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New Class of Cancer Drugs Reduces Cellular Damage From Chemotherapy

The findings were published online in the Proceedings of the National Academy of Sciences (PNAS).

The publication contains results obtained with a novel drug that targets the undesirable effects of damaged and senescent (aging) cells. Such cells are believed to play a key role in cancer and other diseases of aging.

Cellular senescence can result from changes in the chromosomes that develop with age, or it can be induced by DNA damage caused by traditional anticancer drugs and other factors. Senescent cells have been shown to produce cancer-supporting molecules as well as proteins implicated in other diseases of old age, such as Alzheimer’s disease and arthritis. The importance of this senescence-associated secretory pattern in aging has been demonstrated in recent studies, but no practical method for blocking this pattern was previously known. The PNAS paper reports the development of Senexin A, the first of Senex’s drugs that inhibit the secretory pattern of senescent and other damaged cells.

Traditional anticancer drugs produce numerous side effects, some of which support, rather than inhibit, the growth of cancers. The cancer-supporting activity of conventional drugs appears to occur, in part, because these drugs damage both tumor cells and the patient’s normal tissues, causing changes in drug-damaged cells, including the induction of cellular senescence. The damaged cells start producing and secreting multiple proteins that promote the growth of the surviving cancer cells, their resistance to chemotherapy, and their spread throughout the body.

In one of the experiments reported in the PNAS article, mice were treated with a commonly used anticancer drug. After the mice recovered from this treatment, both treated and untreated mice were injected with cancer cells. The mice pretreated with the anticancer drug developed tumors much more efficiently than the untreated mice. Furthermore, the blood of mice pretreated with the anticancer drug had a higher content of proteins that stimulate the growth of tumor cells. Treatment of the mice with Senexin A neutralized the cancer-supporting effects of the anticancer drug, blocking the increases in both the tumor growth and the production of tumor-supporting growth factors. Senexin A also potentiated the antitumor efficacy of the conventional drug.

The molecular target of Senexin A was identified as a protein kinase (an enzyme that modifies other proteins by adding a phosphate) called cyclin-dependent kinase 8 (CDK8). Senexin A is the first selective inhibitor of CDK8 and its nearest relative, CDK19. CDK8 is involved in the regulation of gene expression.

Source: South Carolina College of Pharmacy Web site

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