Abstract
Aurora kinases play key roles in regulating centrosome maturation, mitotic spindle formation, and cytokinesis during cell division, and are considered promising drug targets due to their frequent overexpression in a variety of human cancers. SNS-314 is a selective and potent pan Aurora inhibitor currently in a dose escalation phase 1 clinical trial for the treatment of patients with advanced solid tumors. Here, we report the antiproliferative effects of SNS-314 in combination with common chemotherapeutics in cell culture and xenograft models. The HCT116 colorectal carcinoma cell line, with intact or depleted p53 protein levels, was treated with SNS-314 and a cytotoxic chemotherapeutic from a panel comprised of gemcitabine, 5-fluorouracil (5-FU), carboplatin, daunomycin, SN-38 (the active metabolite of irinotecan), docetaxel, and vincristine. Combinations were administered under either concurrent or sequential schedules. SNS-314 has predominantly additive effects when administered concurrently with commonly used anticancer agents. Sequential administration of SNS-314 with chemotherapeutic compounds showed additive antiproliferative effects with carboplatin, gemcitabine, 5-FU, daunomycin, and SN-38, and synergy was observed in combination with gemcitabine, docetaxel, or vincristine. The most profound antiproliferative effects were observed with sequential administration of SNS-314 followed by docetaxel or vincristine. In vivo, SNS-314 potentiated the antitumor activity of docetaxel in xenografts. Both the in vitro synergies observed between SNS-314 and agents that target the mitotic spindle and the potentiation seen with docetaxel in vivo are consistent with a mechanism of action in which Aurora inhibition bypasses the mitotic spindle assembly checkpoint and prevents cytokinesis, augmenting subsequent spindle toxin-mediated mitotic catastrophe and cell death.
Highlights
Aurora kinases constitute a family of serine-threonine kinases that play fundamental roles in regulating cell division [1,2,3,4]
The drugs surveyed represented a spectrum of mechanisms including DNA strand termination, DNA intercalation, DNA alkylation, topoisomerase-II inhibition (SN-38), activation of the mitotic spindle assembly checkpoint, and disruption of microtubule dynamics
The antiproliferative effects of drug combinations were measured by a high-content screening cell count proliferation assay and scored with a combination index, a numerical value that provides a quantitative measure of the extent of drug interaction
Summary
Aurora kinases (isoforms A, B, and C) constitute a family of serine-threonine kinases that play fundamental roles in regulating cell division [1,2,3,4]. Aurora-A localizes to the centrosomes and functions in centrosome regulation and mitotic spindle formation [5, 6]. Aurora-B is characterized as a subunit of the chromosomal passenger protein complex that functions to insure chromosomal segregation and cytokinesis [7, 8]. Given the central role of all three Aurora kinases in mitotic regulation and the association between their overexpression and tumorigenesis, they are being evaluated as potential targets in cancer therapy [4, 15, 21,22,23,24]
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