Bulk Herbs & Herb Infused Olive Oil
Research regarding the anti-cancer activity of Hydrastis canadensis (goldenseal) and/or its active compounds berberine and hydrastine
This information has been complied in order to facilitate the research efforts of health care professionals and others. These statements have not been evaluated by the Food and Drug Administration and are not intended diagnose, treat, cure, prevent, mitigate, or prevent any disease. Nor are they intended to make specific claims regarding our products. The information is presented with the latest publications first. This is an ongoing work so check back often as we will update these pages as more information becomes available. Last Updated : 08/25/2008
Berberine, a natural cholesterol reducing product, exerts antitumor cytostatic/cytotoxic effects independently from the mevalonate pathway.
Issat T, Jakobisiak M, Golab J.
Oncol Rep. 2006 Dec;16(6):1273-1276.
The aim of this study was to investigate the role of the mevalonate pathway
in the cytostatic/cytotoxic effects of berberine, a natural plant alkaloid
that reduces cholesterol concentration. Berberine as well as lovastatin, an
inhibitor of the mevalonate pathway, exerted dose-dependent
cytostatic/cytotoxic effects against human breast cancer cells (MDA-MB231).
Although the mevalonate pathway metabolites (mevalonic acid, farnesyl
pyrophosphate, geranylgeranyl pyrophosphate) effectively reversed
cytostatic/cytotoxic effects of lovastatin against MDA-MB231 cells, they
were not effective in influencing the cytostatic/cytotoxic effects of
berberine. The cytostatic/cytotoxic effects of berberine do not seem to
result from inhibition of the mevalonate pathway.
Nanostructured electrochemical DNA biosensors for detection of the effect of berberine on DNA from cancer cells.
Ovadekova R, Jantova S, Letasiova S, Stepanek I, Labuda J.
Anal Bioanal Chem. 2006 Oct 20;
Multi walled carbon nanotubes (MWNT) in dimethylformamide (DMF) or aqueous
sodium dodecyl sulfate (SDS) solution, colloidal gold nanoparticles (GNP) in
phosphate buffer solution (PBS), and a GNP-MWNT mixture in aqueous SDS
solution have been investigated for chemical modification of a
screen-printed carbon electrode used as the signal transducer of a dsDNA-based
biosensor. Differential pulse voltammetry of the DNA redox marker [Formula:
see text] and the guanine moiety anodic oxidation and cyclic voltammetry
with K(3)[Fe(CN)(6)] as indicator revealed substantial enhancement of the
response of the biosensor, particularly when MWNT in SDS solution was used.
The biosensor was used in testing of berberine, an isoquinoline plant
alkaloid with significant antimicrobial and anticancer activity. Berberine
had a very strong, concentration-dependent, effect on the structural
stability of DNA from the human cancer cells (U937 cells) whereas non-cancer
cells were changed only when berberine concentrations were relatively high
75 and 50 mug mL(-1). Figure Schematic illustration of preparation of the
nanostructured films: (a) layer-to-layer coverage (DNA/nanomaterial/SPE);
(b) mixed coverage (DNA-nanomaterial/SPE).
Berberine induces apoptosis through a
mitochondria/caspases pathway in human hepatoma cells.
Hwang GM, Kuo HC, Tseng TH, Liu JY, Chu CY
Arch Toxicol.
2005 Sep 28;:1-12
Berberine, a main component of Coptidis Rhizoma, is a plant alkaloid with a
long history of medicinal use in Chinese medicine. Berberine has indicated
significant antimicrobial activity against a variety of organisms including
bacteria, viruses, fungi. The mechanism by which berberine initiates
apoptosis remains poorly understood. In the present study, we
demonstrated that berberine exhibited significant cytotoxicity in hepatoma
HepG2 cells but is ineffective in Chang liver cells. Herein we
investigated cytotoxicity mechanism of berberine in HepG2 cells. The results
showed that HepG2 cells underwent internucleosomal DNA fragmentation after
24-h treatment with berberine (50 muM). Moreover, berberine induced the
activation of caspase-8 and -3, and caused the cleavage of poly ADP-ribose
polymerase (PARP) and the cytochrome c release, whereas the expression of
Bid and anti-apoptosis factor Bcl-XL were decreased markedly. The loss of
mitochondrial membrane potential (Delta psim) at 24 h and activation of Fas
at 12 h were also seen in the berberine-treated HepG2 cells. These findings
supported the fact that the inhibitors of caspases, DEVD-FMK, IETD-FMK and
VAD-FMK, prevented apoptosis and restored the expression of Bcl-XL, Bcl-2
and Bid. These results indicated that the potential of anti-hepatoma
activity of berberine may be mediated through a
caspases-mitochondria-dependent pathway.
Photochemical and phototoxic activity of berberine on murine fibroblast NIH-3T3 and Ehrlich ascites carcinoma cells.
Jantova S, Letasiova S, Brezova V, Cipak L, Labaj J.
