Synergy of GSK-J4 With Doxorubicin in KRAS-Mutant Anaplastic Thyroid Cancer

Abstract

Background: Anaplastic thyroid cancer is the most aggressive thyroid cancer and has a poor prognosis. At present, there is no effective treatment for it. Methods: Here, we used different concentrations of GSK-J4 or a combination of GSK-J4 and doxorubicin to treat human Cal-62, 8505C, and 8305C anaplastic thyroid cancer (ATC) cell lines. The in vitro experiments were performed using cell viability assays, cell cycle assays, annexin-V/PI binding assays, Transwell migration assays, and woundhealing assays. Tumor xenograft models were used to observe effects in vivo. Results: The half maximal inhibitory concentration (IC50) of GSK-J4 in Cal-62 cells was 1.502 mM, and as the dose of GSK-J4 increased, more ATC cells were blocked in the G2-M and S stage. The combination of GSK-J4 and doxorubicin significantly increased the inhibitory effect on proliferation, especially in KRAS-mutant ATC cells in vivo (inhibition rate 38.0%) and in vitro (suppresses rate Fa value 0.624, CI value 0.673). The invasion and migration abilities of the KRAS-mutant cell line were inhibited at a low concentration (p < 0.05). Conclusions: The combination of GSK-J4 with doxorubicin in KRAS-mutant ATC achieved tumor-suppressive effects at a low dose. The synergy of the combination of GSK-J4 and doxorubicin may make it an effective chemotherapy regimen for KRASmutant ATC.

A-Kinase Interacting Protein 1 Knockdown Restores Chemosensitivity via Inactivating PI3K/AKT and β-Catenin Pathways in Anaplastic Thyroid Carcinoma

“…The 8505C cells were incubated with 0, 0.2, 0.4, 0.8, 1.6, 3.2, and 6.4 μM doxorubicin; CAL-62 cells were incubated with 0, 0.02, 0.04, 0.08, 0.16, 0.32, and 0.64 μM doxorubicin; and 8505C/Dox cells were incubated with 0, 2, 4, 8, 16, 32, and 64 μM doxorubicin ( 15 , 16 ). After 48 h of treatment, CCK-8 assay was performed by the methods mentioned in the Cell Viability Assay subsection and half maximal inhibitory concentration (IC 50 ) was calculated using the sigmoidal dose–response function of the GraphPad Prism software (Version 7.0) ( 17 ).…”

“…The lower chambers were covered with 600 μl of DMEM containing 10% FBS. At 24 h after culture, the invasive cells were counted under a microscope after being stained with crystal violet (Beyotime, China) for 10 min at RT ( 16 , 18 ).…”

GSK‐J4: An H3K27 histone demethylase inhibitor, as a potential anti‐cancer agent

“…GSK‐J4 also inhibited the proliferation of Kirsten rat sarcoma virus (KRAS)‐mutant thyroid cancer cells and arrested the cells at the G2M and S phase 21 . GSK‐J4 inhibited TGFβ induced EMT in ovarian cancer cells by inhibiting the expression of mesenchymal markers like fibronectin and vimentin.…”

“…GSK‐J4 is a small molecule inhibitor of JMJD3/UTX. It has been effectively used as an anti‐cancer agent against several types of cancers, including acute myeloid leukemia, 18 glioma, 19 breast cancer, 20 thyroid cancer, 21 lung cancer, 22 colorectal cancer, 23 prostate cancer, 24 neuroblastoma, 25 hemangiosarcoma 26 and ovarian cancer 27 . It has been shown to target different signaling molecules via inhibiting JMJD3, which gives GSK‐J4 its anti‐cancer properties.…”

JMJD family proteins in cancer and inflammation

“… 410 In glioma cells, GSK-J4 is a combination partner for deacetylase inhibitor panobinostat in glioma cells, and for doxorubicin in KRAS-mutant anaplastic thyroid cancer. 411 , 412 GSK-J4 is also involved in the radiosensitization of diffuse intrinsic pontine glioma, an aggressive pediatric brainstem tumor by inducing DNA repair deficiency. 408 Other cancers that responded to GSK-J4 included BC, 413 PC, 131 lung cancer, 414 hemangiosarcoma, 415 SMARCA4-mutant cancer, 416 Ewing sarcoma, 417 and chondrosarcoma 418 where GSK-J4 displayed potent antitumor effect.…”