stf-083010 and Multiple-Myeloma

Multiple myeloma (MM) cells accumulate in the bone marrow and produce enormous quantities of immunoglobulins, causing endoplasmatic reticulum stress and activation of protein handling machinery, such as heat shock protein response, autophagy and unfolded protein response (UPR).. We evaluated cell lines viability after treatment with bortezomib (B) in combination with HSP70 (VER-15508) and autophagy (SBI-0206965) or UPR (STF- 083010) inhibitors.. For RPMI-8226, after 72 hours of treatment with B+VER+STF or B+VER+SBI, we observed 15% of viable cells, but treatment with B alone was better (90% of cell death). For U266, treatment with B+VER+STF or with B+VER+SBI for 72 hours resulted in 20% of cell viability and both treatments were better than treatment with B alone (40% of cell death). After both triplet combinations, RPMI-8226 and U266 presented the overexpression of XBP-1 UPR protein, suggesting that it is acting as a compensatory mechanism, in an attempt of the cell to handle the otherwise lethal large amount of immunoglobulin overload.. Our in vitro results provide additional evidence that combinations of protein homeostasis inhibitors might be explored as treatment options for MM.

Topics: Apoptosis; Autophagy; Benzamides; Bortezomib; Cell Survival; Drug Synergism; HSP70 Heat-Shock Proteins; Humans; Multiple Myeloma; Proteasome Inhibitors; Proteostasis; Pyrimidines; Sulfonamides; Thiophenes; Tumor Cells, Cultured; Unfolded Protein Response

Activation of the adaptive Ire1-XBP1 pathway has been identified in many solid tumors and hematologic malignancies, including multiple myeloma (MM). Here, we report the identification of STF-083010, a novel small-molecule inhibitor of Ire1. STF-083010 inhibited Ire1 endonuclease activity, without affecting its kinase activity, after endoplasmic reticulum stress both in vitro and in vivo. Treatment with STF-083010 showed significant antimyeloma activity in model human MM xenografts. Similarly, STF-083010 was preferentially toxic to freshly isolated human CD138(+) MM cells compared with other similarly isolated cell populations. The identification of this novel Ire1 inhibitor supports the hypothesis that the Ire1-XBP1 axis is a promising target for anticancer therapy, especially in the context of MM.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Cells, Cultured; Cytotoxins; Dose-Response Relationship, Drug; Endoribonucleases; Humans; Mice; Models, Biological; Multiple Myeloma; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Pyrazines; Substrate Specificity; Sulfonamides; Thiophenes; Xenograft Model Antitumor Assays