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Abstract
BackgroundAloperine, a natural alkaloid constituent isolated from the herb Sophora alopecuroides displays anti-inflammatory properties in vitro and in vivo. Our group previously demonstrated that aloperine significantly induced apoptosis in colon cancer SW480 and HCT116 cells. However, its specific target(s) remain to be discovered in multiple myeloma (MM) and have not been investigated.MethodsHuman myeloma cell lines (n = 8), primary myeloma cells (n = 12), drug-resistant myeloma cell lines (n = 2), and animal models were tested for their sensitivity to aloperine in terms of proliferation and apoptosis both in vitro and in vivo, respectively. We also examined the functional mechanisms underlying the apoptotic pathways triggered by aloperine.ResultsAloperine induced MM cell death in a dose- and time-dependent manner, even in the presence of the proliferative cytokines interleukin-6 and insulin-like growth factor I. Mechanistic studies revealed that aloperine not only activated caspase-8 and reduced the expression of FADD-like interleukin-1β-converting enzyme (FLICE)-like inhibitory protein long (FLIPL) and FLICE-inhibitory proteins (FLIPS) but also activated caspase-9 and decreased the expression of phosphorylated (p)-PTEN. Moreover, co-activation of the caspase-8/cellular FLICE-inhibitory protein (cFLIP)- and caspase-9/p-PTEN/p-AKT-dependent apoptotic pathways by aloperine caused irreversible inhibition of clonogenic survival. Aloperine induce more MM apoptosis with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or borterzomib. A U266 xenograft tumor model and 5T33 MM cells recapitulated the antitumor efficacy of aloperine, and the animals displayed excellent tolerance of the drug and few adverse effects.ConclusionsAloperine has multifaceted antitumor effects on MM cells. Our data support the clinical development of aloperine for MM therapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-015-0120-x) contains supplementary material, which is available to authorized users.
Highlights
Multiple myeloma (MM) is a clonal malignancy of plasma cells that is characterized by the presence of a monoclonal protein in the serum and/or urine, widespread osteolysis, renal failure, and anemia [1,2]
Aloperine inhibited the growth of primary patient MM cells obtained from 12 MM patients who relapsed after multiple previous therapies, including bortezomib, lenalidomide, and dexamethasone and melphalan
Aloperine overcomes the cytoprotective effects of MM bone marrow we utilized BrdUrd incorporation assays to investigate the cytotoxicity of aloperine on MM cells with and without adhesion to bone marrow stromal cell (BMSC)
Summary
Multiple myeloma (MM) is a clonal malignancy of plasma cells that is characterized by the presence of a monoclonal protein in the serum and/or urine, widespread osteolysis, renal failure, and anemia [1,2]. The intrinsic apoptosis pathway is initiated at the mitochondria, which are permeabilized in response to intracellular death signals, releasing cytochrome c and other apoptotic factors into the cytosol and activating caspase-9 and caspase-3 [8]. The extrinsic apoptosis pathway is initiated by the binding of death receptor ligands, such as tumor necrosis factor-related. Receptor trimerization leads to the intracellular recruitment of adaptor proteins, such as Fas-associated death domain (FADD), which enable the binding and activation of caspase-8 at the death-inducing signaling complex (DISC) [8]. Cellular FLICE-inhibitory protein (cFLIP) can block death-receptor signaling by interfering with caspase-8 activation at the DISC [10]. Our group previously demonstrated that aloperine significantly induced apoptosis in colon cancer SW480 and HCT116 cells. Its specific target(s) remain to be discovered in multiple myeloma (MM) and have not been investigated
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