J Photochem Photobiol B. 2006 Aug 11;
The present study demonstrates photoinduced generation of superoxide anion radical and singlet oxygen upon UVA irradiation of berberine chloride, and its cytotoxic/phototoxic effects on murine fibroblast non-cancer NIH-3T3 and Ehrlich ascites carcinoma (EAC) cells. The EPR spectra monitored upon photoexcitation of aerated solutions of berberine evidenced the efficient activation of molecular oxygen via Type I and II mechanisms, as the generation of superoxide anion radical and singlet oxygen was observed. The EAC cell line was more sensitive to the effect of non-photoactivated and photoactivated berberine than the NIH-3T3 cell line. UVA irradiation increased the sensitivity of EAC cells to berberine, while the sensitivity of NIH-3T3 cells to photoactivated berberine was not changed. Berberine significantly induced direct DNA strand breaks in tested cells, oxidative lesions were not detected, and the effect of irradiation of cells after berberine treatment did not affect the increase of DNA damage in EAC and NIH-3T3 cells. The DNA damage generated by a combination of berberine with UVA irradiation induced a significant blockage of EAC cells in the S and G(2)/M phases and the stopping/decrease of cell proliferation after 24h of influence. On the other hand, after 36h or 48h of berberine treatment, the DNA damage induced necrotic or apoptotic death of EAC cells. Whether these divergences are caused by differences in the properties of two non-isogenic cell lines or by different berberine uptake and cell localization will be analyzed in our further investigations.
Berberine, a natural product, induces
G1-phase cell cycle arrest and caspase-3-dependent apoptosis in human
prostate carcinoma cells.
Mantena SK, Sharma SD, Katiyar SK.
Mol Cancer Ther. 2006 Feb;5(2):296-308.
Berberine, a naturally occurring isoquinoline alkaloid, has been shown to
possess anti-inflammatory and antitumor properties in some in vitro systems.
Here, we report that in vitro treatment of androgen-insensitive (DU145 and
PC-3) and androgen-sensitive (LNCaP) prostate cancer cells with berberine
inhibited cell proliferation and induced cell death in a dose-dependent
(10-100 mumol/L) and time-dependent (24-72 hours) manner. Treatment of
nonneoplastic human prostate epithelial cells (PWR-1E) with berberine under
identical conditions did not significantly affect their viability. The
berberine-induced inhibition of proliferation of DU145, PC-3, and LNCaP
cells was associated with G(1)-phase arrest, which in DU145 cells was
associated with inhibition of expression of cyclins D1, D2, and E and cyclin-dependent
kinase (Cdk) 2, Cdk4, and Cdk6 proteins, increased expression of the Cdk
inhibitory proteins (Cip1/p21 and Kip1/p27), and enhanced binding of Cdk
inhibitors to Cdk. Berberine also significantly (P < 0.05-0.001) enhanced
apoptosis of DU145 and LNCaP cells with induction of a higher ratio of Bax/Bcl-2
proteins, disruption of mitochondrial membrane potential, and activation of
caspase-9, caspase-3, and poly(ADP-ribose) polymerase. Pretreatment with the
pan-caspase inhibitor z-VAD-fmk partially, but significantly, blocked the
berberine-induced apoptosis, as also confirmed by the comet assay analysis
of DNA fragmentation, suggesting that berberine-induced apoptosis of human
prostate cancer cells is mediated primarily through the caspase-dependent
pathway. The effectiveness of berberine in checking the growth of
androgen-insensitive, as well as androgen-sensitive, prostate cancer cells
without affecting the growth of normal prostate epithelial cells indicates
that it may be a promising candidate for prostate cancer therapy.
Berberine-antiproliferative activity in vitro and
induction of apoptosis/necrosis of the U937 and B16 cells.
Letasovia S, Jantova S, Cipak L, Muckova M
Cancer Lett.
2005 Oct 13
Berberine, an isoquinoline plant alkaloid, is widely distributed in plants
used in the traditional Chinese medicine. It displays a wide range of
biological activities and the mechanism of action. Our previous studies of
the anticancer activity of berberine against the cancer cell lines HeLa and
L1210 were extended to the human tumour U937 cell line and the murine
melanoma B16 cell line growing in vitro. Cytotoxicity was measured by the
growth inhibition assay and by the cell morphology monitoring. The in vitro
cytotoxic studies were complemented by the cell cycle analysis and
determination of apoptotic DNA fragmentation. Berberine acted cytotoxically
on both tumour cell lines. The melanoma B16 cells were much more sensitive
to berberine treatment than the U937 cells. The value of IC(100) was below
100mug/ml for the U937 cells and below 1mug/ml for the B16 cells. As for
both cell lines under the long-term influence the values of IC(50) were
found to be less than 4mug/ml. No effect of berberine on the cell cycle
profile of the U937 and B16 cells was detected, however, berberine induced
apoptosis of the U937 cells. On the other hand, cell lysis/necrosis of the
berberine-treated B16 cells was observed as the result of the integrity
damage of the cytoplasmic membrane.
