The aurora kinase inhibitor AMG 900 increases apoptosis and induces chemosensitivity to anticancer drugs in the NCI-H295 adrenocortical carcinoma cell line.

Abstract

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.

• Authors: Kleiton S Borges, Augusto F Andrade, Vanessa S Silveira, David S Marco Antonio, Elton J R Vasconcelos, Sonir R R Antonini, Luiz G Tone, Carlos A Scrideli
• Journal: Anti-cancer drugs (Anticancer Drugs) Vol. 28 Issue 6 Pg. 634-644 (07 2017) ISSN: 1473-5741 [Electronic] England
• PMID: 28410270 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Histones
• N-(4-((3-(2-amino-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-4-(4-methyl-2-thienyl)-1-phthalazinamine
• Phthalazines
• Protein Kinase Inhibitors
• Mitotane
• Doxorubicin
• Aurora Kinases
• Cisplatin

Topics

• Adrenal Cortex Neoplasms (drug therapy, enzymology, pathology)
• Adrenocortical Carcinoma (drug therapy, enzymology, pathology)
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Apoptosis (drug effects)
• Aurora Kinases (antagonists & inhibitors)
• Cell Line, Tumor
• Cisplatin (administration & dosage, pharmacology)
• Dose-Response Relationship, Drug
• Doxorubicin (administration & dosage, pharmacology)
• Drug Synergism
• Histones (metabolism)
• Humans
• Mitotane (administration & dosage, pharmacology)
• Phosphorylation (drug effects)
• Phthalazines (administration & dosage, pharmacology)
• Protein Kinase Inhibitors (administration & dosage, pharmacology)