Aurora-A is a mitotic kinase that regulates mitotic spindle formation and segregation. In multiple myeloma (MM), high Aurora-A gene expression has been correlated with centrosome amplification and proliferation; thus, inhibition of Aurora-A in MM may prove to be therapeutically beneficial. Here we assess the in vitro and in vivo anti-MM activity of MLN8237, a small-molecule Aurora-A kinase inhibitor. Treatment of cultured MM cells with MLN8237 results in mitotic spindle abnormalities, mitotic accumulation, as well as inhibition of cell proliferation through apoptosis and senescence. In addition, MLN8237 up-regulates p53 and tumor suppressor genes p21 and p27. Combining MLN8237 with dexamethasone, doxorubicin, or bortezomib induces synergistic/ additive anti-MM activity in vitro. In vivo anti-MM activity of MLN8237 was confirmed using a xenograft-murine model of human-MM. Tumor burden was significantly reduced (P ؍ .007) and overall survival was significantly increased (P < . IntroductionMultiple myeloma (MM) is a B-cell disease characterized by accumulation of malignant plasma cells in the bone marrow (BM), bone lesions, and immunodeficiency. Genetic analysis shows that approximately 55% to 60% of MM patients have a hyperdiploid karyotype, which confers a better prognosis than nonhyperdiploid disease. 1 The most frequent chromosomal abnormalities observed in nonhyperdiploid MM are translocations between immunoglobulin heavy chain gene located on chromosome 14q32 and an oncogene chromosome 11q13 (CYCLIN D1), 4p16.3 (FGFR3 and MMSET), 6p21 (CYCLIN D3), 16q23 (MAF), or 20q11 (MAFB); or less frequently, the immunoglobulin light chain locus (2p12, or 22q11). 2 During cell proliferation, activation of each cell-cycle phase is dependent on the progress and completion of the previous one. Regulation of the cell cycle involves detecting and repairing genetic damage, as well as controlling various checkpoints to prevent uncontrolled cell division. MM cells are further influenced by the BM microenvironment because adhesion of MM cells to extracellular-matrix proteins supports cell adhesion-mediated drug resistance. In addition, binding of MM cells to BM accessory cells induces secretion of cytokines, which further promote growth, survival, and migration of tumor cells, as well as resistance to conventional chemotherapy. 2,3 Aberrant or overexpression of D-type cyclins is ubiquitous in MM, 4,5 and Aurora kinases regulate cell-cycle checkpoints 6 and cell cycle-regulatory molecules, including cyclins and cyclindependent kinases. [7][8][9] Aurora serine/threonine kinases localize in the centrosome and play a crucial role in cell division by regulating chromatid segregation in mitotic cells 10 ; moreover, defective chromatid segregation causes genetic instability, leading to tumorigenesis. 11 They were first identified in Xenopus Eg2, yeast Ipl1, and Drosophila aurora. The human genome expresses 3 members of the mitotic Aurora kinase family: Aurora-A serine/threonine kinases, Aurora-B serine/threonine kinases, and Aurora-C s...
The bone marrow (BM) microenvironment consists of extracellular-matrix and the cellular compartment including immune cells. Multiple myeloma (MM) cell and BM accessory cell interaction promotes MM survival via both cell-cell contact and cytokines. Immunomodulatory agents (IMiDs) target not only MM cells, but also MM cell-immune cell interactions and cytokine signaling. Here we examined the in vitro effects of IMiDs on cytokine signaling triggered by interaction of effector cells with MM cells and BM stroma cells. IMiDs diminished interleukin-2, interferonγ, and IL-6 regulator suppressor of cytokine signaling (SOCS)1 expression in immune (CD4T, CD8T, natural-killer T, natural-killer) cells from both BM and PB of MM patients. In addition, coculture of MM cells with healthy PBMCs induced SOCS1 expression in effector cells; conversely, treatment with IMiDs down-regulated the SOCS1 expression. SOCS1 negatively regulates IL-6 signaling and is silenced by hypermethylation in MM cells. To define the mechanism of inhibitory-cytokine signaling in effector cells and MM cells, we next analyzed the interaction of immune cells with MM cells that were epigenetically modified to re-express SOCS1; IMiDs induced more potent CTL responses against SOCS1 re-expressing–MM cells than unmodified MM cells. These data therefore demonstrate that modulation of SOCS1 may enhance immune response and efficacy of IMiDs in MM.
Summary This study investigated the cytotoxicity and mechanism of action of AS703026, a novel, selective, orally bioavailable MEK1/2 inhibitor, in human multiple myeloma (MM). AS703026 inhibited growth and survival of MM cells and cytokine‐induced osteoclast differentiation more potently (9‐ to 10‐fold) than AZD6244. Inhibition of proliferation induced by AS703026 was mediated by G0‐G1 cell cycle arrest and was accompanied by reduction of MAF oncogene expression. AS703026 further induced apoptosis via caspase 3 and Poly ADP ribose polymerase (PARP) cleavage in MM cells, both in the presence or absence of bone marrow stromal cells (BMSCs). Importantly, AS703026 sensitized MM cells to a broad spectrum of conventional (dexamethasone, melphalan), novel or emerging (lenalidomide, perifosine, bortezomib, rapamycin) anti‐MM therapies. Significant tumour growth reduction in AS703026‐ vs. vehicle‐treated mice bearing H929 MM xenograft tumours correlated with downregulated pERK1/2, induced PARP cleavage, and decreased microvessels in vivo. Moreover, AS703026 (<200 nmol/l) was cytotoxic against the majority of tumour cells tested from patients with relapsed and refractory MM (84%), regardless of mutational status of RAS and BRAF genes. Importantly, BMSC‐induced viability of MM patient cells was similarly blocked within the same dose range. Our results therefore support clinical evaluation of AS703026, alone or in combination with other anti‐MM agents, to improve patient outcome.
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