Molecular dissection of a medicinal herb with anti-tumor
activity by oligonucleotide microarray.
Hara A, Iizuka N, Hamamoto Y, Uchimuri T, Miyamoto S,
Tsumedomi R, Miyamoto K, Hazama S, Okita K, Oka M
Life Sci. 2005 Jul 15;77(9):991-1002.
It is difficult to understand precisely the physiological actions of herbs
because they contain a complex array of constituent molecules. In the
present study we used DNA microarray data for 12600 genes to examine the
anti-proliferative activity of the herb Coptidis rhizoma and eight
constituent molecules against eight human pancreatic cancer cell lines. We
identified 27 genes showing strong correlation with the 50% inhibitory dose
(ID50) of C. rhizoma after 72-h exposure. Hierarchical cluster analysis with
correlation coefficients between expression levels of these 27 C.
rhizoma-related genes and the ID50 of each constituent molecule classified
these test molecules into two clusters, one consisting of C. rhizoma and
berberine and the other consisting of the remaining seven molecules. Our
results suggest that one molecule, berberine, can account for the majority
of the anti-proliferative activity of C. rhizoma and that DNA microarray
analyses can be used to improve our understanding of the actions of an
intact herb.
Modulation of apoptosis by berberine through inhibition
of cyclooxygenase-2 and Mcl-1 expression in oral cancer cells.
In Vivo.
2005 Jan-Feb;19(1):247-52.
Kuo CL, Chi CW, Liu TY.
BACKGROUND: We have previously shown that berberine exerts its
anti-inflammatory effects through inhibition of cyclooxygenase-2 (COX-2)
expression. In this study, we explored the biochemical influence of
berberine-induced COX-2 reduction and apoptosis. MATERIALS AND METHODS: KB
cells were treated with berberine, and the apoptosis was measured by
morphology and caspase-3 activity. The effects of prostaglandin E2 (PGE2) on
berberine-mediated cell growth were also determined. The expression of
COX-2, Bcl-2, Mcl-1, Akt and phosphorylated Akt in berberine-treated KB
cells, with or without PGE2, were assessed by Western blots. RESULTS:
Berberine induced apoptosis in KB cells, and was partially reversed by
incorporation of PGE2. Berberine treatment inhibited COX-2 and Mcl-1
expression dose-dependently, but not Bcl-2. PGE2 induced COX-2 and Mcl-1
expression and reversed the repressive effect of berberine on Mcl-1. In
addition, PGE2 had no effect on total Akt, but slightly reversed the
phosphorylated Akt, which was decreased by berberine. CONCLUSION: These
results suggest that berberine-induced apoptosis might be COX-2-dependent
and is related to decreased Akt phosphorylation and Mcl-1 expression.
Berberine inhibits HIF-1alpha expression via enhanced
proteolysis.
Lin S, Tsai SC, Lee CC, Wang BW, Liou JY, Shyu KG.
Mol Pharmacol. 2004 Sep;66(3):612-9.
We have studied the antiangiogenic property of berberine. We showed that
berberine could directly inhibit in vitro human umbilical vein endothelial
cell (HUVEC) tube formation and migration. In addition, to determine whether
berberine could influence the cross-talk between the gastric adenocarcinoma
cell line SC-M1 and vascular endothelial cells, we performed modified
confrontation culture experiments and showed that berberine (7.5 microM, 16
h) could inhibit the capacity of hypoxic SC-M1 cells to stimulate HUVEC
migration. These results demonstrated berberine's antiangiogenic property
and its clinical potential as an inhibitor of tumor angiogenesis. Parallel
Western blot analyses revealed that berberine prevented hypoxic SC-M1
cultures from expressing vascular endothelial growth factor (VEGF) and
hypoxia-inducible factor (HIF)-1alpha, two key factors in mediating tumor
angiogenesis. However, overexpression of HIF-1alpha in SC-M1 cells
dramatically reversed the inhibitory effect of berberine on SC-M1-induced in
vitro HUVEC migration. These data indicated that HIF-1alpha repression is a
critical step in the inhibitory effect of berberine on tumor-induced
angiogenesis. Northern blot analyses plus pulse-chase assays revealed that
berberine did not down-regulate HIF-1alpha mRNA but destabilized HIF-1alpha
protein. We found that berberine-induced HIF-1alpha degradation was blocked
by a 26S proteasome inhibitor. Moreover, immunoprecipitation and Western
blot analyses showed that berberine increased the lysine-acetylated
HIF-1alpha in hypoxic SC-M1 cultures. These data indicated that a
proteasomal proteolytic pathway and lysine acetylation were involved in
berberine-triggered HIF-1alpha degradation. In conclusion, our data provided
molecular evidence to support berberine as a potent antiangiogenic agent in
cancer therapy.
