Adenovirus E1A expression enhances the sensitivity of an ovarian cancer cell line to multiple cytotoxic agents through an apoptotic mechanism.

Brader KR, Wolf JK, Hung MC, Yu D, Crispens MA, van Golen KL, Price JE
Clin Cancer Res. 1997 3 (11): 2017-24

PMID: 9815592

The introduction of adenovirus 5 E1A into the SKOV3ip1 ovarian cancer cell line was shown previously to suppress HER2/neu expression and reduce the malignant potential of these cells (Yu et al., Cancer Res., 53: 891-898, 1993). In this report, we show that reduction of p185 in cells stably expressing E1A protein was coincident with increased sensitivity to cytotoxic agents. The LD50 of cisplatin was reduced 6-fold, and the LD50 of paclitaxel and doxorubicin was reduced 10-fold in E1A-expressing cells compared with control cells. The growth of SKOV3ip1 and control cells was unchanged in the presence of 150 ng/ml of tumor necrosis factor-alpha, whereas the growth of E1A-expressing cells was reduced by 30 to 40%. When we used a physiologically obtainable concentration of paclitaxel (0.5 microM), DNA laddering consistent with apoptotic cell death was seen after a 24-h exposure in the E1A-expressing cells, whereas laddering and DNA fragmentation were only detected in DNA from control cells after longer exposure (48 h) at a 20-fold higher concentration of paclitaxel. The SKOV3ip1 cells do not express p53 protein; hence, the induction of apoptosis by paclitaxel is through a p53-independent pathway. Despite their diverse mechanisms of action, the cytotoxic effects of cisplatin, doxorubicin, paclitaxel, and tumor necrosis factor-alpha were enhanced by the expression of E1A proteins in the SKOV3ip1 ovarian cancer cells. This suggests that these agents share a common final pathway of cell killing, which may represent a potential therapeutic target in resistant ovarian cancers.

MeSH Terms (21)

Adenovirus E1A Proteins Animals Antineoplastic Agents Apoptosis Cell Division Cell Survival Cisplatin DNA Fragmentation Doxorubicin Female Flow Cytometry Humans Mice Mice, Nude Ovarian Neoplasms Paclitaxel Recombinant Proteins Transfection Transplantation, Heterologous Tumor Cells, Cultured Tumor Necrosis Factor-alpha

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