OBJECTIVETo evaluate the anti-proliferation effects of dehydroepiandrosterone (DHEAéand DHEA sulfate (DHEAs) on tumor cells.

METHODSHuman hepatoblastoma cells (HepG2) and colon adenocarcinoma cells (HT-29) were treated with DHEA and DHEAs of various concentrations. The cells were incubated for 8, 24, 48, and 72 hours, and the proliferation, apoptosis, cell cycle and the expression of phosphorylated Akt (Thr308 and Ser473) were analyzed using MTT assay, flow cytometry, and Western blotting at different time points. The influences of an inhibitor (LY294002) and an activator (hepatic growth factor; HGF) of PI3K on the effectiveness of DHEA were determined in HepG2 cells.

RESULTSBy increasing the concentrations of DHEA (1, 10, 50, 100, 200 micromol/L), the percentages of HepG2 and HT-29 survival cells treated with DHEA at 24 h were 92.7%+/-0.9%, 84.7%+/-1.2%, 62.4%+/-0.8%, 49.5%+/-0.8%, 50.7%+/-0.3% and 92.5%+/-0.4%, 89.5%+/-0.7%, 80.5%+/-1.1%, 67.5%+/-1.5%, 70.6%+/-0.6%, respectively. Proliferations of HepG2 and HT-29 cells were significantly inhibited after 24 hours of being incubated with 100 micromol/L DHEA treatment; the inhibition effect was stronger on HepG2 cells than on HT-29 cells. The effect of DHEAs on both cell lines on cell proliferation was weaker than that of the DHEA. In the cell cycle assay, DHEA treatment induced cell arrest in G0/G1 phase in both cell lines. Apoptosis of HepG2 cells was significantly triggered (18.6%+/-2.2%) by 100 micromol/L DHEA treatment for 24 hours, but not by DHEAs. In addition, 100 and 200 micromol/L DHEA treatments for 24 hours markedly inhibited phosphorylations of Akt (Thr308 and Ser473) in HepG2 cells, and these effects were enhanced by exposing them to LY294002 and stopped by exposing them to HGF. The anti-proliferative effects of DHEA on tumor cell lines were much stronger than those of DHEAs, and they were even stronger in HepG2 cells than in HT-29 cells.

CONCLUSIONOur results suggest that the induction of apoptosis through the inhibition of Akt signaling pathway is one of the anti-proliferative mechanisms of DHEA in certain tumors, but DHEA also promotes cell-cycle arrest.

Apoptosis ; drug effects ; Carcinoma, Hepatocellular ; metabolism ; pathology ; Cell Cycle ; drug effects ; Cell Proliferation ; Dehydroepiandrosterone ; pharmacology ; Dehydroepiandrosterone Sulfate ; pharmacology ; Flow Cytometry ; HT29 Cells ; Hep G2 Cells ; Humans ; Liver Neoplasms ; metabolism ; pathology ; Proto-Oncogene Proteins c-akt ; metabolism ; Signal Transduction

BACKGROUND/AIMS: The androgen dehydroepiandrosterone (DHEA) attenuates allergic inflammatory airway reactions by down-regulating the Th2 response in mice. The purpose of this study was to investigate whether DHEA suppresses Th2 cytokine production in cultured peripheral blood mononuclear cells (PBMCs) from asthmatic patients. METHODS: Sixty-one consecutive suspected asthmatic or non-asthmatic men underwent tests for asthma. PBMCs from each subject were cultured with and without DHEA (0.01~10 micrometer) for 48 h. The concentrations of interferon (IFN)-gamma, interleukin (IL)-5, and IL-10 in the culture supernatant were measured via an enzyme-linked immunosorbent assay. RESULTS: In PBMCs from subjects exhibiting methacholine airway hyperresponsiveness (AHR), DHEA significantly suppressed IL-10, IL-5, and IFN-gamma production in a dose-dependent manner (all p<0.001) and tended to increase the IFN-gamma/IL-5 ratio (p=0.087). DHEA (10 micrometer) suppressed cytokine production to a greater degree in subjects with AHR compared with those without AHR (IL-5: 24.0+/-7.8% vs. 40.9+/-3.6%, p<0.01; IFN-gamma: 29.7+/-7.0% vs. 54.5+/-5.1%, p<0.01). Cytokine suppression was significantly related to AHR, serum total IgE levels, and skin reactivity to house dust mites. CONCLUSIONS: DHEA suppressed both Th1 and Th2 responses, with a Th1 bias, and the degree of suppression was associated with the severity of AHR or atopy. Therefore, DHEA may be a useful therapy for asthma.
Adjuvants, Immunologic/*pharmacology ; Adolescent ; Adult ; Asthma/*pathology ; Cell Culture Techniques ; Cytokines/*metabolism ; Dehydroepiandrosterone/*pharmacology ; Humans ; Male ; Th2 Cells/*drug effects/*metabolism ; Young Adult

