• Asian Pacific Journal of Cancer Prevention
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• v.15 no.8
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• pp.3645-3649
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• 2014

The aim of this study was to evaluate the efficacy of third-line combined androgen blockade (CAB) therapy for castration-resistant prostate cancer that relapsed after primary and second-line CAB. We retrospectively reviewed the medical records of 52 patients who received first-, second-, and third-line CAB therapy (medical or surgical castration, plus steroidal antiandrogen of chlormadinone acetate, or nonsteroidal antiandrogen of flutamide or bicalutamide). For cumulative analysis, we searched the PubMed database and identified a total of 50 cases published in English. Including our cases, this provided a total of 102 cases for analysis. In our study cohort, 11 cases (21.2%) achieved more than 50% reduction of serum prostate-specific antigen (PSA) on initiation of third-line CAB. We found that third-line CAB with nonsteroidal antiandrogen after second-line CAB with steroidal antiandrogen exhibited favorable results, with a positive response in six of 13 patients (46.2%). Cumulative analysis findings were comparable. Regarding the timing of third-line CAB administration, 15 patients had started at a PSA equal to or less than 4.0 ng/ml, and eight of them (53.3%) showed a positive response to treatment, compared to only three of 37 patients (8.1%) whose PSA at the initiation of third-line therapy was higher than 4.0 ng/ml (p<0.001). We conclude that third-line CAB with nonsteroidal antiandrogen would be particularly useful for patients whose cancer progressed after second-line CAB with steroidal antiandrogen. The timing of treatment seems to be important because the higher the PSA at the start of third-line therapy, the lower the PSA response rate.

• Journal of Microbiology and Biotechnology
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• v.21 no.5
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• pp.540-544
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• 2011

The molecular mechanisms of apoptotic induction by benzyldihydroxyoctenone (BDH), a nonsteroidal antiandrogen, isolated from the culture broth of Streptomyces sp., have been previously published in prostate cancer LNCaP cells. Apoptotic induction of BDH-treated LNCaP cells was associated with downregulation of Bcl-xL that caused, in turn, cytochrome c release from mitochondria, and activation of procaspases and specific proteolytic cleavage of poly(ADP-ribose) polymerase (PARP). The purpose of the present study was to investigate the patterns of apoptotic induction by BDH in non-prostate, ovarian cancer PA-1 (androgen-independent and -insensitive) cells and prostate cancer cells with different androgen responsiveness, such as C4-2 (androgen-independent and -sensitive), 22Rv1 (androgen-dependent and -low sensitive), and LNCaP (androgen-dependent and -high sensitive) cells. We found that BDH-treated LNCaP cell proliferation was significantly inhibited in a time-dependent manner and induced apoptosis via downregulation of the androgen receptor (AR) and prostate-specific antigen (PSA), as well as antiapoptotic Bcl-xL protein. However, the levels of BDH-mediated apoptotic induction and growth inhibition in 22Rv1 cells were apparently lower than those of LNCaP cells. In contrast, the induction of apoptosis and antiproliferative effect in BDH-treated non-prostate cancer PA-1 and hormone refractory C4-2 cells were not detectable and marginal, respectively. Therefore, BDH-mediated differential apoptotic induction and growth inhibition in a cell type seem to be obviously dependent on its androgen responsiveness; primarily on androgen-dependency, and then on androgensensitivity.

• Korean Journal of Animal Reproduction
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• v.12 no.1
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• pp.48-50
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• 1988

Flehmen is well-known response which often occurs during the process of courtship in most mammals. Recent studies with domestic ruminants suggest that the flehmen may be involved in the mechanism of transferring some pheromonal substances to vomeronasal organ. Thus, variety of its significancehas been supposed, besides that male animals may use it for estrus detection. In this experiment, 8 male, 3 female and3 castrated goats of Saanen and its hybrid were used to ascertain whether urine from alien species can induce flehmen as that from same species. Urine was collected from twenty species consisting of 15 mammals, 3 birds and 2 reptiles and frozen until use. Mostly urine was sprayed to the nose of goats, but some coagulated ones were sniffed. Duration of flehmen was scored to four ranks as 0, 1-19, 20-39 and >40 sec. Each urine sample induced the response in any goats. However, much difference in the in tensity was found between the samples and according to the reproductive state of the receptor goats. Although individual difference was manifest, male goats generally showed more intense response than did female. Castrated goats showed the intermediate pattern. Administration of antiandrogen to the male goat tended to reduce the response. The results indicate that flehmen in the goat could occur for the urine of alien species as that of same species and the androgen may be one of the factors regulating the response.

