Abstract
Antiproliferation and proapoptosis are two major molecular mechanisms of action of drugs used for the treatment of multiple myeloma. Proteasome inhibitors, such as bortezomib (PS-341), and immunomodulatory drugs (IMiDs), such as lenalidomide, are the two drug types approved for the treatment of myeloma. Bortezomib and lenalidomide activate caspase-8 and promote the apoptosis of myeloma cells. However, caspase-8 inhibition potentiated the antiproliferative effect of lenalidomide and bortezomib in myeloma cells, suggesting that caspase-8 could regulate proliferation and apoptosis in the opposite pathway. In this mini-review, I summarized recent advances in determining the molecular mechanisms of caspase-8 in bortezomib–lenalidomide-based therapy for myeloma and explored the possible functions of caspase-8 in the proliferation and apoptosis of myeloma cells. Furthermore, future directions of caspase-8-based therapy for myeloma have been discussed.
Highlights
Caspase-8, as an initiator caspase, is essential for death receptor-dependent apoptosis [1, 2] and is activated in multiple pharmacological treatments for myeloma [3, 4]
We discovered that the proteasome inhibitors bortezomib and MG-132 could induce CRBN cleavage, which possibly attenuates the anti-myeloma effect of lenalidomide [5, 6]
Combination therapy with lenalidomide and bortezomib is the first-line pharmacotherapy for multiple myeloma [15, 16] and has led to the paradoxical therapeutic mechanisms that mediate the action of lenalidomide and bortezomib in myeloma [17]
Summary
Antiproliferation and proapoptosis are two major molecular mechanisms of action of drugs used for the treatment of multiple myeloma Proteasome inhibitors, such as bortezomib (PS-341), and immunomodulatory drugs (IMiDs), such as lenalidomide, are the two drug types approved for the treatment of myeloma. Caspase-8 inhibition potentiated the antiproliferative effect of lenalidomide and bortezomib in myeloma cells, suggesting that caspase-8 could regulate proliferation and apoptosis in the opposite pathway. In this mini-review, I summarized recent advances in determining the molecular mechanisms of caspase-8 in bortezomib–lenalidomide-based therapy for myeloma and explored the possible functions of caspase-8 in the proliferation and apoptosis of myeloma cells.
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