Novel proteasome-inhibitory syrbactin analogs inducing endoplasmic reticulum stress and apoptosis in hematological tumor cell lines

Abstract

The proteasome has been recognized as a druggable target in cancer cells, and this has led to searches for pharmacologic agents that target this cellular organelle for cancer therapeutic purposes. Syrbactins are a group of microbial metabolites consisting of two related families, the glidobactins and the syringolins. Some members of this group have revealed cytotoxic efficacy in tumor cells, and more recently it was discovered that they exert proteasome-inhibitory function. Based on this therapeutic promise and to gain further understanding of their molecular modes of action, we chemically synthesized de-novo three novel syrbactin analogs and characterized their proteasome-inhibitory and in vitro anti-neoplastic activity in human cell lines representing multiple myeloma, Waldenström's macroglobulinemia, and lymphocytic leukemia. Our results show that two of these novel compounds are able to inhibit proteasome activity in the nanomolar range, reduce the expression of anti-apoptotic proteins survivin and Mcl-1, and cause severe endoplasmic reticulum (ER) stress, resulting in pronounced tumor cell death. These anticancer effects can be synergistically enhanced when the agents are combined with thapsigargin, which further aggravates ER stress by a different mechanism. Taken together, our findings support the notion that syrbactin analogs may provide a structural platform for the development of novel cancer therapeutics, and that their efficacy may be further increased when complemented with other agents that trigger ER stress.