TY - JOUR
T1 - A novel salt inducible kinase 2 inhibitor, ARN-3261, sensitizes ovarian cancer cell lines and xenografts to carboplatin
AU - Fan, Dengxuan
AU - Yang, Hailing
AU - Mao, Weiqun
AU - Rask, Philip J.
AU - Pang, Lan
AU - Xu, Congjian
AU - Vankayalapat, Hariprasad
AU - Ahmed, Ahmed A.
AU - Bast, Robert C.
AU - Lu, Zhen
N1 - Funding Information: Funding: This work was supported by the Cancer Prevention and Research Institute of Texas (RP110595-P1), the National Cancer Institute (R01 CA 135354), the MD Anderson Specialized Program of Research Excellence in Ovarian Cancer (P50 CA 83639 and CA 217685 from the National Cancer Institute), the Shared Resources of the MD Anderson Cancer Center Support Grant (P30 CA16672 from the National Cancer Institute), the National Foundation for Cancer Research, and philanthropic support through generous donations from Stuart and Gaye-Lynn Zarrow, the Ann and Henry Zarrow Foundation, the Mossy Foundation, and the Roberson Endowment. Barry Elson, Arthur and Sandra Williams. DF received salary support from National Natural Science Foundation of China (81300552) while completing work for her PhD. Funding Information: This work was supported by the Cancer Prevention and Research Institute of Texas (RP110595-P1), the National Cancer Institute (R01 CA 135354), the MD Anderson Specialized Program of Research Excellence in Ovarian Cancer (P50 CA 83639 and CA 217685 from the National Cancer Institute), the Shared Resources of the MD Anderson Cancer Center Support Grant (P30 CA16672 from the National Cancer Institute), the National Foundation for Cancer Research, and philanthropic support through generous donations from Stuart and Gaye-Lynn Zarrow, the Ann and Henry Zarrow Foundation, the Mossy Foundation, and the Roberson Endowment. Barry Elson, Arthur and Sandra Williams. DF received salary support from National Natural Science Foundation of China (81300552) while completing work for her PhD. Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021
Y1 - 2021
N2 - Carboplatin and paclitaxel constitute first-line treatment for ovarian cancer, producing tumor shrinkage in 70% of patients, but curing less than 20% with advanced stage disease. Previous studies have shown that treatment with ARN-3261, a small molecule inhibitor of the enzyme salt-induced kinase 2, can improve the response to paclitaxel in human ovarian cancer cells grown in culture and in immunocompromised mice. Here we have found that ARN-3261 also increases carboplatin’s ability to kill ovarian cancer cells grown in culture and in immunocompromised mice, causing additional DNA damage and decreasing levels of survivin, a protein that protects cancer cells from programmed cell death. Our studies encourage clinical evaluation of ARN-3261 and a Phase I clinical trial has been initiated to test the drug in ovarian cancer patients. 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.
AB - Carboplatin and paclitaxel constitute first-line treatment for ovarian cancer, producing tumor shrinkage in 70% of patients, but curing less than 20% with advanced stage disease. Previous studies have shown that treatment with ARN-3261, a small molecule inhibitor of the enzyme salt-induced kinase 2, can improve the response to paclitaxel in human ovarian cancer cells grown in culture and in immunocompromised mice. Here we have found that ARN-3261 also increases carboplatin’s ability to kill ovarian cancer cells grown in culture and in immunocompromised mice, causing additional DNA damage and decreasing levels of survivin, a protein that protects cancer cells from programmed cell death. Our studies encourage clinical evaluation of ARN-3261 and a Phase I clinical trial has been initiated to test the drug in ovarian cancer patients. 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.
KW - Apoptosis
KW - Carboplatin sensitivity
KW - Comet assay
KW - Parp inhibitor
KW - Salt inducible kinase 2 (SIK2)
KW - γ-H2AX
UR - http://www.scopus.com/inward/record.url?scp=85099968888&partnerID=8YFLogxK
U2 - https://doi.org/10.3390/cancers13030446
DO - https://doi.org/10.3390/cancers13030446
M3 - Article
C2 - 33503955
SN - 2072-6694
VL - 13
SP - 1
EP - 15
JO - Cancers
JF - Cancers
IS - 3
M1 - 446
ER -