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Butyrate as a model for "gene-regulating chemoprevention and chemotherapy."
1Department of Preventive Medicine, Kyoto Prefectural University of Medicine, Japan.
Abstract:
Recent progress in molecular genetics has facilitated understanding of the mechanisms of carcinogenesis. However, there is not yet any effective therapy or prevention for cancer based on the molecular mechanisms of carcinogenesis. So-called "gene therapy" for cancer is expected to become a new method of treatment, but there are still several serious problems with gene therapy. As a matter of fact, it seems impossible to adopt gene therapy for prevention. We therefore tried to develop a different method of cancer prevention or therapy based on the molecular mechanisms of carcinogenesis. For instance, the tumor-suppressor gene p53 is mutated in about 50% of human malignancies. It is known that p53 stimulates the promoter activities of p21/WAF1, gadd45 and bax genes, resulting in cell cycle arrest, DNA repair and apoptosis, respectively. Therefore, chemical compounds that can stimulate these genes should compensate for the function of p53. As a model of this, we found that histone deacetylase inhibitors such as butyrate or trichostatin A dramatically stimulate the p21/WAF1 gene promoter through the Spl sites, resulting in cell cycle arrest. Interestingly, another group has recently reported that phenylbutyrate, which is also known as a histone deacetylase inhibitor, is very effective for leukemia patients. We therefore consider methods of up-regulating p21/WAF, gadd45 or bax genes should be useful for cancer therapy and termed this method "Gene-regulating chemotherapy". Theoretically, the chemicals up-regulating such genes should be also useful for chemoprevention, and we also termed it as "Gene-regulating chemoprevention". In conclusion, we propose that "Gene-regulating chemotherapy or chemoprevention" may be a promising new method for cancer therapy or prevention and histone deacetylase inhibitor is a good candidate for this method.
Insights
Gene-regulating chemotherapy and chemoprevention offer a novel approach to cancer treatment and prevention by targeting key genes. Histone deacetylase inhibitors show promise in stimulating tumor suppressor gene activity for cancer therapy.
Area of Science:
- Molecular genetics
- Cancer research
- Pharmacology
Background:
- Carcinogenesis mechanisms are increasingly understood, yet effective molecularly-based cancer therapies and preventions remain elusive.
- Gene therapy for cancer faces significant challenges and is not suitable for prevention.
- The tumor-suppressor gene p53, mutated in ~50% of cancers, normally promotes cell cycle arrest, DNA repair, and apoptosis via target genes like p21/WAF1, gadd45, and bax.
Purpose of the Study:
- To develop a novel cancer prevention and therapy strategy based on molecular carcinogenesis mechanisms.
- To identify chemical compounds that can compensate for the loss of p53 function by stimulating its target genes.
- To explore the potential of gene-regulating approaches for cancer treatment and prevention.
Main Methods:
- Investigated chemical compounds that stimulate the promoter activities of p21/WAF1, gadd45, and bax genes.
- Utilized histone deacetylase (HDAC) inhibitors, such as butyrate and trichostatin A, as model compounds.
- Examined the effect of HDAC inhibitors on p21/WAF1 gene promoter activity and cell cycle arrest.
Main Results:
- Histone deacetylase inhibitors (e.g., butyrate, trichostatin A) significantly stimulate the p21/WAF1 gene promoter, leading to cell cycle arrest.
- Phenylbutyrate, an HDAC inhibitor, has shown effectiveness in leukemia patients.
- The study proposes that up-regulating p21/WAF1, gadd45, or bax genes is a viable strategy for cancer therapy.
Conclusions:
- "Gene-regulating chemotherapy" and "Gene-regulating chemoprevention" are proposed as promising new methods for cancer treatment and prevention.
- Histone deacetylase inhibitors are identified as strong candidates for implementing gene-regulating chemotherapy and chemoprevention.
- This approach offers a potential alternative to traditional gene therapy for cancer management.