Radioprotection: smart games with death
Andrei V. Gudkov, Elena A. Komarova
Andrei V. Gudkov, Elena A. Komarova
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Radioprotection: smart games with death

Abstract

The efficacy of cancer treatment by radiation and chemotherapeutic drugs is often limited by severe side effects that primarily affect the hematopoietic system and the epithelium of the gastrointestinal tract. Progress in understanding differences in the mechanisms involved in the responses of normal and tumor cells to genotoxic stress has led to the development of new rational approaches to selective protection of normal cells, such as suppression of apoptosis by pharmacological inhibition of p53 or activation of NF-κB. Another promising approach presented in this issue by Johnson et al. is based on the idea of using pharmacological inhibitors of cyclin-dependent kinases (CDKs) to convert normal cells into a radioresistant state by inducing reversible cell cycle arrest at the G1/S transition. The evidence indicates that this approach is likely to be specific for protection of normal cells and may, therefore, have clinical potential as an adjuvant in anticancer therapies.

Authors

Andrei V. Gudkov, Elena A. Komarova

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Figure 2

Radioprotection by CDK4/6 inhibitors is expected to be highly specific for normal cells.

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Radioprotection by CDK4/6 inhibitors is expected to be highly specific f...
Normal cells respond to CDK4/6 pharmacological inhibition by reversible cell cycle arrest (quiescence). Lack of functional Rb makes cells insensitive to CDK4/6 inhibition, regardless of other genetic alterations. However, even those tumor cells that retain wild-type Rb may not be protected by CDK4/6 inhibitors, since they frequently have mechanisms of quiescence deregulated and respond to CDK4/6 inhibition by apoptosis or irreversible arrest (senescence; ref. 21). The irreversibility of CDK4/6 effects on Rb-positive tumor cells explains the efficacy of CDK4/6 inhibitors as antitumor agents. Only rare tumors retaining functional Rb and p53 and the capacity to respond to CDK4/6 inhibition by quiescence can be protected (red arrow). m, mutant.