• Journal of Physiology & Pathology in Korean Medicine
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• v.23 no.4
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• pp.799-804
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• 2009

Kamikaekyuk-tang(KMKKT), a formula of ten Oriental herbs, was orientally designed to promote vital energy, to remove blood stasis, and to decrease inflammation for treating cancers. KMKKT and its component had potent antiandrogen and androgen receptor activities in prostate cancer and also inhibited angiogenesis induced by basic fibroblast growth factor (bFGF) in human umbilical vein endothelial cells and suppressed the tumor growth in LLC-bearing mice, and liver metastasis of colon 26-L5 cancer cells, suggesting a potent cancer preventive agent. Nevertheless, there is no safety study of KMKKT before clinical trial so far. Thus, in the current study, we investigated the toxicity about ethanol-extracted KMKKT. Male and female Spraque Dawley (SD) rats were given orally by KMKKT at 250, 500, and 1000 mg/kg for 4 weeks. Mortality, clinical signs and measured change of body weight, food consumption and water consumption were observed. In addition, we performed ophthalmologic, urinary, hematological, blood serum biochemical and histopathological examination. Any general toxicity was not found in KMKKT treated group. Also, there were no significant differences in the parameters such as body weight, food consumption and water consumption, a lot of urine and blood factor levels except WBC, MCHC and Ca level compared with control group. Although WBC and MCHC were elevated in female rats and Ca level was decreased in male rats, these were within normal ranges. Finally, we determined that maximum tolerated dose (MTD) was 1000 mg/kg and no observed adverse effect level (NOAEL) was 500 mg/kg. Taken together, these results demonstrated that KMKKT is very safe to SD rats.

• Development and Reproduction
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• v.19 no.4
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• pp.217-226
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• 2015

A proper development of the epididymis during the early postnatal development is required for successful fertility in the adult male. Direct cell-cell communication via connexin (Cx) molecules is a common way of cellular interactions to achieve normal development of a given tissue consisting of different cell types. The present research was attempted to determine the effect of exogenous exposure to estrogenic agonist or antiandrogen at the weaning age on expression of Cx isoforms in the adult corpus epididymis. Male rats were subcutaneously administrated with estradiol benzoate (EB) or flutamide (Flu) at the weaning age. The tissue was collected at 4 months of age. Expressional levels of Cx isoforms were determined by a quantitative real-time PCR. Statistical comparison showed significant increases of Cxs31, 32, 37, 40, and 43 transcript amounts by a treatment of $0.015{\mu}g$ of EB /kg body weight (BW). A treatment of $1.5{\mu}g$ of EB /kg BW caused a significant decrease of Cx43 gene expression but increases of Cxs26, 31, 32, 37, and 40 transcript levels. Exposure to $500{\mu}g$ of Flu/kg BW induced an increase of Cx37 expression but significant decreases of Cxs43 and 45 mRNA levels. Expression of Cx37 was increased by a treatment of 5 mg of Flu/kg BW, while transcript levels of Cxs26, 30.3, 31, 31.1, 32, and 43 were significantly decreased by same treatment. These results demonstrate that exposure to steroidal compounds at the early developmental age alters expression of Cx isoforms in the adult corpus epididymis.

• Journal of the Society of Cosmetic Scientists of Korea
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• v.36 no.4
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• pp.241-251
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• 2010

In recent years, the number of people suffering from depression due to hair loss has been increasing. The treatment methods such as clinical pathology and vanity surgery have been developed. There are therapies and materials for hair growth promotion and hair loss prevention. But the effectiveness of such therapies and materials is not fully evaluated and some side-effects have been reported. In this study, microneedle therapy using very thin and delicate needles promotes absorption of drug. During this therapy, the microneedle makes micro holes that help absorbion of drugs into the scalp. In this study, absorbion of fermented soybean were evaluated. The ingredient has antioxidant, antiandrogen, and antithrombosis effect for alopecia. The fermented soybean is more effective for complex hair loss when used with microneedle. It is because of the microneedle's excellent drug delivery system (DDS). This therapy that increases the absorption of fermented soybean is a very useful scalp care method which prevents, treats and controls alopecia. This microneedle therapy using fermented soybean is an advanced technology for scalp care.

