Beta-glucuronidase activity in prostatic carcinoma and benign prostatic hyperplasia

Pearson, Jeffrey P.; Pretlow, Theresa P.; Bradley, Edwin L.; McGinnis, Michael C.; Pretlow, Thomas G.

doi:10.1002/1097-0142(19890815)64:4<911::aid-cncr2820640425>3.0.co;2-b

Cited by 10 publications

(6 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…β-glucuronidase (β-gd) is overexpressed in most cancer cells with high variability reported in its expression in patients. In human prostate cancer, its expression was 3.6-fold higher than normal tissue (57.5 ± 33.1 versus 16.9 ± 8.5, μg of phenolphthalein liberated/h, activity per 10 mg of tissue) 19 . In healthy human pancreatic tissues, the level of β-gd was lower (median: 74) compared to cancerous tissue (median 133) measured using liberation of 4-Methylumbelliferyl-β-D-glucuronide 20 .…”

Section: Resultsmentioning

confidence: 95%

Pharmacokinetic-pharmacodynamic correlations in the development of ginger extract as an anticancer agent

Mukkavilli

Yang

Tanwar

et al. 2018

Sci Rep

View full text Add to dashboard Cite

Anticancer efficacy of ginger phenolics (GPs) has been demonstrated in various in vitro assays and xenograft mouse models. However, only sub-therapeutic plasma concentrations of GPs were detected in human and mouse pharmacokinetic (PK) studies. Intriguingly, a significant portion of GPs occurred as phase II metabolites (mainly glucuronide conjugates) in plasma. To evaluate the disposition of GPs and understand the real players responsible for efficacy, we performed a PK and tissue distribution study in mice. Plasma exposure of GPs was similar on day 1 and 7, suggesting no induction or inhibition of clearance pathways. Both free and conjugated GPs accumulated in all tissues including tumors. While non-cytotoxicity of 6-ginerol glucuronide precluded the role of conjugated GPs in cell death, the free forms were cytotoxic against prostate cancer cells. The efficacy of ginger was best explained by the reconversion of conjugated GPs to free forms by β-glucuronidase, which is over-expressed in the tumor tissue. This previously unrecognized two-step process suggests an instantaneous conversion of ingested free GPs into conjugated forms, followed by their subsequent absorption into systemic circulation and reconversion into free forms. This proposed model uncovers the mechanistic underpinnings of ginger’s anticancer activity despite sub-therapeutic levels of free GPs in the plasma.

show abstract

Section: Resultsmentioning

confidence: 95%

Pharmacokinetic-pharmacodynamic correlations in the development of ginger extract as an anticancer agent

Mukkavilli

Yang

Tanwar

et al. 2018

Sci Rep

View full text Add to dashboard Cite

show abstract

“…These proteins do not have direct homologs in rats, but we did observe changes in the expression of two genes involved in the sulfate and glucuronide metabolic pathways: Gusb , which encodes the β-glucuronidase enzyme responsible for the hydrolysis of steroid glucuronides, and Arsc1 , which encodes the enzyme responsible for the hydrolysis 17β-estradiol-3-sulfate as well as DHEA-sulfate. Of note, β-glucuronidase has been reported to be increased in prostatic carcinoma compared to in prostatic hyperplasia (Pearson, et al 1989). Thus, it is possible that these metabolic enzymes participate in the maintenance of intraprostatic androgens.…”

Section: Discussionmentioning

confidence: 99%

Low systemic testosterone levels induce androgen maintenance in benign rat prostate tissue

