Cancer cells often exhibit changes in DNA, called epigenetic modifications, that help tumors progress and resist therapies. In malignant mesothelioma, removing those epigenetic modifications could be key to decreasing treatment resistance and improving patients’ prognosis.
According to the study, “Hypomethylation Reduced The Aggressive Potential Of Human Malignant Mesothelioma Cells,” the drug 5-aza-dC, which reduces DNA methylation, could improve the effectiveness of anti-cancer drugs and reduce the most aggressive mesothelioma cells that are often associated with treatment resistance. (DNA methylation is a process in which methyl groups are added to the DNA molecule.)
The study was published in the journal Cancer Gene Therapy,
Certain cancer types are caused by specific genes or genetic mutations, but other less-known mechanisms can promote disease development. Those mechanisms, generally known as epigenetic modifications, include DNA methylation, a process that can influence DNA structure and whether genes are accessible to be “read” by proteins that regulate gene expression. These modifications may explain certain hereditary traits that are not caused by DNA mutations.
Epigenetic modifications have also been associated with the development of resistance to therapy and poor prognosis in patients with malignant mesothelioma. Knowing exactly what modifications are at play in this cancer may help improve treatments for resistant mesothelioma.
Researchers used human malignant mesothelioma (HMM) cells to investigate the effect of an anticancer agent called 5-aza-dC, which acts by decreasing DNA methylation, thereby inducing the accessibility to certain DNA regions and promoting the expression of certain genes.
They observed that although 5-aza-dC did not induce substantial cancer cell death, it significantly reduced several biological processes associated with cancer growth and malignancy, such as cell migration and interaction, colony formation, and invasiveness.
5-aza-dC also reduced the number of side population (SP) cells, which are reportedly enriched for more aggressive cells. These cells had two times higher methylation status in major tumor suppressor genes, meaning the expression of these genes was suppressed, leaving the cancer cells free to grow. However, treatment with 5-aza-dC reverted this occurrence by decreasing DNA methylation in these genes and promoting their expression.
Overall, the results obtained in this study support the theory that modulating DNA methylation in mesothelioma cells might be a valuable strategy to decrease the resistance of mesothelioma cancer cells.
“The present study provides evidence that 5-azadC is a cytostatic agent in mesothelioma with potential implications for a therapeutic measure to overcome chemoresistance,” the researchers wrote. “The therapeutic application of 5-aza-dC would provide a new and effective option for patients with mesothelioma.”