Celprotect

CelProtect is an anti-tumoural compound, which has significant anti-inflammatory characteristics. It is used for breast, prostate and colorectal cancers. It is contraindicated in pregnancy and breast-feeding and should be a part of an overall / strategic protocol.

Baicalin, Baicalein potent inhibitors of angiogenesis

Scutellaria baicalensis Georgi (Huang Qin), a Chinese traditional medicinal herb, is widely used as an anti-inflammatory, antibacterial, and hepatoprotective drug.1 2 Baicalin (7-glucuronic acid,5,6-dihydroxy-flavone), a flavonoid compound isolated from Huang Qin, possesses antioxidant properties and has an inhibitory effect on carrageenan-induced rat paw oedema, suggesting that it may be a potential anti-inflammatory drug. 1 3

The carrageenan-evoked thermal hyperalgesia resulting from the combined effect of the release of proinflammatory cytokines, cyclooxygenase (COX) products, and sympathomimetic amines is a common model used to study inflammatory pain.4 Tumour necrosis factor Alpha has an early and crucial role in the cascade of proinflammatory cytokine production and subsequent inflammatory processes.5 COX catalyses the conversion of arachidonic acid to many biologically active mediators, such as prostaglandin E2 (PGE2). It has been reported that overproduction of inflammatory prostaglandins by an inducible form of COX (COX-2) plays an important pathophysiological role in the development of inflammatory pain.6 7

Nitric oxide (NO), synthesized by the enzyme NO synthase (NOS), is an important mediator in the regulation of cell functions.8 However, overproduction of NO derived from inducible NOS (iNOS) activated by proinflammatory cytokines, free radicals, and lipopolysaccharide (LPS) may cause the pathogenesis of inflammatory diseases, including carrageenan-evoked inflammatory pain.6 9 Inhibition of COX-2 activity in a castor-oil-induced diarrhoea model, as well as NO formation and iNOS expression in LPS-treated RAW 264.7 macrophages by baicalin, suggests that baicalin may suppress the COX-2 and iNOS pathways, a critical mediator accounting for the carrageenan-induced inflammatory pain.10 11

Studies showed that baicalin exhibits an analgesic effect in a rat model of carrageenan-evoked thermal hyperalgesia. The effect of baicalin on the formation of important inflammatory mediators, including cytokine, NO, and PGE2 formation, as well as neutrophil infiltration at inflammatory sites, was also studied.

Baicalin is a flavonoid and a major component of a herbal medicine. Flavonoids including baicalin have been reported to not only function as anti-oxidants but also cause cytotoxic effect. We investigated the mechanism of baicalin-induced cytotoxicity in leukemia-derived T cell line, Jurkat cells. When cells were cultured with 50-200 microg/ml baicalin for 6h, caspase-3 was activated and then cells fell into apoptosis. Induction of apoptosis by baicalin was accompanied with the marginal generation of intracellular reactive oxygen species (ROS), the increase of the cytosolic fractions of cytochrome c, and the disruption of mitochondrial transmembrane potential (DeltaPsi (m)) prior to the activation of caspase-3. The pre-culture with 5 mM of buthionine sulfoximine (BSO), an inhibitor of glutathione (GSH) synthesis, facilitated baicalin-induced disruption of DeltaPsi (m) and induction of apoptosis. The pre-culture with N-benzyloxycarbonyl-valyl-alanyl-aspartyl fluoromethylketone (Z-VAD-fmk), a pan-caspase inhibitor, partially suppressed the induction of apoptosis. On the other hand, baicalin showed little toxic effect on peripheral blood mononuclear cells (PBMCs) from healthy volunteers. These results indicate that baicalin acts as a prooxidant and induces caspase-3 activation and apoptosis via mitochondrial pathway.12