PURPOSE: The purpose of this study was to determine the effect of DHEA on hindlimb muscles(soleus, plantaris and gastrocnemius) in a focal brain ischemia model rat. METHOD: Twenty-seven male Sprague-Dawley rats were randomly divided into three groups: CINS(cerebral ischemia + normal saline), CIDH(cerebral ischemia + DHEA), or SHNS(sham + normal saline). Both the CINS and CIDH groups underwent a transient right middle cerebral artery occlusion operation. In the SHNS group, a sham operation was done. 0.34mmol/kg DHEA was administered daily by an intraperitoneal injection for 7days. RESULT: The muscle weight, muscle fiber cross-sectional area of the Type I muscle fiber of soleus and Type II muscle fiber of plantaris and gastrocnemius, myofibrillar protein content of gastrocnemius, and muscle strength in the CINS group decreased compared with the SHNS group. The muscle weight, muscle fiber cross-sectional area of the Type II muscle fiber of plantaris and gastrocnemius, myofibrillar protein content of soleus, and muscle strength in the CIDH group increased compared with the CINS group. CONCLUSION: It was identified that muscle atrophy could be induced during 7 days after a cerebral infarction, and DHEA administration during the early stages of a cerebral infarction might attenuate muscle atrophy.
Animals ; Brain Ischemia/*pathology ; Dehydroepiandrosterone/*pharmacology ; Hindlimb ; Male ; Muscle, Skeletal/*drug effects/pathology ; Muscular Atrophy/chemically induced ; Rats ; Rats, Sprague-Dawley

OBJECTIVETo investigate the inhibitory effect of dehydroepaimdrosterone (DHEA) on the growth of transplanted Morris hepatomas (7288CTC) in vivo in rats.

METHODS21 Buffalo rats were randomly devided into 4 groups, including one blank control group (n = 5), one group for tumor-bearing control (n = 6), and 2 experimental groups with DHEA (n = 6) or DHEA-s (n = 4). DHEA or DHEA-s was fed to the rats for 4 weeks immediately after Morris hepatomas (7288CTC) was implanted in both flanks. Phenotypes of the spleen lymphocytes were examined by flow cytometry, Akt and PTEN expression in tumor cells was detected by Western blot and immunohistochemistry.

RESULTSTumor weights of DHEA treated group were less than those of the control (P less than 0.05), the inhibitory rate was 43%. The results of Western blot and immunohistochemistry showed that in DHEA tumor group,the expression of phosphorilated Akt protein was decreased, the expression of PTEN was enhanced, the percentage of CD3 positive cells and the ratio of CD4/CD8 were increased (P less than 0.05).

CONCLUSIONDHEA can inhibit tumor growth, possibly via the inhibition of the Akt signaling pathway as well as modulating the immune function.

Animals ; Antineoplastic Agents ; pharmacology ; CD4-Positive T-Lymphocytes ; immunology ; CD8-Positive T-Lymphocytes ; immunology ; Dehydroepiandrosterone ; pharmacology ; Dehydroepiandrosterone Sulfate ; pharmacology ; Flow Cytometry ; Immunohistochemistry ; Liver Neoplasms, Experimental ; immunology ; metabolism ; pathology ; Neoplasm Transplantation ; PTEN Phosphohydrolase ; metabolism ; Proto-Oncogene Proteins c-akt ; metabolism ; Random Allocation ; Rats ; Rats, Inbred BUF ; Signal Transduction ; drug effects

AIMTo determine whether 7-oxo-dehydroepiandrosterone (7-oxo-DHEA) can reverse the hypoimmunity in BALB/c mice exposed to chronic mild stress.

METHODSA chronic mild stress animal model was established by subjecting BALB/c mice to a stressful regimen arranged in an unpredicted manner for 4 consecutive weeks. Immunological function alternations under chronic mild stress were assessed by lymphocytes proliferative response to mitogens and NK cell lysis activity test.

RESULTSThe studies showed the correlation between the state of depression and abnormalities in the immune response, such as a decrease of T lymphocytes proliferative response to Con A and suppression of cytotoxic of NK cell. Meanwhile, significant decrease of T3 and T4 levels was also observed. When stressed mice were daily given 7-oxo-DHEA 15 mg.kg-1, lymphocyte proliferative response and the NK cell activity were significantly enhanced and the decreased levels of T3 and T4 were restored in the stressed mice.

