The Sequence-Selective DNA Cross-Linking Agent SJG-136 (SG2000, BN2629) Is Highly Potent in Multiple Myeloma Cells and Is Synergistic with Bortezimib

Despite recent advances in the treatment of multiple myeloma (MM), including the introduction of bortezimib, it remains an incurable disease with a short median survival. The development of new agents with efficacy in MM therefore remains both important and urgent. SJG-136 (SG2000, BN2629) is a novel DNA cross-linking agent that binds in a sequence-selective manner in the minor groove of the DNA helix. It is structurally novel compared with other clinically used DNA cross-linking agents and has exhibited a unique pattern of activity in the NCI 60-cell line screen. We have previously shown that this agent is highly effective against primary chronic lymphocytic leukaemia cells. In this study we evaluated its potential as a therapy for MM in cell lines and plasma cells derived from patients. The MM cell lines H929, U266 and JJN3 were shown to have a mean LD₅₀ of 5.1nM (±3.4) following in vitro culture with SJG-136 for 48 hours. This was accompanied by a dose-dependent increase in the percentage of apoptotic cells as evidenced by Annexin V positivity and caspase-3 activation. In comparison to the standard therapies for MM, SJG-136 demonstrated significantly lower LD₅₀ values than doxorubicin (P=0.004), Melphalan (P=0.004) and bortezimib (P=0.03). We also assessed the ability of SJG-136 to kill plasma cells from primary myeloma samples (identified by CD38 and CD138 positivity). These cells were sensitive to SJG-136 with a mean LD₅₀ of 2.3nM (± 0.96) following 48 hour exposures to SJG-136. In contrast, normal bone marrow was significantly less affected by SJG-136 than the myeloma samples (P<0.0001). Finally, we assessed the potential for synergy between SJG-136 and these standard treatments using the H929 cell line as a model. SJG-136 was combined with doxorubicin (1:125), melphalan (1:4000) and bortezimib (1:8) and the combination index (CI) was calculated to assess synergy. A CI of less than 1 was considered synergistic. We found no evidence for synergy between SJG-136 and doxorubicin or melphalan (CI=1.29 and 1.75 respectively). However, SJG-136 was synergistic with bortezimib (CI=0.47) possibly reflecting their different mechanisms of action. In conclusion, SJG-136 is a potentially valuable addition to the battery of drugs available for treatment of MM. Not only was SJG-136 highly potent as a single agent in MM cell lines and primary plasma cells but it also showed a high level of synergy with the proteasome inhibitor bortezimib.