When CAMs (chorioallantoic membrane) were treated with either baicalein or baicalin for 48 hr, the angiogenic response induced by basic fibroblast growth factor (bFGF) was markedly reduced in a dose-dependent manner. Further characterization showed that both flavonoids exhibited dual antiproliferative (at low dose) and apoptogenic (at high dose) effects on HUVECs. In biochemical analysis, treatment of HUVECs with baicalein and baicalin for 24 hr resulted in a dose-dependent decrease in the matrix metalloproteinase (MMP)-2 activity. Moreover, the migration of endothelial cells and the differentiation of endothelial cells into branching networks of tubular structures in vitro were also inhibited by these 2 flavonoids in a dose-dependent manner. Baicalein is more potent than baicalin in anti-angiogenesis in vivo as well as in vitro. Taken together, the results of our study provide evidence that baicalein and baicalin possess an anti-angiogenesis potential that is a previously unrecognized biologic activity.13

Baicalin inhibited the proliferation of myeloma cell lines and the survival of primary myeloma cells, especially MPC-1- immature myeloma cells, and induced apoptosis in myeloma cell lines via a mitochondria-mediated pathway by reducing mitochondrial membrane potential and activating caspase-9 and caspase-3. Further experiments confirmed that Scutellaria radix was responsible for the suppressive effect on myeloma cell proliferation, and the baicalein in Scutellaria radix showed strong growth inhibition and induction of apoptosis in comparison with baicalin or wogonin. Baicalein as well as baicalin suppressed the survival in vitro of MPC-1- immature myeloma cells rather than MPC-1+ myeloma cells from myeloma patients. Baicalein inhibited the phosphorylation of IkB-, which was followed by decreased expression of the IL-6 and XIAP genes and activation of caspase-9 and caspase-3. Therefore, HLJDT and Scutellaria radix have an antiproliferative effect on myeloma cells, especially MPC-1- immature myeloma cells, and baicalein may be responsible for the suppressive effect of Scutellaria radix by blocking IkB-degradation.14

Different effects of baicalein, baicalin and wogonin on mitochondrial function, glutathione content and cell cycle progression in human hepatoma cell lines.

The effects of the flavonoids from Scutellaria baicalensis Georgi (baicalein, baicalin and wogonin) in cultured human hepatoma cells (Hep G2, Hep 3B and SK-Hep1) were compared by MTT assay and flow cytometry. All three flavonoids dose-dependently decreased the cell viabilities accompanying the collapse of mitochondrial membrane potential and the depletion of glutathione content. However, the influence of baicalein, baicalin or wogonin on cell cycle progression was different. All three flavonoids resulted in prominent increase of G2/M population in Hep G2 cells, whereas an accumulation of sub G1 (hypoploid) peak in Hep 3B cells was observed. In SK-Hep1 cells, baicalein and baicalin resulted in dramatic boost in hypoploid peak, but wogonin made mainly in G1 phase accumulation. These data, together with the previous findings in other hepatoma cell lines, suggest that baicalein, baicalin and wogonin might be effective candidates for inducing apoptosis or inhibiting proliferation in various human hepatoma cell lines.15

Inhibition of endothelial cell proliferation, migration and differentiation.

In recent studies, we have shown that baicalein and baicalin, 2 major flavonoids of Scutellaria baicalensis Georgi, exhibit anticancer activity against several cancers in vitro. In our present study, we assessed their potential as anti-angiogenic agents in vivo employing chicken chorioallantoic membrane ( CAM ) assay and in vitro human umbilical vein endothelial cells (HUVECs) culture. When CAMs were treated with either baicalein or baicalin for 48 hr, the angiogenic response induced by basic fibroblast growth factor (bFGF) was markedly reduced in a dose-dependent manner. Further characterization showed that both flavonoids exhibited dual antiproliferative (at low dose) and apoptogenic (at high dose) effects on HUVECs. In biochemical analysis, treatment of HUVECs with baicalein and baicalin for 24 hr resulted in a dose-dependent decrease in the matrix metalloproteinase (MMP)-2 activity. Moreover, the migration of endothelial cells and the differentiation of endothelial cells into branching networks of tubular structures in vitro were also inhibited by these 2 flavonoids in a dose-dependent manner. Baicalein is more potent than baicalin in anti-angiogenesis in vivo as well as in vitro. Taken together, the results of our study provide evidence that baicalein and baicalin possess an anti-angiogenesis potential that is a previously unrecognized biologic activity.16

Recent studies on the Chinese herbal medicine PC SPES showed biological activities against prostate cancer in vitro, in vivo and in patients with advanced stages of the disease. In investigating its mode of action, we have isolated a few of the active compounds. Among them, baicalin was the most abundant (about 6%) in the ethanol extract of PC SPES, as determined by HPLC. Baicalin is known to be converted in vivo to baicalein by the cleavage of the glycoside moiety. Therefore, it is useful to compare their activities in vitro. The effects of baicalin and baicalein were studied in androgen-positive and -negative human prostate cancer lines LNCaP and JCA-1, respectively.

