Successful Cancer Treatment Requires Blocking Chemotherapeutic Damage to Normal Tissues

Inhibitors of the transcription-regulating kinase CDK8 (cyclin-dependent kinase 8) and its isoform CDK19 (cyclin-dependent kinase 19) were found to prevent the sort of genomic damage suffered by normal tissues as a result of chemotherapy.

Conventional chemotherapy not only kills tumor cells but also changes gene expression in normal tissues damaged by the treatment including production of multiple tumor-supporting secreted factors. Investigators at the University of South Carolina (Columbia, USA) had previously found that secretion of procancerous signaling molecules was mediated in part by a damage-inducible cell-cycle inhibitor p21 (CDKN1A).

In the current study the investigators developed small-molecule compounds that block the activity of some of the signaling molecules activated by damage induced the activity of p21.

They reported in the August 6, 2012, online edition of the journal Proceedings of the National Academy of Sciences of the USA (PNAS) that these compounds were selective inhibitors of a transcription-regulating kinase CDK8 and its isoform CDK19. Unexpectedly, p21 was found to bind to CDK8 and stimulate its kinase activity. CDK8 and p21 also cooperated in the formation of internucleolar bodies, where both proteins accumulated. Microarray data analysis revealed striking correlations between CDK8 expression and poor survival in breast and ovarian cancers.

The CDK8 inhibitor Senexin A suppressed damage-induced tumor-promoting activities of both tumor cells and normal fibroblasts and reversed the increase in tumor engraftment and serum mitogenic activity in mice pretreated with a chemotherapeutic drug. The inhibitor also increased the efficacy of chemotherapy against xenografts formed by tumor cell/fibroblast mixtures.

“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,” said senior author Dr. Igor Roninson, professor of pharmacy at the University of South Carolina. “We needed to find a way to interrupt that process.”

Results of this study suggest that CDK8 inhibition could be a promising approach to increasing the efficacy of cancer chemotherapy.

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