Chlorpromazine Sensitizes Progestin-Resistant Endometrial Cancer Cells to MPA by Upregulating PRB.

Yunxia Cui,Jian Li,Xiaodi Gong,Xiao Sun,Huiwen Wu,Ting Huang,Yudong Wang,Lijuan Li,Fei Mao,Linlin Yang

doi:10.3389/fonc.2021.665832

Abstract

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.

Highlights

Endometrial cancer (EC) is the most common gynecologic cancer in the United States [1]; the incidence and mortality rates of this disease have increased gradually over the last decade [2]
In order to compare the effect of Medroxyprogesterone acetate (MPA) and CPZ on the endometrial cancer (EC) cell proliferation, we treated different EC cell lines with different concentrations of MPA and CPZ
The staining of cells with annexin V/PI further demonstrated that the rates of apoptosis in CPZtreated EC cells were significantly higher than in cells treated with MPA (Figures 1C, D)

Summary

Introduction

Endometrial cancer (EC) is the most common gynecologic cancer in the United States [1]; the incidence and mortality rates of this disease have increased gradually over the last decade [2]. It typically occurs in postmenopausal women [3], EC is increasingly diagnosed in younger women [4, 5]. Type II EC patients have a poor efficacy due to low expression of PRB and the response rate to hormone therapy was only 8% [9]. It is necessary to explore new strategies for cases of de novo or acquired progestin resistance

Methods

Results

Conclusion