Even though chemotherapy kills tumor cells, it also causes damage to the rest of the body. However, a team of researchers from South Carolina’s College of Pharmacy has now discovered a new class of drugs that can decrease the adverse effects that chemotherapy causes in cellular damage. The discovery seems to apply to various forms of cancers and can potentially improve the efficacy of chemotherapy and afterwards lengthen the remission time. There is also potential for the development of promising new treatments for diseases that are age-related like Alzheimer’s.

Research leader Igor Roninson, the SmartState Endowed Chair of Translational Cancer Therapeutics at the South Carolina College of Pharmacy, who works at both the University of South Carolina and the Medical University of South Carolina, said: “Conventional anticancer drugs, while essential for current cancer therapy, have side effects that can damage healthy cells and cause them to promote the growth of surviving cancer cells. We needed to find a way to interrupt that process.”

The research was a collaboration between Senex Biotechnology, USC, Athens University and several other institutions and was based on Roninson’s discovery in 2000 that p21, a protein that stops division of damaged and aging cells, prompts production of multiple proteins that are involved in Alzheimer’s disease, cancer, and other aging-related diseases. The researchers now provided evidence that the p21 protein, which was known to inhibit other members of the CDK family, actually promotes CDK8 activity and stimulates CDK8-regulated genes.

Conventional drugs cancer-supporting activity is partly due to the fact these drugs destroy both tumor cells but also the patient’s normal tissues, which causes a large variety of changes in drug-damaged cells, such as the onset of aging (senescence). Cellular aging can either occur because of chromosome changes that develop with age, or it can occur through DNA damage that is caused by traditional anticancer drugs and other factors. Senescent cells and other damaged cells can produce cancer-supporting molecules and proteins that play a role in other old age diseases, including arthritis and Alzheimer’s disease.

Although recent studies have provided evidence of the importance of these secretory activities of senescent cells, so far, scientists remained unable to practically block this activity. In a recent report published in the Proceedings of the National Academy of Sciences, Roninson’s team revealed the development of Senexin A, the first of a series of chemicals that block this secretory pattern of the senescent and other damaged cells, which is the key to lower the cancer-promoting impact of chemotherapy.

In one of the trials, co-author Hippokratis Kiaris from Athens University treated mice with a frequently used anticancer drug and injected both drug-treated and untreated mice with cancer cells after they recovered from their initial treatment. To their surprise, they noted that the development of tumors was much more efficient in pretreated mice with the anticancer drug than in those untreated. In addition, they observed that the blood of mice pretreated with the anticancer drug had a higher content of proteins that stimulate tumor cell growth.

When they treated the mice with Senexin A, they observed that the cancer-supporting effects of the anticancer drug were neutralized and that the drug had blocked the increase in production of tumor-supporting growth factors, as well as the increase in tumor growth and elevated the antitumor effectiveness of the conventional drug.

Senexin A is based on a protein kinase, i.e. an enzyme that alters other proteins by adding a phosphate, which is called CDK8 (cyclin-dependent kinase 8). It is the first selective drug to inhibit CDK8 and its closest relative, CDK19. CDK8 plays a role in regulating gene expression by changing the balance of proteins that are produced in a cell, but in contrast to other kinases of the CDK family, which are better known, CDK8 is not involved in the cell division process.

Scientists already know that CDK8 plays a significant part in colon cancer and melanoma, and the researchers observed a significant parallel between the duration of relapse-free survival in patients with breast and ovarian cancer and the gene expression of CDK8. For instance, breast cancer patients whose expression of CDK8 was lower than medium achieved a disease-free survival of around 7 years longer compared with those who had a higher than medium expression of CDK8. The findings also reveal that CDK8 is involved in damage – and senescence-induced production of cancer-supporting proteins. The team believes that the new class of drugs could potentially be of benefit for many forms of cancer.

Written by Petra Rattue