Berberine sensitizes human glioma cells, but not normal glial cells, to ionizing radiation in vitro.
Yount G, Qian Y, Moore D, et al
J Exp Ther Oncol. 2004 Jul;4(2):137-43.
The identification of nontoxic agents that can enhance the efficacy of postoperative radiotherapy for patients with glioblastoma multiforme (GBM) remains a challenge in oncology. We evaluated human GBM cell lines for their responsiveness to berberine, an alkaloid compound used commonly in Asia as an antibiotic. In experiments measuring clonogenic survival, treatment with a nontoxic dose of berberine rendered GBM cells more sensitive than vehicle-treated control cells to x-rays. Such radiosensitization was not observed in parallel experiments with primary human glial cultures. These data suggest that berberine could be integrated with postoperative radiotherapy to selectively promote residual GBM tumor cell death.
Cytotoxic effects of Coptis chinensis and Epimedium sagittatum extracts and their major constituents (berberine, coptisine and icariin) on hepatoma and leukaemia cell growth.
Lin CC, Ng LT, Hsu FF, Shieh DE, Chiang LC.
Clin Exp Pharmacol Physiol. 2004 Jan-Feb;31(1-2):65-9.
1. The present study was conducted to evaluate the cytotoxic effects of Coptis chinensis and Epimedium sagittatum extracts and their major constituents on hepatoma and leukaemia cells in vitro. 2. Four human liver cancer cell lines, namely HepG2, Hep3B, SK-Hep1 and PLC/PRF/5, and four leukaemia cell lines, namely K562, U937, P3H1 and Raji, were used in the present study. 3. Of the two crude drugs, C. chinensis exhibited the strongest activity against SK-Hep1 (IC50 = 7 microg/mL) and Raji (IC50 = 4 microg/mL) cell lines. The IC50 values for C. chinensis on HepG2, Hep3B and PLC/PRF/5 cell lines were 20, 55 and 35 microg/mL, respectively. The IC50 values for C. chinensis on K562, U937 and P3H1 cell lines were 29, 29 and 31 microg/mL, respectively. 4. With the exception of HepG2 and Hep3B, the E. sagittatum extract inhibited the proliferation of all cell lines (SK-Hep1, PLC/PRF/5, K562, U937, P3H1 and Raji), with IC50 values of 15, 57, 74, 221, 40 and 80 microg/mL, respectively. 5. Interestingly, the two major compounds of C. chinensis, berberine and coptisine, showed a strong inhibition on the proliferation of both hepatoma and leukaemia cell lines, with IC50 values varying from 1.4 to 15.2 microg/mL and from 0.6 to 14.1 microg/mL, respectively. However, icariin (the major compound of E. sagittatum) showed no inhibition of either the hepatoma or leukaemia cell lines. 6. The results of the present study suggest that the C. chinensis extract and its major constituents berberine and coptisine possess active antihepatoma and antileukaemia activities.
The anti-inflammatory potential of berberine in vitro and in vivo.
Kuo CL, Chi CW, Liu TY.
Cancer Lett. 2004 Jan 20;203(2):127-37.
Berberine, an isoquinoline alkaloid, has a wide range of pharmacological effects, including anti-inflammation, yet the exact mechanism is unknown. Because cyclooxygenase-2 (COX-2) plays a key role in prostaglandins (PGs) synthesis, which is elevated in inflammation, we examined whether the anti-inflammatory mechanism of berberine is mediated through COX-2 regulation. In oral cancer cell line OC2 and KB cells, a 12 h berberine treatment (1, 10, and 100 microM) reduced prostaglandin E2 (PGE2) production dose-dependently with or without 12-O-tetradecanoylphorbol-13-acetate (TPA, 10 nM) induction. This berberine induced effect occurred rapidly (3 h) as a result of reduced COX-2 protein, but not enzyme activity. The electrophoretic mobility shift assay revealed that activator protein 1 (AP-1) binding was decreased in oral cancer cells treated with berberine for 2 h. Further analysis showed that berberine inhibited AP-1 binding directly. These anti-inflammatory effects paralleled to the in vivo results where berberine pretreatment of Wistar rat inhibited the production of exudates and PGE2 in carrageenan induced air pouch.
Identification of common or distinct genes related to
antitumor activities of a medicinal herb and its major component by
oligonucleotide microarray.
Iizuka N, Oka M, Yamamoto K, Tangoku A, Miyamoto K, Miyamoto
T, Uchimura S, Hamamoto Y, Okita K.
Int J Cancer. 2003 Nov 20;107(4):666-72.
