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 H Cowan

Research output: Contribution to journalArticle

45 Citations (Scopus)

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

Fingerprint

Adenoviridae
Genetic Therapy
Apoptosis
Breast Neoplasms
Cell Line
MCF-7 Cells
Pharmaceutical Preparations
Doxorubicin
Neoplasms
Infection
Cyclin B1
Mitoxantrone
Granulocyte-Macrophage Progenitor Cells
Poisons
DNA Fragmentation
Cell Cycle Checkpoints
Tumor Suppressor Genes
DNA
Population
Proteins

Keywords

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

ASJC Scopus subject areas

  • Cancer Research
  • Genetics

Cite this

A recombinant adenovirus expressing wild type p53 induces apoptosis in drug-resistant human breast cancer cells : A gene therapy approach for drug-resistant cancers. / Seth, Prem; Katayose, Dai; Li, Zhuangwu; Kim, Min; Wersto, Robert; Craig, Caroline; Shanmugam, Naga; Ohri, Ekta; Mudahar, Bali; Rakkar, Amol N S; Kodali, Padmaja; Cowan, Kenneth H.

In: Cancer Gene Therapy, Vol. 4, No. 6, 01.12.1997, p. 383-390.

Research output: Contribution to journalArticle

Seth, P, Katayose, D, Li, Z, Kim, M, Wersto, R, Craig, C, Shanmugam, N, Ohri, E, Mudahar, B, Rakkar, ANS, Kodali, P & Cowan, KH 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, vol. 4, no. 6, pp. 383-390.
Seth, Prem ; Katayose, Dai ; Li, Zhuangwu ; Kim, Min ; Wersto, Robert ; Craig, Caroline ; Shanmugam, Naga ; Ohri, Ekta ; Mudahar, Bali ; Rakkar, Amol N S ; Kodali, Padmaja ; Cowan, Kenneth H. / A recombinant adenovirus expressing wild type p53 induces apoptosis in drug-resistant human breast cancer cells : A gene therapy approach for drug-resistant cancers. In: Cancer Gene Therapy. 1997 ; Vol. 4, No. 6. pp. 383-390.
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