*3.4. Microtubule Targeting Compounds*

Taxane compounds achieve their therapeutic effect through stabilizing the spindle microtubule dynamics resulting in inhibited cell division (Figure 4D) [195]. In combination with OVs, the microtubule stabilizing agents (MSAs), docetaxel and paclitaxel, were able to sensitize a variety of tumor types to cell death following stimulation by a subset of OV infection-induced cytokines [196–202]. In combination with reovirus, even tumor cells not sensitive to paclitaxel alone showed a strongly enhanced cell death, which was less due to increased oncolyis but, rather, resulted from activation of cell death programs prior to viral assembly [203]. OVs, armed with pro-apoptotic cargos, could sensitized the cancer cells even further to combination treatment [204]. More out-of-the-box ideas, such as encapsulating paclitaxel and oncolytic adenovirus, together in extracellular vesicles with improved transduction and efficacy, show that there new modes of synergy still to be elucidated [205].

Another way of interfering with the tubuline network is through destabilization. Indeed, microtubule-destabilizing agents (MDAs), such as vinca alkaloids, colchicine and platinum compounds, have long been used as cancer chemotherapeutics. These compounds can also increase cell death through bystander killing after exposure to OVinduced cytokines [206–208]. The synergy of these types of compounds have been described in numerous animal and human settings [200,201,203,208–213]. In addition, MDAs were able to increase OV replication through a previously unappreciated role of microtubule structures in regulating type I IFN translation (Figure 1). A colchicine-induced drop in IFN and ISG expression allowed for a more robust replication of an oncolytic VSV variant with a heightened IFN sensitivity [206,214]. On the other hand, HSV-induced cisplatin retention

was reported, resulting in increased DNA damage and anti-tumor immunity [215]. An additional route through which OV treatment can facilitate cell death in combination with chemotherapeutics, more specifically platinum compounds, is by downregulating myeloid cell leukemia 1 (MCL-1) (Figure 4B). MCL-1 is an anti-apoptotic member of the BCL-2 protein family that is more strongly degraded during oncolytic adenovirus infection. Its elimination in turn allows compounds like cisplatin to push tumor cells more efficiently towards cell death [216].