Inhibition of cell growth by 50% (ED50) in LNCaP cells was seen at concentrations of 60.8 ± 3.2 and 29.8 ± 2.2 µm baicalin and baicalein, respectively. More potent growth inhibitory effects were observed in androgen-negative JCA-1 cells, for which the ED50 values for baicalin and baicalein were 46.8 ± 0.7 and 17.7 ± 3.4, respectively. Thus, it appears that cell growth inhibition by these flavonoids is independent of androgen receptor status. Both agents (1) caused an apparent accumulation of cells in G1 at the ED50 concentration, (2) induced apoptosis at higher concentrations, and (3) decreased expression of the androgen receptor in LNCaP cells.17

Baicalein, a component of Scutellaria radix from Huang-Lian-Jie-Du-Tang (HLJDT), leads to suppression of proliferation and induction of apoptosis in human myeloma cells

In the search for a more effective adjuvant therapy to treat multiple myeloma (MM), we investigated the effects of the traditional Chinese herbal medicines Huang-Lian-Jie-Du-Tang (HLJDT), Gui-Zhi-Fu-Ling-Wan (GZFLW), and Huang-Lian-Tang (HLT) on the proliferation and apoptosis of myeloma cells. HLJDT inhibited the proliferation of myeloma cell lines and the survival of primary myeloma cells, especially.

MPC-1- immature myeloma cells, and induced apoptosis in myeloma cell lines via a mitochondria-mediated pathway by reducing mitochondrial membrane potential and activating caspase-9 and caspase-3. Further experiments confirmed that Scutellaria radix was responsible for the suppressive effect of HLJDT on myeloma cell proliferation, and the baicalein in Scutellaria radix showed strong growth inhibition and induction of apoptosis in comparison with baicalin or wogonin. Baicalein as well as baicalin suppressed the survival in vitro of MPC-1- immature myeloma cells rather than MPC-1+ myeloma cells from myeloma patients. Baicalein inhibited the phosphorylation of IkB-, which was followed by decreased expression of the IL-6 and XIAP genes and activation of caspase-9 and caspase-3. Therefore, HLJDT and Scutellaria radix have an antiproliferative effect on myeloma cells, especially MPC-1- immature myeloma cells, and baicalein may be responsible for the suppressive effect of Scutellaria radix by blocking IkB-degradation.18

Genistein, Daidzein

Daidzein and Genistein Glucuronides In Vitro Are Weakly Estrogenic and Activate Human Natural Killer Cells at Nutritionally Relevant Concentrations

Daidzein and genistein glucuronides (DG and GG), major isoflavone metabolites, may be partly responsible for biological effects of isoflavones, such as oestrogen receptor binding and natural killer cell (NK) activation or inhibition. DG and GG were synthesized using 3-methylcholanthrene-induced rat liver microsomes. The Km and Vmax for daidzein and genistein were 9.0 and 7.7 µmol/L, and 0.7 and 1.6 µmol/(mg protein · min), respectively. The absence of ultraviolet absorbance maxima shifts in the presence of sodium acetate confirmed that the synthesized products were 7-O-glucuronides. DG and GG were further purified by a Sephadex LH-20 column. DG and GG competed with the binding of 17ß-(3H) oestradiol to oestrogen receptors of B6D2F1 mouse uterine cytosol. The concentrations required for 50% displacement of 17ß-(3H) oestradiol (CB50) were: 17ß-oestradiol, 1.34 nmol/L; diethylstilbestrol, 1.46 nmol/L; daidzein, 1.6 µmol/L; DG, 14.7 µmol/L; genistein, 0.154 µmol/L; GG, 7.27 µmol/L. In human peripheral blood NK cells, genistein at <0.5 µmol/L and DG and GG at 0.1-10 µmol/L enhanced NK cell-mediated K562 cancer cell killing significantly (P < 0.05). At > 0.5 µmol/L, genistein inhibited NK cytotoxicity significantly (P < 0.05). The glucuronides only inhibited NK cytotoxicity at 50 µmol/L. Isoflavones, and especially the isoflavone glucuronides, enhanced activation of NK cells by interleukin-2 (IL-2), additively. At physiological concentrations, DG and GG were weakly oestrogenic, and they activated human NK c ells in nutritionally relevant concentrations in vitro, probably at a site different from IL-2 action.19

