文献类型：期刊文献

英文题名：Chlorpromazine Sensitizes Progestin-Resistant Endometrial Cancer Cells to MPA by Upregulating PRB

作者：Cui, Yunxia[1];Wu, Huiwen[2];Yang, Linlin[1];Huang, Ting[1];Li, Jian[2,3,4];Gong, Xiaodi[1];Li, Lijuan[1];Sun, Xiao[1,5];Mao, Fei[2];Wang, Yudong[1,5]

机构：[1]Shanghai Jiao Tong Univ, Sch Med, Int Peace Matern & Child Hlth Hosp, Dept Gynecol Oncol, Shanghai, Peoples R China;[2]East China Univ Sci & Technol, Shanghai Key Lab New Drug Design, Sch Pharm, State Key Lab Bioreactor Engn, Shanghai, Peoples R China;[3]Dali Univ, Coll Pharm & Chem, Dali, Peoples R China;[4]East China Univ Sci & Technol, Frontiers Sci Ctr Mat & Dynam Chem, Shanghai, Peoples R China;[5]Shanghai Municipal Key Clin Specialty, Female Tumor Reprod Specialty, Shanghai, Peoples R China

年份：2021

卷号：11

外文期刊名：FRONTIERS IN ONCOLOGY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000645551600001)】；

基金：This study was funded by Shanghai Municipal Key Clinical Specialty (No. shslczdzk06302), National Natural Science Foundation of China (No. 81172477, 81402135,22077033), the Project of the Science and Technology Commission of Shanghai Municipality (No. 17441907400) and Shanghai Jiao Tong University Medicine-Engineering Fund (No. YG2017MS41), National Natural Science Foundation of China (No. 20ZR1414800).

语种：英文

外文关键词：endometrial cancer; chlorpromazine; medroxyprogesterone acetate; anticancer activity; sequential treatment

摘要：Medroxyprogesterone acetate (MPA) is the main conservative treatment for endometrial cancer (EC) patients desirable to preserve fertility and those who cannot suffer from surgery. Considering the high incidence of progestin resistance and recurrence of MPA treatment, we reproposed antipsychotics chlorpromazine (CPZ) as a new strategy for both progestin-sensitive and -resistant endometrial cancer. Cytobiology experiments indicated that CPZ could significantly suppress proliferation, migration/invasion and induce apoptosis in Ishikawa (ISK) and KLE EC cell lines. And xenograft mouse models were constructed to validate the antitumor effect and toxicity of CPZ in-vivo. CPZ inhibited the growth at a low dose of 3mg/kg and the mice exhibited no signs of toxicity. Next, concomitant treatment and sequential treatment with CPZ and MPA were proceeded to analysis the synergistic effect in EC cells. Concomitant treatment only performed a limited synergistic effect on apoptosis in ISK and KLE cells. Nevertheless, sequential treatment showed favorable synergistic effects in progestin-resistant KLE cells. Finally, a stable MPA-resistant cell line shRNA was established to explore the mechanism of CPZ reversing progestin resistance. Immunoblot data showed that CPZ inhibited the activation of PI3K/AKT signal in ISK and KLE cells and upregulated PRB expression in progestin-resistant cells, by which CPZ overcame progestin resistance to MPA. Thus, CPZ might act as a candidate drug for conservative treatment and sequential treatment with CPZ and MPA could be a suitable therapeutic option for progestin resistant patients.