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

Bo Lin; Bing Lu; I-Yun Hsieh; Zhen Liang; Zicheng Sun; Yang Yi; Weiming Lv; Wei Zhao; Jie Li

doi:10.3389/fphar.2020.00632

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

Front Pharmacol. 2020 May 13:11:632. doi: 10.3389/fphar.2020.00632. eCollection 2020.

Authors

Bo Lin¹, Bing Lu², I-Yun Hsieh¹, Zhen Liang³, Zicheng Sun¹, Yang Yi⁴, Weiming Lv¹, Wei Zhao^{4

5

6}, Jie Li¹

Affiliations

¹ Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
² Institute of Urology of Shenzhen University, The Third Affiliated Hospital of Shenzhen University, Shenzhen Luohu Hospital Group, Shenzhen, China.
³ Department of Breast Surgery, Guangzhou Women and Children's Medical Center, Guangzhou, China.
⁴ Key Laboratory of Stem Cells and Tissue Engineering (Sun Yat-sen University), Ministry of Education, Guangzhou, China.
⁵ RNA Biomedical Institute, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
⁶ Department of Research and Development, Shenzhen Institute for Innovation and Translational Medicine, Shenzhen, China.

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 wound-healing 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 μM, 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 KRAS-mutant ATC.

Keywords: GSK-J4; KRAS-mutant; anaplastic thyroid cancer; epigenetics; synergistic action.