Although the physiological actions of many herbs are gradually being
elucidated at the molecular level, it remains unclear how individual
components of herbs contribute to their biological activities. In the
present study, the antiproliferative activity of Coptidis rhizoma, a
medicinal herb, and the major component berberine was investigated in 8
human pancreatic cancer cell lines. Gene expression patterns associated with
sensitivities to each agent were analyzed with oligonucleotide arrays that
comprised approximately 11,000 genes. We used a tetrazolium dye (MTT) assay
to determine ID(50) values after the 8 cell lines were exposed to the 2
agents for 72 hr. The ID(50) value for berberine was correlated positively
with that for C. rhizoma (r=0.725, p=0.0401). C. rhizoma killed tumor cells
more effectively than purified berberine when normalized to the level of
berberine present in the herb. From the oligonucleotide array data, we
selected 20 and 13 genes with strong correlations (r(2)>0.81) to ID(50)
values for berberine and C. rhizoma, respectively. Among these 33 genes, the
levels of expression of 12 were correlated with the ID(50) values of both
agents, suggesting that these genes are associated with tumor-killing
activity of berberine in C. rhizoma. Expression of the remaining 21 genes
was correlated with the ID(50) value of either purified berberine or C.
rhizoma. Thus, we identified common and distinct genes responsible for anti-proliferative
activities of purified berberine and C. rhizoma. This strategy may improve
our understanding of the actions of herbs with antitumor activities.
Effect of berberine on proliferation, cell cycle and apoptosis in HeLa and L1210 cells.
Jantova S, Cipak L, Cernakova M, Kost'alova D.
J Pharm Pharmacol. 2003 Aug;55(8):1143-9.
Previous studies on the anticancer activity of protoberberine alkaloids against a variety of cancer cell lines were extended to human tumour HeLa and murine leukemia L1210 cell lines. An attempt was also made to investigate the relationship between the cytotoxic activity of berberine and its molecular mechanism of action. Cytotoxicity was measured in-vitro using a primary biochemical screening according to Oyama and Eagle, and the growth inhibition assay. The in-vitro cytotoxic techniques were complemented by cell cycle analysis and determination of apoptotic DNA fragmentation in L1210 cells. Berberine acted cytotoxically on both tumour cell lines. The sensitivity of leukemia L1210 cells to the berberine was higher than that of HeLa cells. The IC(100) was below 100 microg mL(-1) for HeLa cells and approached a 10 microg mL(-1) limit for the leukemia L1210 cells. For both cell lines the IC(50) was found to be less than 4 microg mL(-1), a limit put forward by the National Cancer Institute (NCI) for classification of the compound as a potential anticancer drug. In L1210 cells treated with 10-50 microg mL(-1) berberine, G(0)/G(1) cell cycle arrest was observed. Furthermore, a concentration-dependent decrease of cells in S phase and increase in G(2)/M phase was detected. In addition, apoptosis detected as sub-G(0) cell population in cell cycle measurement was proved in 25-100 microg mL(-1) berberine-treated cells by monitoring the apoptotic DNA fragmentation (DNA ladder) using agarose gel electrophoresis.
The inhibit effect of berberine on human colon cell line cyclooxygenase-2
Tai WP, Luo HS.
Zhonghua Nei Ke Za Zhi. 2003 Aug;42(8):558-60.
OBJECTIVE: To investigate the effect of berberine on human colon cancer cell line HT-29 and the mechanisms of the effects. METHODS: Add 0.1, 0.3, 3.0, 30.0 micro mol/L berberine into the HT-29 cell culture media. The related values were recorded everyday. NS-398 was used as a cyclooxygenase-2 (COX-2) enzyme activity inhibiting agent. The related values included cell growth, test of COX-2 mRNA using RT-PCR method, expression of COX-2 protein with immunocytochemical method, and concentration of prostaglandin E(2) with ELISA method. RESULTS: When the concentration of berberine was higher than 0.3 micro mol/L, there was a significant dose-dependent effect. When the berberine concentration was higher than 0.3 micro mol/L, berberine could inhibit the COX-2 in mRNA and protein level. It could decrease the concentration of prostaglandin E(2) in the culture media. CONCLUSIONS: Berberine can inhibit COX-2 in mRNA and protein level. It can also inhibit the activity of COX-2. This may be one of the mechanisms that berberine inhibit the growth and proliferation of HT-29 human colon cell line.
Berberine inhibited arylamine N-acetyltransferase activity and gene expression and DNA adduct formation in human malignant astrocytoma (G9T/VGH) and brain glioblastoma multiforms (GBM 8401) cells.
Wang DY, Yeh CC, Lee JH, Hung CF, Chung JG.
Neurochem Res. 2002 Sep;27(9):883-9.
