Common Drugs Can Be Effective Anticancer Drugs
11 Jan, 2007 09:49 am
Worldwide, cancer persists as one of the most important diseases that affects human beings. According to the Globocan series of the International Agency for Research on Cancer, in the year 2002 there were 10.9 million new cases and 6.7 million deaths. The knowledge on the molecular bases of cancer generated during the last decades have allowed the development of more effective and specific therapies, collectively termed "molecular targeted therapies". In the context of these new forms of treatment, epigenetic or transcriptional cancer therapy is one of the most promising.
In the inaugural issue of PLoS ONE, Dr. Duenas-Gonzalez's group, from the Instituto de Investigaciones Biomedicas of the Universidad Nacional Autonoma de Mexico and the Instituto Nacional de Cancerologia, Mexico, demonstrate that two common drugs routinely used for the treatment of non-malignant conditions, the antihypertensive hydralazine and the anticonvulsive magnesium valproate are able to revert DNA methylation and histone deacetylation respectively, which are the two epigenetic alterations common to all forms of cancer. What they did was to perform a single arm study in locally advanced breast cancer patients who were to receive primary chemotherapy with doxorubicin and cyclophosphamide followed by breast surgery. Before patients started chemotherapy, they were treated with hydralazine and valproate for seven days and then their tumours were sampled. Afterwards, patients continued treatment with daily oral doses of hydralazine and valproate along with chemotherapy drugs.
The analysis of the tumour biopsies before and after the seven days of treatment, as well as blood samples revealed a significant decrease in global 5(m)C of content and histone deacetylase activity. which was accompanied by up- and down-regulation of at least 3-fold, 1,091 and 89 genes, respectively. Among reactivated genes are those implicated in the regulation of cell proliferation, cell differentiation, programmed cell death, invasion, metastasis and immune recognition of tumour cells, such as p53, p21, 18 members of the oxidative phosphorylation pathway, interferon-regulatory factors, NM23, negative regulators of Wnt signalling and Major Histocompatibility Complex Class-I and -II genes. Interestingly, the gene ABCB5, a recently identified member of the ABC transporter family implicated in multidrug resistance, which is predominantly expressed by tumour "stem" cells, was found to be down-regulated. Despite these major changes at the gene expression, the treatment was proven safe and promising regarding its clinical efficacy as compared to historical controls treated only with chemotherapy. These findings are clearly suggestive that the epigenetic "principle" works and calls for increased preclinical and clinical efforts toward epigenetic cancer therapy, as epigenetic aberrations are common to all forms of cancer.
Arce C, Perez-Plasencia C, Gonzalez-Fierro A, de la Cruz-Hernandez E, Revilla-Vazquez A, et al. A Proof-Of-Principle Study of Epigenetic Therapy Added to Neoadjuvant Doxorubicin Cyclophosphamide for Locally Advanced Breast Cancer. PLoS ONE 1(1): e98. doi:10.1371/journal.pone.0000098.