Genistein is the aglycone (aglucon) of genistin. The isoflavone is found naturally as the glycoside genistin and as the glycosides 6"-O-malonylgenistin and 6"-O-acetylgenistin. Genistein and its glycosides are mainly found in legumes, such as soybeans and chickpeas. Soybeans and soy foods are the major dietary sources of these substances. Non-fermented soy foods, such as tofu, contain higher levels of the genistein glycosides, while fermented soy foods, such as tempeh and miso, contain higher levels of the aglycone.

Genistein is a solid substance that is practically insoluble in water. Its molecular formula is C 15 H 10 O 5 , and its molecular weight is 270.24 daltons. Genistein is also known as 5, 7-dihydroxy-3- (4-hydroxyphenyl)-4 H -1-benzopyran-4-one, and 4', 5, 7-trihydroxyisoflavone.

Genistein has oestrogenic and antioxidant activities. It may also have anticarcinogenic, anti-atherogenic and anti-osteoporotic activities.

Researchers from Wake Forest University Baptist Medical Center in Winston-Salem , N.C. , say their study in monkeys suggests oestrogen-like compounds in soy called isoflavones do not increase breast cancer markers in postmenopausal women and may, in fact, protect some women.

The study evaluated how oestrogen levels in the body may influence the effects of soy isoflavones. Monkeys were given one of eight different diets, each containing one of four different isoflavone doses along with either a low or high dose of oestrogen designed to mimic levels found in postmenopausal women.

Investigators measured how the various diets affected markers for breast cancer risk. They found no increased breast cell proliferation at any level of isoflavone exposure in the low-oestrogen environment. In the high-oestrogen environment, they found higher proliferation when isoflavones were not in the diet and when they were in lower doses. Higher levels of isoflavones, however, tended to block oestrogen effects in breast tissue. This suggests postmenopausal women with higher levels of oestrogen may benefit the most from soy.20

The chemopreventive effect of the soy isoflavone, genistein, has been observed through the suppression of cell proliferation, inhibition of angiogenesis and stimulation of apoptosis in breast carcinoma cells. Cancer metastasis consists of interdependent processes, including cell adhesion, migration and invasion. In the present study, we compare the effect of soy isoflavones in the form of aglycones (genistein, daidzein and glycitein) and glucosides (genistin, daidzin and glycitin) on the behavior of highly invasive breast cancer cells. Here we demonstrate that genistein suppresses cell adhesion and migration by inhibiting the constitutively active transcription factors NF-kappaB and AP-1, resulting in the suppression of secretion of urokinase-type plasminogen activator (uPA) in breast cancer cells. In addition, we show that all tested soy isoflavone aglycones (genistein, daidzein, glycitein) and glucosides (genistin, daidzin, glycitin) markedly reduced motility of MDA-MB-231 cells. However, only genistein and daidzein inhibited constitutively active NF-kappaB and AP-1 and suppressed secretion of uPA from breast cancer cells.21

Genistein inhibits protein tyrosine kinase (PTK), which is involved in phosphorylation of tyrosyl residues of membrane-bound receptors leading to signal transduction, and it inhibits topoisomerase II, which participates in DNA replication, transcription and repair. By blocking the activities of PTK, topoisomerase II and matrix metalloprotein (MMP9) and by down-regulating the expression of about 11 genes, including that of vascular endothelial growth factor (VEGF), genistein can arrest cell growth and proliferation, cell cycle at G2/M, invasion and angiogenesis. Furthermore, genistein can alter the expression of gangliosides and other carbohydrate antigens to facilitate their immune recognition. Genistein acts synergistically with drugs such as tamoxifen, cisplatin, 1,3-bis 2-chloroethyl-1-nitrosourea (BCNU), dexamethasone, daunorubicin and tiazofurin, and with bioflavonoid food supplements such as quercetin, green-tea catechins and black-tea thearubigins.22

