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

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.

Targeting GRP75 with a Chlorpromazine Derivative Inhibits Endometrial Cancer Progression Through GRP75–IP3R‐Ca2+‐AMPK Axis

“…[ 40 ] CPZ, which belongs to the phenothiazine class of antipsychotic drugs, was identified as a potential candidate for drug repurposing in cancer treatment, specifically for EC. [ 7 , 36 ] It has been reported to have anti‐proliferative effects, as it alters the expression of proteins that regulate the cell cycle and intracellular mitochondrial functions. [ 41 , 42 , 43 , 44 ] However, the repurposing of CPZ for cancer therapy is challenging, as CPZ is a first‐generation antipsychotic that also has some serious limitations, such as extrapyramidal symptoms.…”

“…[ 6 ] In particular, the utilization of antipsychotics for EC has been an area of ongoing research, but the targets of these investigations remain unclear. [ 7 ] Preliminary screening of 20 tricyclic antipsychotic drugs for an anti‐EC phenotype against 1400 approved drugs in our library revealed that the phenothiazine medicine chlorpromazine (CPZ), which has been widely used as an antipsychotic drug, also has strong anti‐EC activity. Through traditional drug structure optimization, the CPZ derivatives JX57 and JX66 were developed and found to have stronger anti‐EC activities than CPZ in vitro and in vivo ( Figure 1 A ), with minor extrapyramidal side effects.…”

Verteporfin reverses progestin resistance through YAP/TAZ-PI3K-Akt pathway in endometrial carcinoma

“…A previous study showed that Nrf2 plays an important role in the development of progestin resistance while Nrf2 could lead to the progression of cell cycle by activating Akt pathway [ 41 ]. It was also reported that chlorpromazine reverses progestin resistance by inhibiting PI3K-Akt pathway [ 42 ]. So PI3K-Akt pathway may be a key link in regulating progestin resistance of EC.…”

Progestin Resistance and Corresponding Management of Abnormal Endometrial Hyperplasia and Endometrial Carcinoma

“…Antipsychotic agents, including chlorpromazine (CPZ) and thioridazine (THIO), exert anti-oncogenic and progestin-sensitizing effects in EC. It was found that low-dose CPZ (5 mM) pre-treatment could effectively upregulate PRB expression [ 186 ]. Additionally, CPZ downregulated IGF-1R expression and induced PI3K/AKT phosphorylation, thereby inhibiting the development of EC [ 186 ].…”

“…It was found that low-dose CPZ (5 mM) pre-treatment could effectively upregulate PRB expression [ 186 ]. Additionally, CPZ downregulated IGF-1R expression and induced PI3K/AKT phosphorylation, thereby inhibiting the development of EC [ 186 ]. Another antipsychotic drug, THIO, combined with MPA, may suppress the development of EC and enhance progestin sensitivity by upregulating the PRB expression and downregulating the EGFR expression.…”