• Development and Reproduction
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• v.21 no.4
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• pp.441-448
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• 2017

Bisphenol-A(BPA) is a member of alkylphenol family, and shows adverse effects including reduced fertility, reproductive tract abnormalities, metabolic disorder, cancer induction, neurotoxicity and immunotoxicity. In the present study, we conducted Hershberger assay to evaluate whether the two candidates to replace BPA have androgenic or antiandrogenic activity. The assay was carried out using immature castrated Sprague-Dawley male rats. After 7 days of the surgery, testosterone propionate (TP, 0.4 mg/kg/day) and test materials (low dose, 40 mg/kg/day; high dose, 400 mg/kg/day) were administered for 10 consecutive days by subcutaneous (s.c.) injection and oral gavage, respectively. Test materials were BPA, isosorbide (ISO) and cyclohexanedimethanol (CHDM). The rats were necropsied, and then the weights of five androgen-dependent tissues [ventral prostate, seminal vesicle, levator ani-bulbocavernosus (LABC) muscle, paired Cowper's glands, and glans penis] and three androgen-insensitive tissues (kidney, spleen and liver) were measured. All test materials including BPA did not exhibit any androgenic activity in the assay. On the contrary, antiandrogen-like activities were found in all test groups, and the order of the intensity was CHDM > BPA > ISO in the five androgen-sensitive tissues. There was no statistical difference between low dose treatment and high dose treatment of BPA group as well as ISO group. In CHDM group, high dose treatment exhibited most severe weight reduction in all measured tissues. There was no statistical difference in androgen-insensitive tissue measurements, except BPA groups. Since the effects of ISO treatment on the accessory sex organs were much less or not present at all when compared to those of BPA, ISO could be a strong candidate to replace BPA. CHDM treatment brought most severe weight reduction in all of androgen-sensitive tissues, so this material should be excluded for further screening of BPA substitute selection.

• Development and Reproduction
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• v.22 no.1
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• pp.19-27
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• 2018

In the present study, we employed Hershberger assay to determine possible androgenic or antiandrogenic activities of three di-2-ethylhexyl phthalate (DEHP) substitute candidates. The assay was carried out using immature castrated Sprague-Dawley male rats. After 7 days of the surgery, testosterone propionate (TP, 0.4 mg/kg/day) and test materials (low dose, 40 mg/kg/day; high dose, 400 mg/kg/day) were administered for 10 consecutive days by subcutaneous (s.c.) injection and oral gavage, respectively. Test materials were DEHP, 2-ethylhexyl oleate (IOO), 2-ethylhexyl stearate (IOS) and triethyl 2-acetylcitrate (ATEC). The rats were necropsied, and then the weights of five androgen-dependent tissues [ventral prostate, seminal vesicle, coagulating glands, levator ani-bulbocavernosus (LABC) muscle, paired Cowper's glands, and glans penis] and four androgen-insensitive tissues (kidney, adrenal glands, spleen and liver) were measured. All test materials including DEHP did not exhibit any androgenic activity in the assay. On the contrary, antiandrogen-like activities were found in all test groups, and the order of the intensity was ATEC < DEHP < ISO < IOO in the five androgen-sensitive tissues. There was no statistical difference between low dose treatment and high dose treatment of all replacement candidate groups. In DEHP groups, high dose treatment exhibited significant weight gains in LABC and Glan Penis. There was no statistical difference in androgen-insensitive tissue measurements. Since the effects of ATEC treatment on the accessory sex organs were much less or not present at all when compared to those of DEHP, ATEC could be a strong candidate to replace DEHP. IOO treatment brought most severe weight reduction in all of androgen-sensitive tissues, so this material should be excluded for further screening of DEHP substitute selection.