Genistein Induces p21 or p27 Activity

Genistein Inhibits NF-kB and AP-1

Genistein Facilitates Gap Junction Communication

Dietary effects of soy isoflavones daidzein and genistein on 7,12-dimethylbenz [a] anthracene-induced mammary mutagenesis and carcinogenesis in ovariectomized Big Blue® transgenic rats

Mugimane G. Manjanatha*, Sharon Shelton, Michelle E. Bishop, Lascelles E. Lyn-Cook and Anane Aidoo. Division of Genetic and Reproductive Toxicology, National Center for Toxicological Research, U.S. FDA Jefferson Laboratories Jefferson, AR, USA

The major constituents of isoflavones, daidzein (DZ) and genistein (GE) are known to interact with the a and ß oestrogen receptors (ER/ß) in several tissues including mammary. In this study, we used ovariectomy (OVX) to model menopause and determined the effects of DZ, GE or 17ß-estradiol (E2) exposures on chemically induced mutagenesis and carcinogenesis in the mammary glands of female Big Blue® (BB) transgenic rats. The rats were fed control diet containing the isoflavones and E2 and treated with a single oral dose of 7,12-dimethylbenz[a]anthracene (DMBA) at PND 50. Animals were sacrificed at 16 or 20 weeks post-carcinogen treatment to assess mutant frequencies (MFs) and histopathological parameters, respectively. The isoflavones or E2 supplementation alone resulted in modest increases in the lacI MF that were not significantly different from the MFs measured in rats fed the control diet alone. DMBA exposure, however, induced significant increases in the lacI MFs in the mammary of both OVX and ovary intact (INT) rats and Hprt MFs in spleen lymphocytes (P 0.01). In general, feeding the isoflavones or E2 separately did not cause any significant changes in DMBA-induced mutagenicity in the mammary. However, feeding the isoflavone mixture (DZG) resulted in a significant reduction in the DMBA-induced lacI MFs (P 0.05). Cell proliferation as measured by PCNA immunohistochemistry was increased in both OVX and INT rats exposed to DMBA as compared with rats fed control diet (P 0.05). Mammary histology indicated that hyperplasia was induced in most of the treatment groups including control. Although DMBA treatment did not induce mammary tumors in the OVX rats, adenoma and adenocarcinoma were detected in the mammary glands of INT rats.

Anticancer therapeutic potential of soy isoflavone, genistein.

Ravindranath MH, Muthugounder S, Presser N, Viswanathan S. Adv Exp Med Biol. 2004;546:121-65.

Genistein (4'5, 7-trihydroxyisoflavone) occurs as a glycoside (genistin) in the plant family Leguminosae, which includes the soybean (Glycine max). A significant correlation between the serum/plasma level of genistein and the incidence of gender-based cancers in Asian, European and American populations suggests that genistein may reduce the risk of tumour formation. Other evidence includes the mechanism of action of genistein in normal and cancer cells. Genistein inhibits protein tyrosine kinase (PTK), which is involved in phosphorylation of tyrosyl residues of membrane-bound receptors leading to signal transduction, and it inhibits topoisomerase II, which participates in DNA replication, transcription and repair. By blocking the activities of PTK, topoisomerase II and matrix metalloprotein (MMP9) and by down-regulating the expression of about 11 genes, including that of vascular endothelial growth factor (VEGF), genistein can arrest cell growth and proliferation, cell cycle at G2/M, invasion and angiogenesis. Furthermore, genistein can alter the expression of gangliosides and other carbohydrate antigens to facilitate their immune recognition. Genistein acts synergistically with drugs such as tamoxifen, cisplatin, 1,3-bis 2-chloroethyl-1-nitrosourea (BCNU), dexamethasone, daunorubicin and tiazofurin, and with bioflavonoid food supplements such as quercetin, green-tea catechins and black-tea thearubigins. Genistein can augment the efficacy of radiation for breast and prostate carcinomas. Because it increases melanin production and tyrosinase activity, genistein can protect melanocytes of the skin of Caucasians from UV-B radiation-induced melanoma. Genistein-induced antigenic alteration has the potential for improving active specific immunotherapy of melanoma and carcinomas. When conjugated to B43 monoclonal antibody, genistein becomes a tool for passive immunotherapy to target B-lineage leukemias that over express the target antigen CD19. Genistein is also conjugated to recombinant EGF to target cancers over expressing the EGF receptor. Although genistein has many potentially therapeutic actions against cancer, its biphasic bioactivity (inhibitory at high concentrations and activating at low concentrations) requires caution in determining therapeutic doses of genistein alone or in combination with chemotherapy, radiation therapy, and/or immunotherapies. Of the more than 4500 genistein studies in peer-reviewed primary publications, almost one fifth pertain to its antitumour capabilities and more than 400 describe its mechanism of action in normal and malignant human and animal cells, animal models, in vitro experiments, or phase I/II clinical trials. Several biotechnological firms in Japan , Australia and in the United States (e.g., Nutrilite) manufacture genistein as a natural supplement under quality controlled and assured conditions.