Studies have demonstrated that berberine exhibits the antineoplastic action in rat model. Rat glial tumor cells also have been shown to have N-acetyltransferase activity. In this study, we reported the effects of berberine on arylamine N-acetyltransferase (NAT) activity, gene expression, and DNA adduct formation in human brain tumor cell lines (G95/VGH and GBM 8401). The activity of NAT (N-acetylation of substrate) was measured and determined by high-performance liquid chromatography (HPLC) assaying for the amounts of acetylated 2-aminofluorene (AF) and nonacetylated AF. Human brain tumor cells (G9T/VGH and GBM 8401) were used for examining NAT activity and gene expression and AF-DNA adduct formation. NAT gene expression was determined by polymerase chain reaction (PCR) for the levels of mRNA NAT in both examined cells lines. The amounts of AF-DNA adducts were also determined and quantities by HPLC. The results demonstrated that NAT activity, levels of mRNA NAT1 and AF-DNA adduct formation in both examined cell were inhibited and decreased by berberine in a dose-dependent manner. The apparent values of Km and Vmax from NAT of both examined cells were also determined with or without berberine cotreatment. The data also indicated that berberine decreased the apparent values of Km and Vmax. These effects also indicate that berberine is a uncompetitive inhibitor.
Potential antimutagenic activity of berberine, a
constituent of Mahonia aquifolium.
Cernakova M, Kost'alova D, Kettmann
V, Plodova M, Toth J, Drimal J.
BMC Complement Altern Med. 2002 Feb 19;2(1):2.
BACKGROUND: As part of a study aimed at developing new pharmaceutical products from natural resources, the purpose of this research was twofold: (1) to fractionate crude extracts from the bark of Mahonia aquifolium and (2) to evaluate the strength of the antimutagenic activity of the separate components against one of the common direct-acting chemical mutagens. METHODS: The antimutagenic potency was evaluated against acridine orange (AO) by using Euglena gracilis as an eukaryotic test model, based on the ability of the test compound/fraction to prevent the mutagen-induced damage of chloroplast DNA. RESULTS: It was found that the antimutagenicity of the crude Mahonia extract resides in both bis-benzylisoquinoline (BBI) and protoberberine alkaloid fractions but only the protoberberine derivatives, jatrorrhizine and berberine, showed significant concentration-dependent inhibitory effect against the AO-induced chloroplast mutagenesis of E. gracilis. Especially berberine elicited, at a very low dose, remarkable suppression of the AO-induced mutagenicity, its antimutagenic potency being almost three orders of magnitude higher when compared to its close analogue, jatrorrhizine. Possible mechanisms of the antimutagenic action are discussed in terms of recent literature data. While the potent antimutagenic activity of the protoberberines most likely results from the inhibition of DNA topoisomerase I, the actual mechanism(s) for the BBI alkaloids is hard to be identified. CONCLUSIONS: Taken together, the results indicate that berberine possesses promising antimutagenic/anticarcinogenic potential that is worth to be investigated further.
Inhibitory effect of berberine on the mediastinal lymph node metastasis produced by orthotopic implantation of Lewis lung carcinoma.
Mitani N, Murakami K, Yamaura T, Ikeda T, Saiki I.
Cancer Lett. 2001 Apr 10;165(1):35-42.
We examined the effect of berberine, a major component with anti-fungal properties contained in Coptidis Rhizoma and Phellodendri Cortex, on the lymph node metastasis of murine lung cancer. Oral administration of berberine for 14 days significantly inhibited the spontaneous mediastinal lymph node metastasis produced by orthotopic implantation of Lewis lung carcinoma (LLC) into the lung parenchyma in a dose-dependent manner, but did not affect the tumor growth at the implantation site of the lung. Combined treatment with berberine and an anti-cancer drug, CPT-11, resulted in a marked inhibition of tumor growth at the implantation site and of lymphatic metastasis, as compared with either treatment alone. Anti-activator protein-1 (anti-AP-1) transcriptional activity of non-cytotoxic concentrations of berberine caused the inhibition of the invasiveness of LLC cells through the repression of expression of urokinase-type plasminogen activator (u-PA).
Inhibition of chemical carcinogenesis by berberine in rats
and mice.
Anis KV, Rajeshkumar NV, Kuttan R.
J Pharm Pharmacol. 2001 May;53(5):763-8.
Berberine, an alkaloid isolated from the plant Berberis aristata, has been found to inhibit significantly the carcinogenesis induced by 20-methylcholanthrene (200 microg/0.1 mL/mouse) or N-nitrosodiethylamine (NDEA; 0.02% NDEA in distilled water, 2.5 mL/animal by gavage, five days a week for 20 weeks) in a dose-dependent manner in small animals. Administration of berberine (0.5, 2.5 or 5.0 mg kg(-1)) could reduce significantly the incidence of tumour in animals after an injection of 20-methylcholanthrene and increased their life span compared with the control. When berberine (10, 25 or 50 mg kg(-1)) was administered simultaneously with NDEA, the markers of liver injury (liver weight, gamma-glutamyl transpeptidase activity and glutathione S-transferase level) were reduced significantly compared with animals treated with NDEA only, which resulted in all the values being elevated. A similar decrease was noted in the serum levels of lipid peroxide, bilirubin and glutamate pyruvate transaminase. Morphology of liver tissue and levels of marker enzymes indicated that berberine offered protection against chemical carcinogenesis.
Anticachectic effects of Coptidis rhizoma, an anti-inflammatory herb, on esophageal cancer cells that produce interleukin 6.
