Effect of a combination of aurora kinase A inhibitor MLN-8237 and cisplatin on gastrointestinal tumors.

Abstract

58 Background: Gastric cancers respond poorly to current chemotherapeutic protocols indicating active intrinsic mechanisms against drug induced cell death. We have previously reported that AURKA overexpression induces pro-survival (AKT and β-catenin) and inhibits apoptotic (p53 and p73) pathways. Methods: We evaluated the effect of AURKA specific inhibitor (MLN-8237) alone and/or in combination with cisplatin (CDDP) in gastrointestinal (GI) cancer cells. Following treatment with MLN-8237 and/or CDDP, cell survival, cell viability, western blot and qRT-PCR analyses were done on GI cancer cell lines. Additionally, tumor xenografted mice were treated with MLN (30mg/kg) and/or CDDP (2mg/kg) for 21 days and tumor volume was measured every alternate day. Results: The ATP-Glo cell viability and cell survival assay data indicated that in comparison to single agent treatments alone; the combination treatment with MLN-8237 (0.5µM) and CDDP (2.5µM) significantly increased inhibition of cellular viability and survival (p<0.05) in AGS, KATO-III, MKN28, FLO-1, OE-19 and OE33 cell lines. Similarly, the western blot data exhibited higher levels of p73, Puma, Noxa, cleaved caspase 3 and cleaved PARP with MLN (0.5µM) and CDDP (2.5µM) combination treatment, as compared to single agent treatments in AGS, FLO-1 and OE33 cell lines. The tumor growth results for OE33 mouse xenograft study demonstrate synergistic antitumor effect with MLN-8237 and CDDP combination in the following order of effectiveness: Control > CDDP > MLN-8237 > and MLN-8237/CDDP (p<0.01). Moreover, the qRT-PCR data from tumor xenograft samples treated with MLN-8237/CDDP combination showed significantly higher mRNA levels of p73 downstream transcriptional target genes (P21, PUMA, NOXA and BAX) (p<0.05). Conclusions: Our in vitro and in vivo data indicate that inhibition of AURKA with MLN-8237 in combination with CDDP enhances the antitumor activity of MLN-8237 against GI cancer cells. Therefore, our study demonstrates that MLN-8237 is an effective anti-tumor agent which can be potentially combined with CDDP for better therapeutic outcome in GI cancer patients.