• Biomolecules & Therapeutics
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• v.31 no.2
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• pp.210-218
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• 2023

Prostate cancer is the fifth leading cause of cancer-related mortality in men, primarily because of treatment resistance, recurrence, and metastasis. In the present study, we investigated the role of paracrine interleukin-8 (IL-8) in the antagonistic expression of IL-8 and androgen receptor (AR), and the contribution of IL-8 to prostate cancer aggressiveness. In hormone-responsive LNCaP cells that do not express IL-8, recombinant IL-8 treatment significantly increased expressions of IL-8, CXC chemokine receptor 2 (CXCR2), matrix metalloproteinase (MMP)-2/9, Snail, and vimentin. IL-8 treatment significantly decreased AR and E-cadherin expression. IL-8-induced gene expression changes were suppressed by navarixin, a CXCR1/2 inhibitor, and gallein, a Gβγ inhibitor. In PC-3 androgen-refractory prostate cancer cells, IL-8 knockdown reduced expressions of CXCR2, MMP-2/9, Snail, and vimentin, and increased AR and E-cadherin expressions at the mRNA and protein levels. Co-culture with MEG-01 human megakaryocytic cells secreting high levels of IL-8 induced gene expression changes in both LNCaP and PC-3 cells, similar to those induced by IL-8 treatment. The altered gene expressions were accompanied by significant activation of transcription factor Snail in LNCaP and PC-3 cells. Treatment with the CXCR blocker navarixin inhibited the invasion of PC-3 cells but not LNCaP cells. However, invasion induced by MEG-01 was inhibited by navarixin in both LNCaP and PC-3 cells. The collective findings demonstrate that IL-8 enhances CXCR2 expression, which antagonistically regulates AR expression. More importantly, through changes in IL-8/CXCR2-regulated gene expression, IL-8 induces antiandrogen therapy resistance and epithelial-mesenchymal transition in prostate cancer.

• Proceedings of the Korean Society of Embryo Transfer Conference
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• 2002.11a
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• pp.109-109
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• 2002

In recent reports, the multiple reproductive defects such as cryptorchidism, hypospadias, epididymal cysts, low sperm counts, and testicular cancers are increased in humans, and these changes were doubted by the chemicals with estrogenic or antiandrogenic activities in our environment. To compare the effects of neonatal exposure of di (n-butyl) phthalate and flutamide on the development of reproductive organs and to identify the specific mechanisms of these abnormalities related to the male reproducton, Sprague-Dawley neonate male rats were injected subcutaneously during 5-14 days after birth with corn oil (control), flutamide (0.05, 0.1, and 0.5 mg/animal) and DBP (5, 10, and 20 mg/animal). Animals were killed at 31 (immature) and 42 (pubertal) days of age respectively and blood was collected from abdominal aorta for serum testosterone analysis. Testes, epididymides, seminal vesicles, ventral prostate, levator ani plus bulbocavernosus muscle (LABC), cowpers glands and glans penis were weighed. Expression of steroid hormone receptors (AR and ER) was examined in the testes and ventral prostate. At 31 days of age, ventral prostate, seminal vesicles, LABC, and cowpers glands significantly decreased in the flutamide (0.5 mg/animal) and DBP (20 mg/animal), but serum testosterone levels were not changed. Flutamide slightly delayed the testes descent at the high dose (0.5 mg/animal), but DBP did not show any significant effect on the testes descent at all doses. DBP and flutamide decreased the expression of AR protein in the testes but did not affect the expression of ERa and ER protein in the testes. At 42 days of age, ventral prostate, seminal vesicles, and cowpers glands weights were still significantly decreased at the high dose of flutamide (0.5 mg/animal) and DBP (20 mg/animal), but the weights of testes and epididymides were not different. Serum testosterone decreased significantly in DBP treated animals and slightly, not significantly, in flutamide group. While DBP still significantly decreased the expression of AR protein in testis, flutamide recovered from downregulation of AR protein and did not affect the expression of ERa and ER protein in the testes. Based on these results, flutamide and DBP have shown several similar patterns in reproductive abnormalitis, but some marked differences which may be caused by different acting mechanism.