Zhou

Otto‐Duessel

et al. 2013

Journal of Molecular Endocrinology

View full text Add to dashboard Cite

Prostate cancer (PC) is both an age and androgen-dependent disease. Paradoxically, systemic levels of androgens decline with age as the risk of PC rises. While there is no correlation between systemic androgen levels and the risk of PC, systemic androgen levels do not reflect the levels of androgen in prostate tissue. In metastatic PC, changes in the androgen biosynthesis pathway during hormone therapy cause increased levels of androgens in cancer tissue and contribute to continued androgen receptor (AR) signaling. It is possible that similar changes occur in normal prostate tissue as androgens decline with age and that this contributes to tumorigenesis. We sought to determine if the rat prostate is able to maintain functional levels of androgens despite low serum testosterone (T). Rats were castrated and implanted with capsules to achieve castrate, normal, sub- and supra-physiological levels of T. After six weeks of treatment, LC-MS/MS was used to quantify the levels of T and dihydrotestosterone (DHT) in serum and prostate tissue. QRT-PCR was used to quantify expression of genes involved in the androgen/AR signaling axis. Despite having significantly different levels of T and DHT in the serum, T and DHT concentrations in prostate tissue from different T treatment groups were very similar. Furthermore, the expression of androgen-regulated genes in the prostate was similar among all T treatment groups, demonstrating that the rat prostate can maintain a functional level of androgens despite low serum T levels. Low T treatment resulted in significant alterations in the expression of androgen biosynthesis genes, which may be related to maintaining functional androgen levels.

show abstract

“…This contrasts with a glucuronide prodrug of p-hydroxyaniline mustard (BHAMG), which only displays anti-tumour activity when tumours are pre-targeted with bG immunoenzymes (Chen et al, 1997). Some tumours express high levels of bG (Pearson et al, 1989;Albin et al, 1993) and bG may also be secreted by monocytes and granulocytes in necrotic areas of tumours (Bosslet et al, 1998). Extracellular bG effectively activated a glucuronide prodrug of doxorubicin in solid tumours (Bosslet et al, 1998), suggesting that a similar mechanism may be responsible for the in vivo activity of 9ACG.…”

Section: Discussionmentioning

confidence: 99%

“…These properties of glucuronides, together with the relatively high b-glucuronidase (bG, E.C.3.2.1.31) activities found in some cancers (Pearson et al, 1989;Albin et al, 1993), suggests that glucuronide prodrugs may be useful for cancer treatment. Although several normal tissues such as liver, spleen, colon and bone marrow contain high activities of bG, this enzyme is located in lysosomes (Price and Dance, 1967) and is therefore largely inaccessible to highly hydrophilic glucuronides which pass poorly through the cell membrane (Haisma et al, 1992).…”

mentioning

confidence: 99%

Anti-tumour activity and toxicity of the new prodrug9-aminocamptothecin glucuronide (9ACG) in mice

et al. 2002

View full text Add to dashboard Cite

Cancer chemotherapy is limited by the modest therapeutic index of most antineoplastic drugs. Some glucuronide prodrugs may display selective anti-tumour activity against tumours that accumulate b-glucuronidase. We examined the toxicity and anti-tumour activity of 9-aminocamptothecin glucuronide, a new glucuronide prodrug of 9-aminocamptothecin, to evaluate its potential clinical utility. 9-aminocamptothecin glucuronide was 25 -60 times less toxic than 9-aminocamptothecin to five human cancer cell lines. b-glucuronidase activated 9-aminocamptothecin glucuronide to produce similar cell killing as 9-aminocamptothecin or topotecan. The in vivo toxicity of 9-aminocamptothecin glucuronide in BALB/c mice was dose-, route-, sex-and age-dependent. 9-aminocamptothecin glucuronide was significantly less toxic to female than to male mice but the difference decreased with age. 9-aminocamptothecin glucuronide and 9-aminocamptothecin produced similar inhibition (*80%) of LS174T human colorectal carcinoma tumours. 9-aminocamptothecin glucuronide cured a high percentage of CL1-5 human lung cancer xenografts with efficacy that was similar to or greater than 9-aminocamptothecin, irinotecan and topotecan. The potent anti-tumour activity of 9-aminocamptothecin glucuronide suggests that this prodrug should be further evaluated for cancer treatment.

show abstract

Beta-glucuronidase activity in prostatic carcinoma and benign prostatic hyperplasia

Cited by 10 publications

References 19 publications

Pharmacokinetic-pharmacodynamic correlations in the development of ginger extract as an anticancer agent

Pharmacokinetic-pharmacodynamic correlations in the development of ginger extract as an anticancer agent

Low systemic testosterone levels induce androgen maintenance in benign rat prostate tissue

Anti-tumour activity and toxicity of the new prodrug9-aminocamptothecin glucuronide (9ACG) in mice

Contact Info

Product

Resources

About