*3.1. ER Stress Inducers*

One approach to promote tumor cell death is by amplifying ER stress. When cells synthesize secretory proteins in amounts that exceed the processing machinery, proteins are accumulated in the ER. Because this setting is linked to cells with high protein synthesis levels such as cancer cells and virally infected cells [155,156], OV-infected tumor cells would be particularly sensitive to disruption of ER homeostasis. The protein accumulation triggers the unfolded protein response (UPR) which tries to alleviate the ER by increasing ER chaperone gene transcription, lowering protein synthesis, and, if all else fails, inducing cell death (Figure 4C) [157]. Inhibiting these adaptive UPR measures has been studied in combination with the oncolytic M1- and adenovirus using the valosin-containing protein (VCP) inhibitor Eeyarestatin I and the Golgi-specific brefeldin A-resistant guanine nucleotide exchange factor 1 (GBF-1) inhibitor golgicide A (GCA-2), respectively. These combinations resulted in the significantly enhanced anticancer efficacy of the OV treatment [158,159]. The fine balance between homeostasis and apoptotic induction by the UPRER, now requires more mechanistic knowledge of virus interactions with the UPRER and drug synergy experiments, before this field is ripe for clinical applications [160]. Indirect effects of ER stress inducers, such as thapsigargin (Tg) and ionomycin (Im), can also enhance the activity of oncolytic adenoviruses through an alteration in Ca2+ flux and protein kinase C signaling [161].
