The aurora kinase inhibitor AMG 900 increases apoptosis and induces chemosensitivity to anticancer drugs in the NCI-H295 adrenocortical carcinoma cell line Kleiton S. Borges a , Augusto F. Andrade a , Vanessa S. Silveira a , David S. Marco Antonio c , Elton J.R. Vasconcelos d , Sonir R.R. Antonini b , Luiz G. Tone a,b and Carlos A. Scrideli a Adrenocortical tumor (ACT) is a malignancy with a low incidence rate and the current therapy for advanced disease has a limited impact on overall patient survival. A previous study from our group suggested that elevated expression of aurora-A and aurora-B is associated with poor outcome in childhood ACT. Similar results were also reported for adult ACTs. The present in-vitro study shows that AMG 900 inhibits aurora kinases in adrenocortical carcinoma cells. AMG 900 inhibited cell proliferation in NCI-H295 cells as well as in the ACT primary cultures and caused apoptosis in the cell line NCI-H295. Furthermore, it potentialized the mitotane, doxorubicin, and etoposide effects on apoptosis induction and acted synergistically with mitotane and doxorubicin in the inhibition of proliferation. In addition, we found that AMG 900 activated Notch signaling and rendered the cells sensitive to the combination of AMG 900 and Notch signaling inhibition. Altogether, these data show that aurora kinases inhibition using AMG 900 may be an adjuvant therapy to treat patients with invasive or recurrent adrenocortical carcinomas. Anti-Cancer Drugs 28:634–644 Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved. Anti-Cancer Drugs 2017, 28:634–644 Keywords: adrenocortical carcinoma, AMG 900, aurora kinases, Notch signaling Departments of a Genetics, b Pediatrics, c Hemocenter, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil and d Seattle Biomedical Research Institute, Seattle, Washington, USA Correspondence to Carlos A. Scrideli, MD, PhD, Department of Pediatrics, Ribeirão Preto Medicine School, University of São Paulo Av. Bandeirantes 3900, Monte Alegre 14049-900, Ribeirão Preto, São Paulo, Brazil Tel: + 55 163 602 2672; fax: + 55 163 602 2810; e-mail: scrideli@fmrp.usp.br Received 30 September 2016 Revised form accepted 13 March 2017 Introduction Adrenal tumors are common, affecting 3–10% of the population, and most of them are benign tumors. Adrenocortical carcinomas (ACCs), in turn, are a rare malignancy with an estimated annual incidence of about 0.5–2.0 cases per million [1]. Different from adult patients, the differentiation between benign (adenoma) and malignant (carcinoma) adrenocortical tumors (ACTs) is a challenge in the pediatric population. Thus, the term ‘adrenocortical tumor’ is usually used to describe adre- nocortical cancers in this age group [2]. Pediatric ACTs are very rare tumors corresponding to only 0.2% of all pediatric cancers; however, their incidence is 10–15-fold higher in the south and southeast regions of Brazil [1,3]. This is mainly attributed to the high prevalence of the p. R337H TP53 germline mutation [4]. Current data show that 2.4% of children carrying this mutation develop ACTs [5]. The clinical manifestations of childhood and adult adreno- cortical cancers are usually similar, but they differ in terms of the correlation between histopathological characteristics and clinical outcomes [2,6]. The most frequent abnormality pre- sented by these patients is the alteration in hormone levels that leads to excessive production of cortisol, androgens, and, more commonly in adults, aldosterone. Hormone synthesis resulting from ACTs in children is relatively inefficient and usually leads to elevated levels of hormone precursors such as dehydroepiandrosterone sulfate and 17-hydroxyprogesterone [1,2,6]. About 45–70% of adult patients and 95% of pediatric patients present hormone secreting tumors [1,2]. Treatment options for advanced adrenocortical cancer are limited. Extensive surgical intervention and the current systemic cytotoxic therapies result in only a modest improvement in overall survival in advanced cases [7]. Mitotane (MIT) is the only available drug therapy, but the effects are limited and systemic toxicity is significant. Other chemotherapeutic drugs regimens have been reported to patients with advanced metastatic disease such as MIT combined with doxorubicin (DOX), cis- platin (CDDP), and etoposide (ETO); however, the results are not promising [1]. Thus, the low impact on survival of traditional therapies for this tumor has led to the study of new approaches to treatment using targeted agents [1,7,8]. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (www.anti-cancerdrugs.com). 634 Preclinical report 0959-4973 Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/CAD.0000000000000504 Copyright r 2017 Wolters Kluwer Health, Inc. All rights reserved.