Self-resistance mechanisms to DNA-damaging antitumor antibiotics in actinobacteria

Streptomyces and few other Actinobacteria naturally produce compounds currently used in chemotherapy for being cytotoxic against various types of tumor cells by damaging the DNA structure and/or inhibiting DNA functions. DNA-damaging antitumor antibiotics belong to different classes of natural compounds that are structurally unrelated such as anthracyclines, bleomycins, enediynes, mitomycins, and prodiginines. By targeting a ubiquitous molecule and housekeeping functions, these compounds are also cytotoxic to their producer. How DNA-damaging antitumor antibiotics producing actinobacteria avoid suicide is the theme of the current review which illustrates the different strategies developed for self-resistance such as toxin sequestration, efflux, modification, destruction, target repair/protection, or stochastic activity. Finally, the observed spatio-temporal correlation between cell death, morphogenesis, and prodiginine production in S. coelicolor suggests a new physiological role for these molecules, that, together with their self-resistance mechanisms, would function as new types of toxin-antitoxin systems recruited in programmed cell death processes of the producer.