Increased expression of type 2 3α-hydroxysteroid dehydrogenase/type 5 17β-hydroxysteroid dehydrogenase (AKR1C3) and its relationship with androgen receptor in prostate carcinoma

Fung, Kar Ming; Samara, E. N S; Wong, Corrine; Metwalli, Adam R.; Krlin, R.; Bane, Barbara L.; Liu, Cheng Z.; Yang, Jeyul; Pitha, Josef; Culkin, Daniel J.; Kropp, Bradley P.; Penning, T.M.; Lin, Hsueh Kung

doi:10.1677/erc.1.01048

Cited by 114 publications

(96 citation statements)

References 31 publications

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“…It has previously been shown that mRNA levels of the enzymes are correlated with protein amounts and activities in other studies [46][47][48][49][50] so we did not repeat these studies.…”

Section: Discussionmentioning

confidence: 99%

“…There are several enzymes which are involved in intracellular testosterone synthesis in the prostate cancer cell (25,(36)(37)(38)(39). HSD3B2 catalyzes the conversion of dehydroepi-androsterone (DHEA) to androstenedione [25,36].…”

Section: Discussionmentioning

confidence: 99%

“…HSD3B2 catalyzes the conversion of dehydroepi-androsterone (DHEA) to androstenedione [25,36]. In addition, AKR1C3 converts androstenedione to testosterone and increased amounts of AKR1C3 have been demonstrated in prostatic adenocarcinoma and carcinoma [37]. Testosterone is converted to DHT by 5α-reductase (SRD5A1) [38].…”

Section: Discussionmentioning

confidence: 99%

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Pomegranate polyphenols down-regulate expression of androgen-synthesizing genes in human prostate cancer cells overexpressing the androgen receptor

Hong

Seeram

Heber

2008

The Journal of Nutritional Biochemistry

137

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Prostate cancer is dependent on circulating testosterone in its early stages and is treatable with radiation and surgery. However, recurrent prostate tumors advance to an androgen-independent state where they progress in the absence of circulating testosterone leading to metastasis and death. During the development of androgen independence, prostate cancer cells are known to increase intracellular testosterone synthesis which maintains cancer cell growth in the absence of significant amounts of circulating testosterone. Overexpression of the androgen receptor (AR) occurs in androgenindependent prostate cancer and has been proposed as another mechanism promoting the development of androgen independence. The LNCaP-AR cell line is engineered to overexpress AR but is otherwise similar to the widely studied LNCaP cell line. We have previously shown that pomegranate extracts inhibit both androgen-dependent and androgen-independent prostate cancer cell growth. In the present study, we examined the effects of pomegranate polyphenols, ellagitanninrich extract and whole juice extract on the expression of genes for key androgen synthesizing enzymes and the AR. We measured expression of the HSD3B2, AKR1C3 and SRD5A1 genes for the respective androgen synthesizing enzymes in LNCaP, LNCaP-AR, and DU-145 human prostate cancer cells. A two-fold suppression of gene expression was considered statistically significant. Pomegranate polyphenols inhibited gene expression and AR most consistently in the LNCaP-AR cell line (P =.05). Therefore, inhibition by pomegranate polyphenols of gene expression involved in androgen synthesis enzymes and the AR may be of particular importance in androgen-independent prostate cancer cells and the subset of human prostate cancers where AR is upregulated.

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“…It has previously been shown that mRNA levels of the enzymes are correlated with protein amounts and activities in other studies [46][47][48][49][50] so we did not repeat these studies.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Pomegranate polyphenols down-regulate expression of androgen-synthesizing genes in human prostate cancer cells overexpressing the androgen receptor

Hong

Seeram

Heber

2008

The Journal of Nutritional Biochemistry

137

View full text Add to dashboard Cite

show abstract

“…Several reports and our results revealed that 17-HSD5 (known as AKR1C3) positive cases were significantly associated with clinical stage. [37,38] Fung et al revealed that elevated expression of AKR1C3 is highly associated with prostate cancer. [37] We also revealed that both AR and androgen-converting enzymes were up-regulated in the highgrade or advanced prostate cancer.…”

Section: Prostate Cancer Aggressiveness and The Androgen Milieu In Thmentioning

confidence: 99%

“…[37,38] Fung et al revealed that elevated expression of AKR1C3 is highly associated with prostate cancer. [37] We also revealed that both AR and androgen-converting enzymes were up-regulated in the highgrade or advanced prostate cancer. [38] AKR1C3 (17-HSD5) may be involved in increasing the local concentration of testosterone in prostate cancer tissues, resulting in the progression, invasion and further development of prostate cancer following ADT.…”

Section: Prostate Cancer Aggressiveness and The Androgen Milieu In Thmentioning

confidence: 99%

Paradigm Shift in the Concept of Hormonal Milieu of Prostate Cancer

Nishiyama¹

2011

Prostate Cancer - From Bench to Bedside

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Characterization of AST‐001 non‐clinical pharmacokinetics: A novel selective AKR1C3‐activated prodrug in mice, rats, and cynomolgus monkeys

Meng,

Jung,

Cai

et al. 2024

Biopharm & Drug Disp

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AST‐001 is a chemically synthesized inactive nitrogen mustard prodrug that is selectively cleaved to a cytotoxic aziridine (AST‐2660) via aldo‐keto reductase family 1 member C3 (AKR1C3). The purpose of this study was to investigate the pharmacokinetics and tissue distribution of the prodrug, AST‐001, and its active metabolite, AST‐2660, in mice, rats, and monkeys. After single and once daily intravenous bolus doses of 1.5, 4.5, and 13.5 mg/kg AST‐001 to Sprague‐Dawley rats and once daily 1 h intravenous infusions of 0.5, 1.5, and 4.5 mg/kg AST‐001 to cynomolgus monkeys, AST‐001 exhibited dose‐dependent pharmacokinetics and reached peak plasma levels at the end of the infusion. No significant accumulation and gender differences were observed after 7 days of repeated dosing. In rats, the half‐life of AST‐001 was dose independent and ranged from 4.89 to 5.75 h. In cynomolgus monkeys, the half‐life of AST‐001 was from 1.66 to 5.56 h and increased with dose. In tissue distribution studies conducted in Sprague‐Dawley rats and in liver cancer PDX models in female athymic nude mice implanted with LI6643 or LI6280 HepG2‐GFP tumor fragments, AST‐001 was extensively distributed to selected tissues. Following a single intravenous dose, AST‐001 was not excreted primarily as the prodrug, AST‐001 or the metabolite AST‐2660 in the urine, feces, and bile. A comprehensive analysis of the preclinical data and inter‐species allometric scaling were used to estimate the pharmacokinetic parameters of AST‐001 in humans and led to the recommendation of a starting dose of 5 mg/m2 in the first‐in‐human dose escalation study.

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Increased expression of type 2 3α-hydroxysteroid dehydrogenase/type 5 17β-hydroxysteroid dehydrogenase (AKR1C3) and its relationship with androgen receptor in prostate carcinoma

Cited by 114 publications

References 31 publications

Pomegranate polyphenols down-regulate expression of androgen-synthesizing genes in human prostate cancer cells overexpressing the androgen receptor

Pomegranate polyphenols down-regulate expression of androgen-synthesizing genes in human prostate cancer cells overexpressing the androgen receptor

Paradigm Shift in the Concept of Hormonal Milieu of Prostate Cancer

Characterization of AST‐001 non‐clinical pharmacokinetics: A novel selective AKR1C3‐activated prodrug in mice, rats, and cynomolgus monkeys

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