Suppression of Oral Cancer via PUMA Gene Therapy
Date Issued
2004
Date
2004
Author(s)
Yeh, Cheng-Chang
DOI
en-US
Abstract
Oral cancer is the fourth leading cause of cancer-related deaths in male population in Taiwan. Despite recent advances in radiotherapy and chemotherapy, the survival of patients with oral cancer has not improved significantly. As traditional treatments have not curbed this menace, many innovative approaches are being looked at for a cure. Recent studies have shown that polyethylenimine (PEI) nonviral vector is significantly more potent in cells bearing mitotic activity. This higher efficiency of gene transfer using PEI in proliferative cells, could reveal particularly interesting in heterogeneous tumor tissues, such as oral SCC tissue, containing both proliferating tumor cells and differentiated non proliferating stromal cells. Furthermore, PUMA (p53 upregulated modulator of apoptosis) was recently been found as an essential mediator of p53-dependent and -independent apoptosis in vivo. Therefore, we used PEI nonviral vector to transfer PUMA gene DNA into oral cancer cells for gene therapy on oral cancer. Firstly, we found the endogenous p53 in SAS cells could activate the PUMA promoter. The exogenous PUMA protein in SAS cells could induce apoptosis through the mitochondrial pathway. PUMA protein expression results in cytochome c release from mitochondria to cytoplasm, thereby activating caspases-9, caspase-3 and PARP. Furthermore, we found animals treated with PEI/wild-type PUMA DNA have significantly reduction in tumor size when compared with those treated with PEI/mutant DNA controls (p <0.05).
PUMA would be an ideal candidate tumor suppressor gene for oral cancer gene therapy. Our results suggest that PEI-mediated PUMA gene transfer is also a good candidate for adjuvant therapy with radiation or chemotherapy.
It has been shown that the antitumoral efficacy with gene therapy plus standard chemotherapeutic agents was significantly greater than with either agent alone. In the second part of study, we evaluated two standard chemotherapeutic agents (cisplatin, 5-FU) and four flavonoids (apigenin, berberine, resveratrol, gallic acid) for their effects on cell growth. Among the flavonoids, gallic acid is the most effective in inducing cell growth inhibition (ID50 =15.75
Subjects
基因治療
口腔癌
p53
oral cancer
PEI
gallic acid
gene therapy
PUMA
SDGs
Type
other
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