohri, Bali Mudahar, Amol N.S. Rakkar, Padmaja Kodali, Kenneth Cowan

Research output: Contribution to journalArticle

45 Scopus citations

Abstract

The cytotoxicity of a recombinant adenovirus expressing the wild type tumor suppressor gene p53 (AdWTp53) was studied in two human breast cancer MCF-7 sublines selected for resistance to adriamycin (MCF-Adr) and mitoxantrone (MCF-Mito). Although the levels of wild type p53 protein following infection with AdWTp53 are comparable in all cell lines, the two drug-resistant MCF-7 sublines were 300- and 18-fold more sensitive to killing by AdWTp53 compared with the drug-sensitive parental MCF-7 cell lines. In each cell line, AdWTp53 infection led to cell cycle arrest, and reduction of Cdk2 and cyclin B1-Cdc2 activity. Nucleosomal DNA fragmentation analysis (as a function of apoptosis) following AdWTp53 infection revealed that, while the parental MCF-7 cells failed to undergo apoptosis, both drug-resistant cell lines showed distinct DNA laddering. In MCF-Adr cells, a combination treatment of AdWTp53 and adriamycin was much more toxic than either of the reagents used individually. Finally, exposure of a mixed population of MCF-Adr and CD34+ cells to AdWTp53 selectively prevented MCF-Adr cell colony formation, while there was no inhibition of CFU-GM colony formation from CD34+ cells. These findings suggest that some drug-resistant human breast cancers may be effectively treated with adenovirus expressing wild type p53.

Original languageEnglish (US)
Pages (from-to)383-390
Number of pages8
JournalCancer Gene Therapy
Volume4
Issue number6
StatePublished - Dec 1 1997

Keywords

  • Adenovirus
  • Bone marrow purging
  • Breast cancer
  • Drug resistance
  • Gene therapy

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Cancer Research

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    Seth, P., Katayose, D., Li, Z., Kim, M., Wersto, R., Craig, C., Shanmugam, N., Ohri, E., Mudahar, B., Rakkar, A. N. S., Kodali, P., & Cowan, K. (1997). A recombinant adenovirus expressing wild type p53 induces apoptosis in drug-resistant human breast cancer cells: A gene therapy approach for drug-resistant cancers. Cancer Gene Therapy, 4(6), 383-390.