Researchers from Dartmouth Medical School and Dartmouth-Hitchcock Medical Center recently conducted an investigation on the potential of anaphase catastrophe as a target for cancer therapy. Fabrizio Galimberti, Sarah Thompson, Saranya Ravi, Duane Campton, and Ethan Dmitrovsky discovered that the phenomenon can be pharmacologically induced, which would consequently result in apoptosis in cancer cells. Their findings were published through Clinical Cancer Research OnlineFirst on February 2.
Anaphase catastrophe refers to an apoptotic mechanism that specifically targets tumor cells with more than two centrosomes. Tumor cells generally survive with extra centrosomes through pathways that cluster centrosomes, thus maintaining the bipolar chromosome segregation evident in normal mitotic processes. However, disruption of these pathways stimulates apoptotic events as chromosomes segregate to multiple daughter cells.
The researchers discovered that the depletion of cyclin-dependent kinase 2 (Cdk2) results in anaphase catastrophe in lung cancer cells. Using low concentrations of seliciclib, a Cdk2 inhibitor, they succeeded in inducing anaphase catastrophe, and found that pulmonary epithelial cells were relatively unharmed.
The researchers also discovered that integrin-linked kinase (ILK) plays an essential role in centrosome clustering in cancer cells. Past studies elucidated the protein’s role in mitosis-it regulates actin and cell adhesion, as well as microtubule-associated components. The recent study showed how small molecule inhibitors of ILK can induce anaphase catastrophe in breast cancer cells, while simultaneously leaving normal cells and cancer cells without extra centrosomes relatively unharmed.
Interestingly, the researchers observed how drugs that induce anaphase catastrophe generate greater effects when implemented under certain circumstances. For example, when either Cdk2 inhibitor seliciclib or ILK inhibitor QTL-0267 was used in conjunction with taxanes, agents that target microtubules, increases in cancer cell death followed. Furthermore, researchers detected that lung cancer cells with k-ras mutations are especially susceptible to Cdk inhibition.
Cancer is currently the second leading cause of death, and accounts for over half a million deaths per year in America. Researchers have relentlessly investigated the potential of numerous mechanisms and agents for cancer therapy, namely those that target dividing cells. However, such drugs as vinca alkaloids often fail to distinguish between cancer and non-cancer cells. The fact that anaphase catastrophe has been shown to specifically target cancer cells with extra centrosomes makes it a viable target for cancer therapy.