Aurora B kinase inhibition in mitosis: Strategies for optimizing the use of Aurora kinase inhibitors such as AT9283

Abstract

Aurora kinases play a key role in regulating mitotic division and are attractive oncology targets. AT9283, a multi-targeted kinase inhibitor with potent activity against Aurora A and B kinases, inhibited growth and survival of multiple solid tumor cell lines and was efficacious in mouse xenograft models. AT9283-treatment resulted in endoreduplication and ablation of serine-10 histone H3 phosphorylation in both cells and tumor samples, confirming that in these models it acts as an Aurora B kinase inhibitor. In vitro studies demonstrated that exposure to AT9283 for one complete cell cycle committed an entire population of p53 checkpoint-compromised cells (HCT116) to multinucleation and death whereas treatment of p53 checkpointcompetent cells (HMEC, A549) for a similar length of time led to a reversible arrest of cells with 4N DNA. Further studies in synchronized cell populations suggested that exposure to AT9283 during mitosis was critical for optimal cytotoxicity. We therefore investigated ways in which these properties might be exploited to optimize the efficacy and therapeutic index of Aurora kinase inhibitors for p53 checkpoint compromised tumors in vivo. Combining Aurora B kinase inhibition with paclitaxel, which arrests cells in mitosis, in a xenograft model resulted in promising efficacy without additional toxicity. These findings have implications for optimizing the efficacy of Aurora kinase inhibitors in clinical practice.

Characterisation of a multimeric protein complex associated with ERp57 within the nucleus in paclitaxel-sensitive and -resistant epithelial ovarian cancer cells: The involvement of specific conformational states of β-actin

“…For this reason, the Aurora kinases are currently one of the most interesting targets for cancer therapy. Moreover, recent studies demonstrated that Aurora kinase inhibitors synergize with microtubule targeted agents to induce apoptosis in several tumor cell lines (56,57) and are potent killers of taxane-sensitive and -resistant ovarian cancer cells (58). Interestingly, our results show that ERp57 in the nucleus is phosphorylated and suggest the involvement of a specific kinase and/or phosphatase activity in the modulation of ERp57 subcellular distribution.…”

The heat shock protein 90 inhibitor, AT13387, displays a long duration of action in vitro and in vivo in non‐small cell lung cancer

“…Floating and adherent cells were collected and treated as described previously. (34) Samples were resolved by SDS-PAGE and immunoblotted with antibodies specific for Akt, pAkt, androgen receptor, cleaved PARP, c-Met, EGFR, phospho-EGFR, Erk, phospho-Erk, S6, phospho-S6, Stat3, phospho-Stat3 (Cell Signaling Technologies, Cambridge, UK), B-Raf, CDK4, HER2 Raf-1 (Santa Cruz Antibodies, Santa Cruz, CA, USA), actin (Abcam, Cambridge, UK), HSP70 (StressGen Biotechnologies, Victoria, BC, Canada), or GAPDH (Chemicon International, Temecula, CA, USA). This was followed by infrared dye labeled anti-rabbit or anti-mouse antibodies (Licor Bioscience, Lincoln, NE, USA).…”

“…Samples were prepared for analysis as described previously. (34) Quantification was by comparison with a standard calibration line. The limit of detection for AT13387 was 150 nM in blood and 120 nM in tumor.…”

RETRACTED ARTICLE: Frequency of TP53 Mutations and its Impact on Drug Sensitivity in Acute Myeloid Leukemia?

“…Drug AZD1152 is an aurora kinase inhibitor especially of Aurora kinase B. Aurora kinases are chromosomal passenger proteins, located near the spindle and help in various process of mitosis. It has been proved to be novel anticancer drug for acute leukemia [7][8][9][10][11].…”