title: The aurora kinase inhibitor VX-680 shows anti-cancer effects in primary metastatic cells and the SW13 cell line.
abstract: New therapeutic targets are needed to fight cancer. Aurora kinases (AK) were recently identified as vital key regulators of cell mitosis and have consequently been investigated as therapeutic targets in preclinical and clinical studies. Aurora kinase inhibitors (AKI) have been studied in many cancer types, but their potential capacity to limit or delay metastases has rarely been considered, and never in adrenal tissue. Given the lack of an effective pharmacological therapy for adrenal metastasis and adrenocortical carcinoma, we assessed AKI (VX-680, SNS314, ZM447439) in 2 cell lines (H295R and SW13 cells), 3 cell cultures of primary adrenocortical metastases (from lung cancer), and 4 primary adrenocortical tumor cell cultures. We also tested reversan, which is a P-gp inhibitor (a fundamental efflux pump that can extrude drugs), and we measured AK expression levels in 66 adrenocortical tumor tissue samples. Biomolecular and cellular tests were performed (such as MTT, thymidine assay, Wright's staining, cell cycle and apoptosis analysis, Western blot, qRT-PCR, and mutation analysis). Our results are the first to document AK overexpression in adrenocortical carcinoma as well as in H295R and SW13 cell lines, thus proving the efficacy of AKI against adrenal metastases and in the SW13 cancer cell model. We also demonstrated that reversan and AKI Vx-680 are useless in the H295R cell model, and therefore should not be considered as potential treatments for ACC. Serine/threonine AK inhibition, essentially with VX-680, could be a promising, specific therapeutic tool for eradicating metastases in adrenocortical tissue.
authors.affiliation: Endocrinology Unit, Department of Medicine, University of Padova, Via Ospedale 105, 35128, Padova, Italy. raffaele.pezzani@unipd.it.
authors.forename: Raffaele
authors.initials: R
authors.lastname: Pezzani
authors.affiliation: Endocrinology Unit, Department of Medicine, University of Padova, Via Ospedale 105, 35128, Padova, Italy.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Rubin
authors.affiliation: Endocrinology Unit, Department of Medicine, University of Padova, Via Ospedale 105, 35128, Padova, Italy.
authors.forename: Loris
authors.initials: L
authors.lastname: Bertazza
authors.affiliation: Department of Molecular Medicine, University of Padova, Via Marzolo 3, 35131, Padova, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Redaelli
authors.affiliation: Endocrinology Unit, Department of Medicine, University of Padova, Via Ospedale 105, 35128, Padova, Italy.
authors.forename: Susi
authors.initials: S
authors.lastname: Barollo
authors.affiliation: Endocrinology Unit, Department of Medicine, University of Padova, Via Ospedale 105, 35128, Padova, Italy.
authors.forename: Halenya
authors.initials: H
authors.lastname: Monticelli
authors.affiliation: Department of Experimental Medicine, University of Roma "La Sapienza", Viale Regina Elena 324, 00161, Rome, Italy.
authors.forename: Enke
authors.initials: E
authors.lastname: Baldini
authors.affiliation: Endocrinology Unit, Department of Medicine, University of Padova, Via Ospedale 105, 35128, Padova, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Mian
authors.affiliation: Department of Molecular Medicine, University of Padova, Via Marzolo 3, 35131, Padova, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Mucignat
authors.affiliation: Endocrinology Unit, Department of Medicine, University of Padova, Via Ospedale 105, 35128, Padova, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Scaroni
authors.affiliation: Endocrinology Unit, Department of Medicine, University of Padova, Via Ospedale 105, 35128, Padova, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Mantero
authors.affiliation: Department of Experimental Medicine, University of Roma "La Sapienza", Viale Regina Elena 324, 00161, Rome, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Ulisse
authors.affiliation: Endocrine Surgery Unit, Department of Surgical and Gastroenterological Sciences, University of Padova, Via Giustiniani, 2, 35128, Padova, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Iacobone
authors.affiliation: Endocrinology Unit, Department of Medicine, University of Padova, Via Ospedale 105, 35128, Padova, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Boscaro
mesh_terms: D000293:Adolescent; D000306:Adrenal Cortex Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D018268:Adrenocortical Carcinoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology*; D064127:Aurora Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002648:Child; D002675:Child, Preschool; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D055815:Young Adult; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines
chemical_list: D000970:Antineoplastic Agents; D064127:Aurora Kinases; D010879:Piperazines; D047428:Protein Kinase Inhibitors; C484810:tozasertib; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines
keywords: Adrenal gland; Aurora kinases; Lung carcinoma; Metastasis; Primary cell cultures; Reversan; SW13 cells; VX-680