Iizuka N, Miyamoto K, Hazama S, Yoshino S, Yoshimura K, Okita K, Fukumoto T, Yamamoto S, Tangoku A, Oka M.
Cancer Lett. 2000 Sep 29;158(1):35-41.
Herbs as alternative cancer therapies have attracted a great deal of recent attention due to their low toxicity and costs. In this study, the antitumor activity and anticachectic effect of Coptidis rhizoma, an anti-inflammatory herb, were investigated in nude mice carrying a human esophageal cancer cell line YES-2, which constitutively secretes interleukin-6 (IL-6) and induces cachexia when injected into these mice. In this study, in vivo growth of YES-2 cells was not affected by an oral supplement containing the extract powder of C. rhizoma at a final concentration of 1% (CR supplement). However, in comparison with normal diet, CR supplement significantly attenuated weight loss of tumor-bearing mice without a change in food or water intake. Tumor IL-6 levels were significantly lower in mice treated with CR supplement than in control mice (P<0.001). Serum IL-6 was detectable in four (50%) of eight control mice; IL-6 was not detected in mice treated with CR supplement. We also confirmed that berberine (8-32 microM), a major component of C. rhizoma, dose-dependently inhibited secretion of IL-6 by YES-2 cells in vitro. Moreover, reverse transcription-PCR assay showed that treatment of YES-2 cells with berberine (8-32 microM) for 24 h reduced IL-6 mRNA expression. Our results suggest that C. rhizoma may have an anticachectic effect on esophageal cancer and an effect is associated with the ability of berberine to down-regulate tumor IL-6 production.
Inhibitory effect of Coptidis Rhizoma and berberine on the proliferation of human esophageal cancer cell lines.
Iizuka N, Miyamoto K, Okita K, Tangoku A, Hayashi H, Yosino S,
Cancer Lett. 2000 Jan 1;148(1):19-25.
Our previous study demonstrated that the herbal medicine, Oren-to, had antitumor effects on esophageal cancer cells (ECCs) in vitro. The purpose of this study was to examine which of the seven constituents of Oren-to had antitumor effects on esophageal cancer cells. MTT assay showed that, of the seven constituents, only the aqueous extract of Coptidis Rhizoma had potent inhibitory effect on the proliferation of two types of ECC lines, YES-3 and YES-4. In addition, the proliferation of all six types of ECC lines (YES-1 to YES-6) was inhibited in a dose-dependent manner (P<0.001 for all), when co-cultured at each concentration of Coptidis Rhizoma for 72 h. The ID50 of Coptidis Rhizoma for YES-1 to YES-6 was 2.2 microg/ml, 3.0 microg/ml, 0.25 microg/ml, 2.8 microg/ml, 2.5 microg/ml, and 0.5 microg/ml, respectively, berberine, one of protoberberine components of Coptidis Rhizoma, showed potent antitumor effects on all six types of ECC lines as well as Coptidis Rhizoma. In addition, the ID50 of berberine showed a positive correlation with that of Coptidis Rhizoma in six types of ECC lines examined (r2 = 0.763, P = 0.023). Cell cycle analysis of Coptidis Rhizoma-treated cancer cells showed the accumulation of cells in the G0/G1 phase and relative decrease of the S phase. These results support the possibility that the use of Coptidis Rhizoma containing abundant berberine may be useful as one of alternative therapies for esophageal cancers.
Berberine modulates expression of mdr1 gene product and the responses of digestive track cancer cells to Paclitaxel.
Lin HL, Liu TY, Wu CW, Chi CW.
Br J Cancer. 1999 Oct;81(3):416-22.
Berberine is the major constituent of Coptis chinese and is commonly used in Chinese herbal medicine to treat patients with gastrointestinal disorders. In this study, using flow cytometry, we have found that a 24-h berberine treatment up-regulated the multidrug-resistant transporter (pgp-170) expression in two oral (KB, OC2), two gastric (SC-M1, NUGC-3) and two colon (COLO 205, CT 26) cancer cell lines. Decreased retention of rhodamine 123 was observed in berberine-treated cells as compared to vehicle control. To examine whether the berberine modulated pgp-170 expression in cancer cells is associated with changes in drug resistance, we determined the cytotoxicity, cell cycle progression and cell morphology of Paclitaxel-treated cells. Paclitaxel (1 nM-10 microM) treatment for 24 h induced cytotoxicity in OC2, SC-M1 and COLO 205 cells in a dose-dependent manner. Pretreatment of cells with 32 microM berberine for 24 h prior to Paclitaxel treatment resulted in increased viability as compared to that of Paclitaxel-treated cells. In addition, Paclitaxel-induced apoptosis and/or G2/M arrest in these three cancer cell lines. Pretreatment of cells with berberine prior to Paclitaxel blocked the Paclitaxel-induced cell cycle responses and morphological changes. These results together suggest that berberine modulated the expression and function of pgp-170 that leads to reduced response to Paclitaxel in digestive track cancer cells.
