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p73 beta-expressing recombinant adenovirus: a potential anticancer agent
Sanjeev Das1, Srikanth Nama, Sini Antony
1Department of Microbiology and Cell Biology, Indian Institute of Science, Sir CV Raman Road, Bangalore 560012, India.
Abstract:
Tumor suppressor p53-based gene therapy strategy is ineffective in certain conditions. p73, a p53 homologue, could be a potential alternative gene therapy agent as it has been found to be an important determinant of chemosensitivity in cancer cells. Previously, we have reported the generation of a replication-deficient adenovirus expressing p73 beta (Ad-p73). In this study, we evaluated the therapeutic potential of Ad-p73 against a panel of cancer cells (n=12) of different tissue origin. Ad-p73 infected all the cell lines tested very efficiently resulting in several-fold increase in p73 beta levels, which is also functional as it activated the known target gene p21(WAF1/CIP1). Infection with Ad-p73 resulted in potent cytotoxicity in all the cell lines tested. The mechanism of p73-induced cytotoxicity in these cell lines is found to be due to a combination of cell cycle arrest and induction of apoptosis. In addition, exogenous overexpression of p73 by Ad-p73 infection increased the chemosensitivity of cancer cells by many fold to commonly used drug adriamycin. Moreover, Ad-p73 is more efficient than Ad-p53 in enhancing the chemosensitivity of mutant p53 harboring cells. Furthermore, Ad-p73 infection did not induce apoptosis in human normal lung fibroblasts (HEL 299) and human immortalized keratinocytes (HaCaT). These results suggest that Ad-p73 is a potent cytotoxic agent specifically against cancer cells and could be developed as a cancer gene therapy agent either alone or in combination with chemotherapeutic agents.
Insights
Adenovirus expressing p73 beta (Ad-p73) shows potent anti-cancer activity. Ad-p73 effectively kills cancer cells via cell cycle arrest and apoptosis, enhancing chemosensitivity without harming normal cells.
Area of Science:
- Molecular Biology
- Cancer Research
- Gene Therapy
Background:
- Tumor suppressor p53 gene therapy is limited in some cases.
- p73, a p53 homologue, is crucial for cancer cell chemosensitivity.
- Replication-deficient adenovirus expressing p73 beta (Ad-p73) has been developed.
Purpose of the Study:
- To evaluate the therapeutic potential of Ad-p73 against various cancer cell lines.
- To investigate the mechanism of Ad-p73-induced cytotoxicity.
- To assess Ad-p73's ability to enhance chemosensitivity and its safety in normal cells.
Main Methods:
- Infection of 12 cancer cell lines and normal cells with Ad-p73.
- Quantification of p73 beta levels and activation of target gene p21(WAF1/CIP1).
- Assessment of cell cycle arrest, apoptosis, and chemosensitivity to adriamycin.
Main Results:
- Ad-p73 efficiently infected all tested cancer cell lines, increasing p73 beta levels and activating p21(WAF1/CIP1).
- Ad-p73 induced potent cytotoxicity through cell cycle arrest and apoptosis in cancer cells.
- Ad-p73 significantly enhanced cancer cell chemosensitivity to adriamycin and showed greater efficacy than Ad-p53 in mutant p53 cells.
- Ad-p73 did not induce apoptosis in normal human lung fibroblasts (HEL 299) or keratinocytes (HaCaT).
Conclusions:
- Ad-p73 is a potent cytotoxic agent specifically targeting cancer cells.
- Ad-p73 demonstrates potential as a standalone cancer gene therapy or in combination with chemotherapy.
- Ad-p73 offers a promising alternative for gene therapy, especially when p53-based strategies are ineffective.
