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The Activity of SN33638, an Inhibitor of AKR1C3, on Testosterone and 17β-Estradiol Production and Function in Castration-Resistant Prostate Cancer and ER-Positive Breast Cancer.

Yin YD, Fu M, Brooke DG, Heinrich DM, Denny WA, Jamieson SM - Front Oncol (2014)

Bottom Line: AKR1C3 is a novel therapeutic target in castration-resistant prostate cancer (CRPC) and estrogen receptor (ER)-positive breast cancer because of its ability to produce testosterone and 17β-estradiol intratumorally, thus promoting nuclear receptor signaling and tumor progression.SN33638 had little effect on 17β-estradiol production or estrone-stimulated cell proliferation in ER-positive breast cancer cell lines.These results suggest that inhibition of AKR1C3 is unlikely to produce therapeutic benefit in CRPC and ER-positive breast cancer patients, except possibly in the small subpopulation of CRPC patients with tumors that have upregulated AKR1C3 expression and are dependent on AKR1C3 to produce the testosterone required for their growth.

View Article: PubMed Central - PubMed

Affiliation: Auckland Cancer Society Research Centre, The University of Auckland , Auckland , New Zealand.

ABSTRACT
AKR1C3 is a novel therapeutic target in castration-resistant prostate cancer (CRPC) and estrogen receptor (ER)-positive breast cancer because of its ability to produce testosterone and 17β-estradiol intratumorally, thus promoting nuclear receptor signaling and tumor progression. A panel of CRPC, ER-positive breast cancer and high/low AKR1C3-expressing cell lines were treated with SN33638, a selective inhibitor of AKR1C3, in the presence of hormone or prostaglandin (PG) precursors, prior to evaluation of cell proliferation and levels of 11β-PG F2α (11β-PGF2α), testosterone, 17β-estradiol, and prostate-specific antigen (PSA). A meta-analysis of AKR1C3 mRNA expression in patient samples was also conducted, which revealed that AKR1C3 mRNA was upregulated in CRPC, but downregulated in ER-positive breast cancer. 11β-PGF2α and testosterone levels in the cell line panel correlated with AKR1C3 protein expression. SN33638 prevented 11β-PGF2α formation in cell lines that expressed AKR1C3, but partially inhibited testosterone formation and subsequently cell proliferation and/or PSA expression only in high (LAPC4 AKR1C3-overexpressing cells) or moderate (22RV1) AKR1C3-expressing cell lines. SN33638 had little effect on 17β-estradiol production or estrone-stimulated cell proliferation in ER-positive breast cancer cell lines. Although SN33638 could prevent 11β-PGF2α formation, its ability to prevent testosterone and 17β-estradiol production and their roles in CRPC and ER-positive breast cancer progression was limited due to AKR1C3-independent steroid hormone production, except in LAPC4 AKR1C3 cells where the majority of testosterone was AKR1C3-dependent. These results suggest that inhibition of AKR1C3 is unlikely to produce therapeutic benefit in CRPC and ER-positive breast cancer patients, except possibly in the small subpopulation of CRPC patients with tumors that have upregulated AKR1C3 expression and are dependent on AKR1C3 to produce the testosterone required for their growth.

No MeSH data available.


Related in: MedlinePlus

Chemical structures of AKR1C3 inhibitors.
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Figure 1: Chemical structures of AKR1C3 inhibitors.

Mentions: We recently reported the synthesis of a novel series of N-(4-(2-oxopyrrolidin-1-yl)phenyl)piperidine-1-sulfonamides as potent and isoform-selective inhibitors of AKR1C3 (35). The lead compound, SN33638, had low nanomolar potency against AKR1C3 and >300-fold selectivity for AKR1C3 over the other AKR1C isoforms. This compared favorably with other drugs with AKR1C3 inhibitory activity, such as non-steroidal anti-inflammatory drugs (NSAIDs; e.g., indomethacin and flufenamic acid), which are less potent against AKR1C3 and are non-selective for cyclooxygenase enzymes (36, 37) and medroxyprogesterone acetate (MPA), which is non-selective for the other AKR1C isoforms (38) (Figure 1). Here, we investigate AKR1C3 expression and activity across a panel of CRPC and ER-positive breast cancer cell lines. We use this cell line panel to evaluate the ability of SN33638 to inhibit 11β-PGF2α, testosterone, and 17β-estradiol production, and to determine the effect of AKR1C3 inhibition on cell proliferation and prostate-specific antigen (PSA) expression.