CONCLUSION7-oxo-DHEA can improve the depressive symptoms and hypoimmunity of BALB/c mice induced by chronic mild stress as its parent DHEA.

Adjuvants, Immunologic ; pharmacology ; Animals ; Antidepressive Agents ; pharmacology ; Cell Division ; drug effects ; Chronic Disease ; Dehydroepiandrosterone ; analogs & derivatives ; pharmacology ; Killer Cells, Natural ; immunology ; Male ; Mice ; Mice, Inbred BALB C ; Stress, Physiological ; blood ; immunology ; T-Lymphocytes ; immunology ; pathology ; Thyroxine ; blood ; Triiodothyronine ; blood

OBJECTIVETo study the effect of Guishen Pill (GSP) on expression levels of Oct-4, MVH, and Egr-1 in mice with diminished ovarian reserve (DOR).

METHODSTotally 40 female C57BL/6J mice were randomly divided into 4 groups, the normal control group, the model group, the GSP group, and the dehydroepiandrosterone (DHEA) group, 10 in each group. Pregnant mare serum gonadotropin (PMSG), human chorionic gonadotropin (HCG), and prostaglandin F2α (PGF2α) were sequentially administrated to produce superovulation. The DOR model was established by exposing to ozone inhalation. Mice in the GSP group were intragastrically administered with GSP at 0.3 mL. Those in the DHEA group were intragastrically administered with DHEA at 0.3 mL. Equal volume of normal saline was intragastrically administered to mice in the normal control group and the model group. All mice wer treated for 21 days. Serum levels of estrogen (E2), progestogen (P), and anti-Müllerian hormone (AMH) were measured by ELISA. Changes of Oct-4, anti-AMH, and early growth response gene-1 (Egr-1) mRNA in ovaries were dtected by Real-time PCR.

RESULTSCompared with the model group, serum levels of E2, P, and AMH, as well as contents of estrogen receptor (ER), progestogen receptor (PR), MVH, and Oct-4 mRNA significantly increased in the GSP group and the DHEA group (P < 0.05).

CONCLUSIONGSP could improve expression levels of Oct-4, MVH, and Egr-1 mRNA in DOR mice and their ovarian function.

Animals ; Anti-Mullerian Hormone ; metabolism ; Dehydroepiandrosterone ; metabolism ; Drugs, Chinese Herbal ; pharmacology ; Early Growth Response Protein 1 ; metabolism ; Estrogens ; Female ; Mice ; Mice, Inbred C57BL ; Octamer Transcription Factor-3 ; metabolism ; Ovarian Reserve ; Ovary ; Pregnancy ; Receptors, Estrogen ; metabolism ; Superovulation

Animals ; Aorta ; pathology ; Atherosclerosis ; blood ; etiology ; metabolism ; Chemokine CCL2 ; metabolism ; Cholesterol ; blood ; Cholesterol, Dietary ; administration & dosage ; Cholesterol, HDL ; blood ; Cholesterol, LDL ; blood ; Dehydroepiandrosterone ; pharmacology ; Diet, Atherogenic ; Immunohistochemistry ; Rabbits ; Random Allocation ; Triglycerides ; blood ; Vascular Cell Adhesion Molecule-1 ; metabolism

The steroidal enzyme cytochrome P45017alpha catalyzes the conversion of progesterone and pregnenolone into androgens, androstenedione and dehydroepiandrosterone, respectively, the direct precursors of estrogens and testosterone. Dihydrotestosterone is the principal active androgen in the prostate, testosterone is also an active stimulant of the growth of prostatic cancer tissue. Inhibition of this enzyme as a mechanism for inhibiting androgen biosynthesis could be a worthwhile therapeutic strategy for the treatment of PCA. In this paper, four categories of steroidal inhibitors of cytochrome P45017alpha will be reviewed, a diverse range of steroidal inhibitors had been synthesized and shown to be potent inhibitors of P45017alpha.
Androstenedione ; biosynthesis ; Androstenes ; Androstenols ; chemical synthesis ; chemistry ; pharmacology ; Animals ; Antineoplastic Agents ; chemical synthesis ; chemistry ; pharmacology ; Dehydroepiandrosterone ; biosynthesis ; Dihydrotestosterone ; metabolism ; Enzyme Inhibitors ; chemical synthesis ; chemistry ; pharmacology ; Humans ; Male ; Molecular Structure ; Pregnenolone ; metabolism ; Progesterone ; metabolism ; Prostatic Neoplasms ; pathology ; Steroid 17-alpha-Hydroxylase ; antagonists & inhibitors ; Testosterone ; biosynthesis

BACKGROUNDDehydroepiandrosterone (DHEA) is widely known for its beneficial effect on postmenopausal osteoporosis, although the underlying mechanisms remain mainly unclear. In this study, we tried to determine the activation of mitogen-activated protein kinase signal pathways during DHEA treatment and the indirect role of osteoblasts (OBs) on osteoclasts under the DHEA treatment of postmenopausal osteoporosis.

