In this essay, I propose that DNA-binding anti-cancer drugs work more via chromatin disruption than DNA damage. Success of long-awaited drugs targeting cancer-specific drivers is limited by the heterogeneity of tumors. Therefore, chemotherapy acting via universal targets (e.g., DNA) is still the mainstream treatment for cancer. Nevertheless, the problem with targeting DNA is insufficient efficacy due to high toxicity. I propose that this problem stems from the presumption that DNA damage is critical for the anti-cancer activity of these drugs. DNA in cells exists as chromatin, and many DNA-targeting drugs alter chromatin structure by destabilizing nucleosomes and inducing histone eviction from chromatin. This effect has been largely ignored because DNA damage is seen as the major reason for anti-cancer activity. I discuss how DNA-binding molecules destabilize chromatin, why this effect is more toxic to tumoral than normal cells, and why cells die as a result of chromatin destabilization.
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