A Novel Salt Inducible Kinase 2 Inhibitor, ARN-3261, Sensitizes Ovarian Cancer Cell Lines and Xenografts to Carboplatin

Cancers

Hariprasad Vankayalapat¹  PhilipJ. Rask²  Lan Pang²  RobertC. Bast²  Zhen Lu²  Weiqun Mao²  Dengxuan Fan²  Hailing Yang²  Congjian Xu³  AhmedA. Ahmed⁴ 

[1] Arrien Pharmaceuticals, 9980 South, 300 West, Suite200, Salt Lake City, UT 84070, USA;Department of Experimental Therapeutics, University of Texas M.D. Anderson Cancer Center, Houston, TX 77054, USA;Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011, China;The Nuffield Department of Obstetrics and Gynecology, University of Oxford, Oxford OX3 9DU, UK;

关键词: salt inducible kinase 2 (SIK2);    PARP inhibitor;    carboplatin sensitivity;    γ-H2AX;    comet assay;    apoptosis;   

DOI  :  10.3390/cancers13030446

来源: DOAJ

【 摘 要 】

Salt-induced kinase 2 (SIK2) is a serine-threonine kinase that regulates centrosome splitting, activation of PI3 kinase and phosphorylation of class IIa HDACs, affecting gene expression. Previously, we found that inhibition of SIK2 enhanced sensitivity of ovarian cancer cells to paclitaxel. Carboplatin and paclitaxel constitute first-line therapy for most patients with ovarian carcinoma, producing a 70% clinical response rate, but curing <20% of patients with advanced disease. We have asked whether inhibition of SIK2 with ARN-3261 enhances sensitivity to carboplatin in ovarian cancer cell lines and xenograft models. ARN-3261-induced DNA damage and apoptosis were measured with γ-H2AX accumulation, comet assays, and annexin V. ARN-3261 inhibited growth of eight ovarian cancer cell lines at an IC50 of 0.8 to 3.5 µM. ARN-3261 significantly enhanced sensitivity to carboplatin in seven of eight ovarian cancer cell lines and a carboplatin-resistant cell line tested. Furthermore, ARN-3261 in combination with carboplatin produced greater inhibition of tumor growth than carboplatin alone in SKOv3 and OVCAR8 ovarian cancer xenograft models. ARN-3261 enhanced DNA damage and apoptosis by downregulating expression of survivin. Thus, a SIK2 kinase inhibitor enhanced carboplatin-induced therapy in preclinical models of ovarian cancer and deserves further evaluation in clinical trials.

【 授权许可】

Unknown