METHODSPrimary human OBs and osteoclast-like cells were cultured and, we pretreated OBs with or without U0126 (a highly selective inhibitor of both MEK1 and MEK2). The OBs were treated with DHEA. We then tested the effects of DHEA on human osteoblastic viability, osteoprotegerin production and the expression of phosphor-ERK1/2 (extracellular signal-regulated kinase). In the presence or absence of OBs, the function of osteoclastic resorption upon DHEA treatment was calculated.

RESULTSDHEA promoted the human osteoblastic proliferation and inhibited the osteoblastic apoptosis within the concentration range of 10(-8) - 10(-6) mol/L (P < 0.05, P < 0.01, respectively). Within the effective concentration range, the expression of phosphor-ERK1/2 and osteoprotegerin was increased by DHEA and blocked by U0126. In the presence of OBs, DHEA could significantly decrease the number and the area of bone resorption lacuna (P < 0.05 and P < 0.01, respectively). Without OBs, however, the effects of DHEA on the bone resorption lacuna were almost completely abolished.

CONCLUSIONSDHEA could indirectly inhibit the human osteoclastic resorption through promoting the osteoblastic viability and osteoprotegerin production, which is mediated by mitogen-activated protein kinases signal pathway involving the phosphor-ERK1/2.

Apoptosis ; drug effects ; Butadienes ; pharmacology ; Cell Proliferation ; drug effects ; Cells, Cultured ; Dehydroepiandrosterone ; pharmacology ; Extracellular Signal-Regulated MAP Kinases ; metabolism ; Female ; Humans ; Immunoblotting ; Mitogen-Activated Protein Kinases ; metabolism ; Nitriles ; pharmacology ; Osteoblasts ; cytology ; drug effects ; metabolism ; Osteoclasts ; cytology ; drug effects ; metabolism ; Osteoprotegerin ; metabolism ; RANK Ligand ; metabolism ; Signal Transduction ; drug effects

OBJECTIVEThe chemopreventive activity and mechanism of dehydroepiandrosterone (DHEA) were studied.

METHODSModel of 7, 12-dimethylbenz (alpha) anthracene (DMBA) induced breast carcinoma in Sprague-Dawley rats, uitra-violet (UV)-induced DNA damage and Salmonella mutation assay were used.

RESULTSIn DMBA-induced rat mammary tumor model, the rats were orally given daily DHEA for 2 weeks before DMBA and continued for 10 weeks after DMBA administration. The results showed significant inhibition of tumor development by DHEA. The incidence of mammary carcinoma also decreased significantly on daily dose of oral 25 mg/kg DHEA with the mean tumor volume per rat also remarkably reduced by 92%. Moreover, 25 mg/kg DHEA treatment could significantly increase the carcinoma latency for about 3.5 weeks as compared with the control. Using polymerase chain reaction (PCR) assay, in vitro 10(-9) mol/L DHEA showed significant inhibitory effect on UV-induced DNA damage by 90%. In Ames test, DHEA was found to decrease DMBA and benzo (alpha) pyrene-induced TA98 and TA100 His(+) revertants markedly and the number of Salmonella clones were significantly reduced by 53.2% and 73.0% on dose of 5 microgram DHEA/plate. It was also shown that in vitro 10(-7) mol/L DHEA could also effectively inhibit the G-6-PDH activity, which might play an important role in its chemoprophylaxis activities.

CONCLUSIONThe results strongly prove that DHEA is a potent cancer chemoprophylaxis agent, which exhibits inhibitory potential on mutation and chemical carcinogen in vivo and in vitro.

9,10-Dimethyl-1,2-benzanthracene ; administration & dosage ; Adjuvants, Immunologic ; pharmacology ; Animals ; Antimutagenic Agents ; pharmacology ; DNA Damage ; drug effects ; Dehydroepiandrosterone ; pharmacology ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Glucosephosphate Dehydrogenase ; antagonists & inhibitors ; metabolism ; Mammary Neoplasms, Experimental ; chemically induced ; prevention & control ; Mutagenicity Tests ; Rats ; Rats, Sprague-Dawley ; Salmonella ; drug effects ; genetics ; Time Factors ; Tumor Cells, Cultured