*3.5. Topoisomerase Inhibitors*

DNA topoisomerases are enzymes that solve topological problems associated with DNA replication, transcription, recombination, and chromatin remodeling by introducing temporary single- or double-strand breaks in the DNA [217]. Topoisomerase inhibitors are small molecules that interfere with the function of these enzymes through either intercalation or alkylation, leading to single and double stranded DNA breaks (Figure 4C). When the integrity of the genome is sufficiently compromised, apoptosis and cell death will follow, particularly in fast dividing cells, such as tumor cells, which are especially sensitive to this [218,219]. Improving the potency of these inhibitors, specifically in tumor cells, could allow lower dosing of these compounds, thereby limiting their adverse effects. This is of special importance for these therapeutics, since their use has been linked to the development of leukemia later in life [220,221]. An important mode of action of the reported synergy between OV treatment and doxorubicin is believed to be both treatments pushing the tumor cells in conflicting states of mitotic progression, resulting in higher tumor cell death than either monotherapy could achieve [222]. In addition, the effect of doxorubicin can be augmented by OV-mediated MCL-1 downregulation with co-treatment significantly increasing tumor cell death (Figure 4B,C) [223].For several cancer types, doxorubicin-treated senescent tumor cells, which are resistant to more classical methods of treatment, were efficiently killed by an oncolytic measles virus [167]. The combination of doxorubicin with an oncolytic adenovirus improved cell death in a more immunogenic fashion. This was further enhanced with additional co-treatment of the cyclophosphamide analogue ifosfamide [224]. Alternatively, the co-application of doxorubicin can also promote an increased infectivity of tumor cells by oncolytic viruses such as certain reovirus strains [225,226]. A more complex interplay has also been reported, where OV treatment induces the nuclear translocation of the cytoplasmic transcription factor cAMP response element-binding protein 3-like 1 (CREB3L1) [227], which in turn is associated with augmented doxorubicin-mediated cell death [228].
