In a study published in the Proceedings of the National Academy of Sciences (PNAS) on Aug. 6, an international team led by Igor Roninson, of the University of South Carolina and the Medical University of South Carolina, reported the development of a new class of drugs that may prove useful in the treatment of cancer and aging-associated disorders.
In 2000, Roninson led a group that reported in PNAS that a single protein, called p21, turns on multiple genes implicated in cancer and in other disorders associated with advanced age such as Alzheimer's disease and arthritis. These harmful changes are especially prominent in senescent (aged) cells. Senescence in cells arises with the passage of time, but it can also be brought on after damage by various factors, including chemotherapeutic drugs and radiation used in cancer treatment.
Since the original discovery, Roninson has sought to understand the mechanism of this surprising effect of p21 and develop drugs that would block the harmful effects of senescent cells in different diseases. In the Aug. 6 publication, Roninson and colleagues reported a solution to this puzzle that holds significant therapeutic promise.
The gene expressing p21 is turned on in damaged cells, and the protein stops these cells from dividing by binding to enzymes that are called cyclin-dependent kinases (CDKs). The best-known CDKs are essential for cell division, and p21 binding inhibits their activity. The new study reports that the disease-promoting effects of p21 are mediated, at least in part, by its effect on a different CDK, called CDK8, which regulates the activity of many different genes but is not required for cell division. In contrast to its effect on other CDKs, p21 stimulates rather than inhibits CDK8, turning on multiple CDK8-regulated genes. Roninson's team, together with Senex Biotechnology, a company he founded, has developed a new class of drugs that inhibit CDK8, and they showed that these drugs overcome some of the most troublesome effects of cancer chemotherapy.
Chemotherapy can shrink or even eliminate tumors, but it also wreaks havoc on the rest of the body, damaging normal tissues. Among other harmful effects, chemotherapy causes damaged cells to produce molecules that promote the growth, drug resistance and the spread of those tumor cells that survived the treatment. Co-author Hippokratis Kiaris of the University of Athens (Greece) demonstrated this adverse effect of chemotherapy by treating healthy mice with a common chemotherapy drug, allowing the mice to recover, and then injecting them with cancer cells. These mice, having undergone a chemotherapy-like regimen, developed tumors much more efficiently than a control group not treated with the anticancer drug.
Furthermore, the blood of the mice pre-treated with the anticancer drug contained a higher amount of proteins that stimulate the growth of tumor cells. However, when the mice were injected with Senexin A, a synthetic CDK8 inhibitor developed by Roninson's team, the anticancer drug no longer stimulated the growth of tumors. The CDK8 inhibitor also increased the ability of the anticancer drug, when injected in tumor-bearing animals, to destroy the tumors. While the CDK8 inhibitor stopped the production of the harmful proteins by senescent cells, it did not reverse senescence, which is a necessary cancer-preventive program in our cells. By creating a synthetic chemical that can inhibit the harmful effects of senescence, the team offers a new pharmacological approach to treating cancer and potentially age-related diseases such as Alzheimer's, atherosclerosis and arthritis.
- D. C. Porter, E. Farmaki, S. Altilia, G. P. Schools, D. K. West, M. Chen, B.-D. Chang, A. T. Puzyrev, C.-u. Lim, R. Rokow-Kittell, L. T. Friedhoff, A. G. Papavassiliou, S. Kalurupalle, G. Hurteau, J. Shi, P. S. Baran, B. Gyorffy, M. P. Wentland, E. V. Broude, H. Kiaris, I. B. Roninson. Cyclin-dependent kinase 8 mediates chemotherapy-induced tumor-promoting paracrine activities. Proceedings of the National Academy of Sciences, 2012; DOI: 10.1073/pnas.1206906109
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