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The STAT3 inhibitor GPB730 enhances the sensitivity to enzalutamide in prostate cancer cells

Hellsten, Rebecka LU ; Stiehm, Anna LU ; Palominos, Macarena ; Persson, Margareta LU and Bjartell, Anders LU (2022) In Translational Oncology 24.
Abstract

Enzalutamide is a second-generation anti-androgen which has shown increased survival in patients with metastatic prostate cancer. However, some patients do not respond to this therapy or will develop resistance to treatment over time. Signal Transducer and Activator of Transcription 3 (STAT3) is known to be involved in castration-resistant prostate cancer and to interact with androgen receptor (AR)-signaling. This study aims to investigate the combination enzalutamide and the small molecule STAT3 inhibitor GPB730 for enhanced therapeutic effect in advanced prostate cancer in vitro. The prostate cancer cell lines LNCaP (androgen dependent) and C4–2 (androgen insensitive) were used. The effect of enzalutamide and GPB730, alone and in... (More)

Enzalutamide is a second-generation anti-androgen which has shown increased survival in patients with metastatic prostate cancer. However, some patients do not respond to this therapy or will develop resistance to treatment over time. Signal Transducer and Activator of Transcription 3 (STAT3) is known to be involved in castration-resistant prostate cancer and to interact with androgen receptor (AR)-signaling. This study aims to investigate the combination enzalutamide and the small molecule STAT3 inhibitor GPB730 for enhanced therapeutic effect in advanced prostate cancer in vitro. The prostate cancer cell lines LNCaP (androgen dependent) and C4–2 (androgen insensitive) were used. The effect of enzalutamide and GPB730, alone and in combination, was investigated on viability and IC50 values calculated. Enzalutamide and GPB730 treated LNCaP and C4–2 cells were subjected to western blot and QPCR analyses in order to investigate the expression of AR, STAT3 and down-stream targets. C4–2 were less sensitive to growth inhibition by enzalutamide than LNCaP cells. GPB730 enhanced the growth inhibitory effect of enzalutamide in LNCaP and C4–2 cells. The addition of GPB730 to enzalutamide decreased the IC50 values for enzalutamide by 3.3-fold for LNCaP and by 12-fold for C4–2. In C4–2 cells, GPB730 alone decreased PSA expression and enhanced the enzalutamide induced decrease in NKX3.1 expression. GPB730 and enzalutamide in combination enhanced inhibition of c-myc and survivin expression. This study suggests that enzalutamide may be combined with the STAT3 inhibitor GPB730 in order to enhance the efficacy of enzalutamide, offering a new therapeutic approach in advanced prostate cancer.

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author
; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Combination therapy, CRPC, Enzalutamide, Prostate cancer, Small molecule inhibitor, STAT3
in
Translational Oncology
volume
24
article number
101495
publisher
Neoplasia Press
external identifiers
  • scopus:85135003028
  • pmid:35917644
ISSN
1936-5233
DOI
10.1016/j.tranon.2022.101495
language
English
LU publication?
yes
id
7917fcb5-3e88-4203-9aa4-83b17e6a8a20
date added to LUP
2022-10-06 15:11:06
date last changed
2024-06-13 19:58:46
@article{7917fcb5-3e88-4203-9aa4-83b17e6a8a20,
  abstract     = {{<p>Enzalutamide is a second-generation anti-androgen which has shown increased survival in patients with metastatic prostate cancer. However, some patients do not respond to this therapy or will develop resistance to treatment over time. Signal Transducer and Activator of Transcription 3 (STAT3) is known to be involved in castration-resistant prostate cancer and to interact with androgen receptor (AR)-signaling. This study aims to investigate the combination enzalutamide and the small molecule STAT3 inhibitor GPB730 for enhanced therapeutic effect in advanced prostate cancer in vitro. The prostate cancer cell lines LNCaP (androgen dependent) and C4–2 (androgen insensitive) were used. The effect of enzalutamide and GPB730, alone and in combination, was investigated on viability and IC<sub>50</sub> values calculated. Enzalutamide and GPB730 treated LNCaP and C4–2 cells were subjected to western blot and QPCR analyses in order to investigate the expression of AR, STAT3 and down-stream targets. C4–2 were less sensitive to growth inhibition by enzalutamide than LNCaP cells. GPB730 enhanced the growth inhibitory effect of enzalutamide in LNCaP and C4–2 cells. The addition of GPB730 to enzalutamide decreased the IC<sub>50</sub> values for enzalutamide by 3.3-fold for LNCaP and by 12-fold for C4–2. In C4–2 cells, GPB730 alone decreased PSA expression and enhanced the enzalutamide induced decrease in NKX3.1 expression. GPB730 and enzalutamide in combination enhanced inhibition of c-myc and survivin expression. This study suggests that enzalutamide may be combined with the STAT3 inhibitor GPB730 in order to enhance the efficacy of enzalutamide, offering a new therapeutic approach in advanced prostate cancer.</p>}},
  author       = {{Hellsten, Rebecka and Stiehm, Anna and Palominos, Macarena and Persson, Margareta and Bjartell, Anders}},
  issn         = {{1936-5233}},
  keywords     = {{Combination therapy; CRPC; Enzalutamide; Prostate cancer; Small molecule inhibitor; STAT3}},
  language     = {{eng}},
  publisher    = {{Neoplasia Press}},
  series       = {{Translational Oncology}},
  title        = {{The STAT3 inhibitor GPB730 enhances the sensitivity to enzalutamide in prostate cancer cells}},
  url          = {{http://dx.doi.org/10.1016/j.tranon.2022.101495}},
  doi          = {{10.1016/j.tranon.2022.101495}},
  volume       = {{24}},
  year         = {{2022}},
}