The combination of a sphingosine kinase 2 inhibitor (ABC294640) and a Bcl‐2 inhibitor (ABT‐199) displays synergistic anti‐myeloma effects in myeloma cells without a t(11;14) translocation

Abstract

Multiple myeloma (MM) remains an incurable disease in need of the development of novel therapeutic agents and drug combinations. ABT‐199 is a specific Bcl‐2 inhibitor in clinical trials for MM; however, its activity as a single agent was limited to myeloma patients with the t(11;14) translocation who acquire resistance due to co‐expression of Mcl‐1 and Bcl‐xL. These limitations preclude its use in a broader patient population. We have recently found that a sphingosine kinase 2‐specific inhibitor (ABC294640) induces apoptosis in primary human CD138+ cells and MM cell lines. ABC294640 is currently in phase I/II clinical trials for myeloma (clinicaltrials.gov: #NCT01410981). Interestingly, ABC294640 down‐regulates c‐Myc and Mcl‐1, but does not have any effects on Bcl‐2. We first evaluated the combinatorial anti‐myeloma effect of ABC294640 and ABT‐199 in vitro in 7 MM cell lines, all of which harbor no t(11;14) translocation. Combination index calculation demonstrated a synergistic anti‐myeloma effect of the combination of ABC294640 and ABT‐199. This synergistic anti‐myeloma effect was maintained even in the presence of bone marrow (BM) stromal cells. The combination of ABC294640 and ABT‐199 led to enhanced cleavage of PARP and caspase‐3/9 and increased Annexin‐V expression, consistent with the induction of apoptosis by the combination treatment. In addition, the combination of ABC294640 and ABT‐199 resulted in the down‐regulation of the anti‐apoptotic proteins Mcl‐1, Bcl‐2, and Bcl‐xL and the cleavage of Bax and Bid. The combination induced both the mitochondrial mediated‐ and caspase‐mediated apoptosis pathways. Finally, the combination of ABC294640 and ABT‐199 resulted in augmented anti‐myeloma effect in vivo in a mouse xenograft model. These findings demonstrate that the co‐administration of ABC294640 and ABT‐199 exhibits synergistic anti‐myeloma activity in vitro and in vivo, providing justification for a clinical study of this novel combination in patients with relapsed/refractory multiple myeloma.

Inhibitors of Ceramide- and Sphingosine-Metabolizing Enzymes as Sensitizers in Radiotherapy and Chemotherapy for Head and Neck Squamous Cell Carcinoma

“…ABC294640 increased the transcription of pro-apoptotic Noxa and degradation of prosurvival Bcl-2 family molecule Mcl-1 in human cholangiocarcinoma cells. ABC294640 synergized with Bcl-2/Bcl-xL inhibitors ABT-263 and Obatoclax to induce cholangiocarcinoma cell death [182,183].…”

MITF Regulates Downstream Genes in Response to Vibrio parahaemolyticus Infection in the Clam Meretrix Petechialis

“…The relationship between BCL-2 and the apoptosis rate was then evaluated. To inhibit the activity of BCL-2, the specific inhibitor, ABT199, was used in this study (30). The haemocytes were treated with the BCL-2 inhibitor for 12 h (ABT199, diluted with DMSO), while the haemocytes of the control group were treated with equal volume of DMSO.…”

Intense Uptake of Liposomal Curcumin by Multiple Myeloma Cell Lines: Comparison to Normal Lymphocytes, Red Blood Cells and Chronic Lymphocytic Leukemia Cells

“…Curcumin blocks the actions of indoleamine 2,3-dioxygenase, an important checkpoint molecule which cancer cells secrete in order to cause suppression of the patient's immune system (13)(14)(15). A role for curcumin as maintenance therapy in the treatment of cancer has been proposed based on its inhibition of sphingosine kinase (16); sphingosine kinase inhibitors have been shown to possess synergistic anti-myeloma effects in myeloma cells (17). Sphigosine kinase is responsible for the production in the cell membrane of sphigosine 1-phosphate, which promotes cell proliferation and survival as well as angiogenesis (16,17).…”

“…A role for curcumin as maintenance therapy in the treatment of cancer has been proposed based on its inhibition of sphingosine kinase (16); sphingosine kinase inhibitors have been shown to possess synergistic anti-myeloma effects in myeloma cells (17). Sphigosine kinase is responsible for the production in the cell membrane of sphigosine 1-phosphate, which promotes cell proliferation and survival as well as angiogenesis (16,17). Thus, curcumin has both cell membrane and intracellular (nuclear) targets that may mediate its anticancer effects.…”