A novel Aurora-A kinase inhibitor MLN8237 induces cytotoxicity and cell-cycle arrest in multiple myeloma

Abstract

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...

Repression of cancer cell senescence by PKCι

“…VX-680, either alone or in combination with PKCi depletion, did not increase the numbers of gH2AX foci beyond those seen in control cells, suggesting that the two treatments promote senescence by similar mechanisms (Figure 6b). Consistent with results reported for the aurora kinase-A-selective inhibitors MLN8237 and MLN8054 (Gorgun et al, 2010;Huck et al, 2010), VX-680 also increased the levels of p21 in MCF7 cells prior to the onset of the senescence phenotype (Figures 6c and d). PKCi depletion does not induce senescence in normal breast epithelial cells In hTert-HMEC cells, depletion of PKCi had no effect on proliferation (Figures 7a and b).…”

The polo-like kinase inhibitor BI 2536 exhibits potent activity against malignant plasma cells and represents a novel therapy in multiple myeloma

“…However, both kinases have different effects on the mitotic process [18]. Numerous inhibitors have been developed against both classes of kinases and some aurora kinase inhibitors have been shown to have effects on multiple myeloma [25][26][27][28][29][30][31]. Indeed, ENMD-2076 is currently undergoing phase I trial [18].…”

Standard and novel imaging methods for multiple myeloma: correlates with prognostic laboratory variables including gene expression profiling data

“…31 The role of STK6 in MM growth has been recently evaluated, and several STK6 inhibitors have been successfully tested against myeloma cells in pre-clinical studies. 43,44 TRIP13 is a AAA + ATPase family member associated with and required for completion of proper meiosis, 32 and is involved in promotion of early steps of the double-strand breaks repair process upstream of the assembly of RAD51 complexes. 45 Increased homologous recombination activity and elevated expression of HR-related genes, including RAD51, has been suggested to mediate DNA instability and progression of MM.…”