Apoptosis, a biological process through which a cell dies, occurs regularly, allowing the body to rid itself of extra, old, or abnormal cells. In a healthy individual, over 200 billion cells undergo apoptosis daily, and this number can increase when the immune system is active due to illnesses such as viral infections.
In the cancer setting, the potential of inducing apoptosis in cancer cells through a new strategy is a promising development. A recent study published in Science unveils this strategy, where researchers created synthetic molecules that linked two components with a pro-apoptotic result. The components of the bivalent molecules included ligands of the transcription factor B cell lymphoma 6 (BCL6) and inhibitors of cyclin-dependent kinases (CDKs).
BCL6 regulates cellular growth and division and plays a vital role in many cancers. In diffuse large B-cell lymphoma (DLBCL) BCL6 can prevent expression of a tumor suppressor gene TP53. Because tumor suppressor genes prevent tumor growth, by blocking TP53 BCL6 promotes the survival of lymphoma cells. Notably, BCL6 is expressed almost exclusively on diffuse large B-cell lymphoma cells.
CDKs make up a family of enzymes that also play a role in regulating cell division. Some CDKs control when to increase or decrease rates of transcription, the process by which RNA is created by coping a section of DNA. Several drugs target different CDKs, usually to inhibit their activity.
The researchers linked CDK9 to BCL6 ligands making the BCL6-target genes pro-apoptotic. By relocating CDK9 near BCL6, the two molecules that typically do not interact had impressive anti-cancer effects. This led to subsequent apoptosis of diffuse large B cell lymphoma cells in a laboratory setting. Due to the specificity of BCL6 to diffuse large B cell lymphoma, the compound did not induce cell death when tested in any other type of cancer cell. The researchers observed no severe toxicities when testing their approach in healthy mouse models.
Next steps involve testing the compound in tumor-bearing mice to determine if it can control cancer growth in an animal model.
Sources: Nature, Science, Molec Cancer Res, Genome Biol