The Activity of SN33638, an Inhibitor of AKR1C3, on Testosterone and 17β-Estradiol Production and Function in Castration-Resistant Prostate Cancer and ER-Positive Breast Cancer.

Yin YD, Fu M, Brooke DG, Heinrich DM, Denny WA, Jamieson SM - Front Oncol (2014)

Chemical structures of AKR1C3 inhibitors.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4061482&req=5

Figure 1: Chemical structures of AKR1C3 inhibitors.
Mentions: We recently reported the synthesis of a novel series of N-(4-(2-oxopyrrolidin-1-yl)phenyl)piperidine-1-sulfonamides as potent and isoform-selective inhibitors of AKR1C3 (35). The lead compound, SN33638, had low nanomolar potency against AKR1C3 and >300-fold selectivity for AKR1C3 over the other AKR1C isoforms. This compared favorably with other drugs with AKR1C3 inhibitory activity, such as non-steroidal anti-inflammatory drugs (NSAIDs; e.g., indomethacin and flufenamic acid), which are less potent against AKR1C3 and are non-selective for cyclooxygenase enzymes (36, 37) and medroxyprogesterone acetate (MPA), which is non-selective for the other AKR1C isoforms (38) (Figure 1). Here, we investigate AKR1C3 expression and activity across a panel of CRPC and ER-positive breast cancer cell lines. We use this cell line panel to evaluate the ability of SN33638 to inhibit 11β-PGF2α, testosterone, and 17β-estradiol production, and to determine the effect of AKR1C3 inhibition on cell proliferation and prostate-specific antigen (PSA) expression.

Bottom Line: AKR1C3 is a novel therapeutic target in castration-resistant prostate cancer (CRPC) and estrogen receptor (ER)-positive breast cancer because of its ability to produce testosterone and 17β-estradiol intratumorally, thus promoting nuclear receptor signaling and tumor progression.SN33638 had little effect on 17β-estradiol production or estrone-stimulated cell proliferation in ER-positive breast cancer cell lines.These results suggest that inhibition of AKR1C3 is unlikely to produce therapeutic benefit in CRPC and ER-positive breast cancer patients, except possibly in the small subpopulation of CRPC patients with tumors that have upregulated AKR1C3 expression and are dependent on AKR1C3 to produce the testosterone required for their growth.

View Article: PubMed Central - PubMed

Affiliation: Auckland Cancer Society Research Centre, The University of Auckland , Auckland , New Zealand.

ABSTRACT
AKR1C3 is a novel therapeutic target in castration-resistant prostate cancer (CRPC) and estrogen receptor (ER)-positive breast cancer because of its ability to produce testosterone and 17β-estradiol intratumorally, thus promoting nuclear receptor signaling and tumor progression. A panel of CRPC, ER-positive breast cancer and high/low AKR1C3-expressing cell lines were treated with SN33638, a selective inhibitor of AKR1C3, in the presence of hormone or prostaglandin (PG) precursors, prior to evaluation of cell proliferation and levels of 11β-PG F2α (11β-PGF2α), testosterone, 17β-estradiol, and prostate-specific antigen (PSA). A meta-analysis of AKR1C3 mRNA expression in patient samples was also conducted, which revealed that AKR1C3 mRNA was upregulated in CRPC, but downregulated in ER-positive breast cancer. 11β-PGF2α and testosterone levels in the cell line panel correlated with AKR1C3 protein expression. SN33638 prevented 11β-PGF2α formation in cell lines that expressed AKR1C3, but partially inhibited testosterone formation and subsequently cell proliferation and/or PSA expression only in high (LAPC4 AKR1C3-overexpressing cells) or moderate (22RV1) AKR1C3-expressing cell lines. SN33638 had little effect on 17β-estradiol production or estrone-stimulated cell proliferation in ER-positive breast cancer cell lines. Although SN33638 could prevent 11β-PGF2α formation, its ability to prevent testosterone and 17β-estradiol production and their roles in CRPC and ER-positive breast cancer progression was limited due to AKR1C3-independent steroid hormone production, except in LAPC4 AKR1C3 cells where the majority of testosterone was AKR1C3-dependent. These results suggest that inhibition of AKR1C3 is unlikely to produce therapeutic benefit in CRPC and ER-positive breast cancer patients, except possibly in the small subpopulation of CRPC patients with tumors that have upregulated AKR1C3 expression and are dependent on AKR1C3 to produce the testosterone required for their growth.

No MeSH data available.


Related in: MedlinePlus