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Chlorpromazine Sensitizes Progestin-Resistant Endometrial Cancer Cells to MPA by Upregulating PRB
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 chl...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087176/ https://www.ncbi.nlm.nih.gov/pubmed/33937078 http://dx.doi.org/10.3389/fonc.2021.665832 |
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author | Cui, Yunxia Wu, Huiwen Yang, Linlin Huang, Ting Li, Jian Gong, Xiaodi Li, Lijuan Sun, Xiao Mao, Fei Wang, Yudong |
author_facet | Cui, Yunxia Wu, Huiwen Yang, Linlin Huang, Ting Li, Jian Gong, Xiaodi Li, Lijuan Sun, Xiao Mao, Fei Wang, Yudong |
author_sort | Cui, Yunxia |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8087176 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-80871762021-05-01 Chlorpromazine Sensitizes Progestin-Resistant Endometrial Cancer Cells to MPA by Upregulating PRB Cui, Yunxia Wu, Huiwen Yang, Linlin Huang, Ting Li, Jian Gong, Xiaodi Li, Lijuan Sun, Xiao Mao, Fei Wang, Yudong Front Oncol Oncology 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. Frontiers Media S.A. 2021-04-16 /pmc/articles/PMC8087176/ /pubmed/33937078 http://dx.doi.org/10.3389/fonc.2021.665832 Text en Copyright © 2021 Cui, Wu, Yang, Huang, Li, Gong, Li, Sun, Mao and Wang https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Oncology Cui, Yunxia Wu, Huiwen Yang, Linlin Huang, Ting Li, Jian Gong, Xiaodi Li, Lijuan Sun, Xiao Mao, Fei Wang, Yudong Chlorpromazine Sensitizes Progestin-Resistant Endometrial Cancer Cells to MPA by Upregulating PRB |
title | Chlorpromazine Sensitizes Progestin-Resistant Endometrial Cancer Cells to MPA by Upregulating PRB |
title_full | Chlorpromazine Sensitizes Progestin-Resistant Endometrial Cancer Cells to MPA by Upregulating PRB |
title_fullStr | Chlorpromazine Sensitizes Progestin-Resistant Endometrial Cancer Cells to MPA by Upregulating PRB |
title_full_unstemmed | Chlorpromazine Sensitizes Progestin-Resistant Endometrial Cancer Cells to MPA by Upregulating PRB |
title_short | Chlorpromazine Sensitizes Progestin-Resistant Endometrial Cancer Cells to MPA by Upregulating PRB |
title_sort | chlorpromazine sensitizes progestin-resistant endometrial cancer cells to mpa by upregulating prb |
topic | Oncology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087176/ https://www.ncbi.nlm.nih.gov/pubmed/33937078 http://dx.doi.org/10.3389/fonc.2021.665832 |
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