Phytoestrogen tissue levels in benign prostate hyperplasia and prostate cancer and their association with prostate diseases.

Urology. 2004 Oct;64(4):707-11.

Prostate tissue samples of men consuming a Western diet who underwent surgery for prostate enlargement or prostate cancer were collected and frozen. In the tissue samples, the enterolactone and genistein levels were determined. We subsequently compared the tissue levels in patients with prostate enlargement and prostate cancer and studied the impact of enterolactone and genistein on prostate volume. RESULTS: The enterolactone tissue levels were comparable in patients with prostate enlargement and prostate cancer and revealed no correlation to prostate volume. The genistein tissue levels tended to be lower in patients with prostate cancer compared with the entire prostate enlargement group. In addition, the genistein tissue levels were significantly greater in men with small-volume prostate enlargement compared with those with large-volume prostate enlargement.

Inhibition of proliferation and induction of apoptosis by genistein in colon cancer HT-29 cells.

Cancer Lett. 2004 Nov 25;215(2):159-66.

Genistein has multiple anticancer properties. However, its mechanisms of action and its molecular targets on human colon cells remain to be further elucidated. Here, we demonstrated that genistein reduced proliferation and induced G2/M phase arrest and apoptotic death in colon cancer HT-29 cells. We then investigated the effects of genistein on molecules that regulate apoptosis and cell cycle progress. Genistein increased expression of Bax and p21(WAF1) and slightly decreased Bcl-2 level. Our results demonstrated that genistein inhibited the viability of human colon cancer HT-29 cell via induction of apoptosis mainly through regulation of p21(WAF1) and Bax/Bcl-2 expression. These data suggested a role of genistein in prevention of colon tumour and might reduce colon tumour growth.

Inhibitory effect of genistein and daidzein on ovarian cancer cell growth.

Anticancer Res. 2004 Mar-Apr;24(2B):795-800.

Survival from ovarian cancer has not changed significantly in the past twenty years requiring development of additional treatment protocols. We studied the effect of genistein and daidzein on ovarian cancer cell growth. Five ovarian cancer cell lines from Stage IIIC disease were evaluated. Sulforhodamine B and colony formation assays were used to analyse growth inhibitory effects of genistein and daidzein alone and with cisplatin, paclitaxel or topotecan. Apoptosis induction was studied by determining caspase-3 activity. RESULTS: Inhibition of growth (50-80%), colony formation and colony size was seen at 144 microm of genistein, 0-23% reduction was demonstrated at 9 microm. At 144 microm, the colony size was inhibited >75%; at 9 microm 4/5 cell lines had >50% reduction. Caspase-3 activity was induced with all concentrations of genistein. Cisplatin and topotecan combined with genistein resulted in a mostly additive effect, paclitaxel was slightly less than additive. CONCLUSION: We demonstrate an inhibitory effect of genistein on ovarian cancer cell growth.

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Charles E. Wood, D.V.M, Ph.D., lead researcher from Wake Forest University Baptist Medical Center , says, "For women at increased risk of breast cancer due to higher oestrogen levels, a diet rich in soy isoflavones may offer a modest breast-protective effect." Cancer Research , 2006;66(2):1-9

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Adv Exp Med Biol. 2004;546:121-65.