Effects of berberine on arylamine N-acetyltransferase activity in human colon tumor cells.
Lin JG, Chung JG, Wu LT, Chen GW, Chang HL, Wang TF.
Am J Chin Med. 1999;27(2):265-75.
Berberine was used to determine loss of viable cells and inhibition of arylamine Nacetyltransferase (NAT) activity in a human colon tumor (adenocarcinoma) cell line. The viable cells were determined by trypan blue exclusion under a light microscope. The NAT activity was measured by high performance liquid chromatography for the amounts of N-acetyl-2-aminofluorene (AAF), N-acetyl-p-aminobenzoic acid (N-Ac-PABA), and the remaining 2-aminofluorene (AF) and p-aminobenzoic acid (PABA). The viability and NAT activity in a human colon tumor cell line was inhibited by berberine in a dose-dependent manner, i.e., the higher the concentration of berberine, the higher the inhibition of NAT activity and cell death. The NAT activities measured in the intact human colon tumor cells were decreased over 50% by AAF and NAc-PABA production from acetylation of AF and PABA. The apparent values of Kmoff and Vmax of NAT from colon tumor cells were also inhibited by berberine in cytosols and in intact cells. This report is the first to show that berberine did affect human colon tumor cell NAT activity.
Inhibition by berberine of cyclooxygenase-2 transcriptional activity in human colon cancer cells.
Fukuda K, Hibiya Y, Mutoh M, Koshiji M, Akao S, Fujiwara H.
J Ethnopharmacol. 1999 Aug;66(2):227-33.
The enzyme cyclooxygenase-2 (COX-2) is abundantly expressed in colon cancer cells and plays a key role in colon tumorigenesis. Compounds inhibiting COX-2 transcriptional activity have therefore potentially a chemopreventive property against colon tumor formation. An assay method for estimating COX-2 transcriptional activity in human colon cancer cells was established using a beta-galactosidase reporter gene system, and examination was made of various medicinal herbs and their ingredients for an inhibitory effect on COX-2 transcriptional activity. We found that berberine, an isoquinoline alkaloid present in plants of the genera Berberis and Coptis, effectively inhibits COX-2 transcriptional activity in colon cancer cells in a dose- and time-dependent manner at concentrations higher than 0.3 microM. The present findings may further explain the mechanism of anti-inflammatory and anti-tumor promoting effects of berberine.
Inhibitory effect of Coptidis Rhizoma and Scutellariae Radix on azoxymethane-induced aberrant crypt foci formation in rat colon.
Fukutake M, Yokota S, Kawamura H, Iizuka A, Amagaya S, Fukuda K, Komatsu Y.
Biol Pharm Bull. 1998 Aug;21(8):814-7.
This study was conducted to obtain effective cancer chemopreventive agents with low toxicity from medicinal herbs. The effect of aqueous extracts from 9 medicinal herbs with antiinflammatory effect were examined on the formation of azoxymethane (AOM)-induced aberrant crypt foci (ACF), putative preneoplastic lesions of the colon. Male F344 rats were treated with 15 mg/kg body weight of AOM once a week for two weeks. Herbal extract consisting of 2% of the diet was administered from 1 d prior to the first carcinogen treatment. The number of AOM-induced ACF per colon was counted at 4 week. Extracts of Coptidis Rhizoma and Scutellariae Radix significantly inhibited AOM-induced ACF formation. The number of ACF was decreased to 54% and 78% of that of the control by 2% Coptidis Rhizoma and Scutellariae Radix extract in the diet, respectively. Berberine and Baicalin, major ingredients of Coptidis Rhizoma and Scutellariae Radix, inhibited ACF formation at a dose equivalent to the amount in each herbal extract. Therefore, to investigate the mechanisms of action of berberine and baicalein which is the active substances of orally administered baicalin, their effects on cyclooxygenase 1 and 2 activities were studied. Berberine was found to inhibit cyclooxygenase 2 activity without inhibition of cyclooxygenase 1 activity, and baicalein inhibited cyclooxygenase 1 activity. Thus, Coptidis Rhizoma and Scutellariae Radix suppressed experimental colon carcinogenesis, and their chemopreventive effects were explained from the inhibition of berberine on cyclooxygenase 2 activity and baicalein on cyclooxygenase 1 activity.
Berberine sulfate inhibits tumor-promoting activity of
teleocidin in two-stage carcinogenesis on mouse skin.
Nishino H, Kitagawa K, Fujiki H, Iwashima A.
Oncology. 1986;43(2):131-4.
Berberine sulfate, an isoquinoline alkaloid isolated from Hydrastis canadensis L., inhibited the effects of the tumor promoters 12-O-tetradecanoylphorbol-13-acetate and teleocidin, such as increased 32Pi-incorporation into phospholipids of cell membrane and hexose transport. Berberine sulfate also markedly suppressed the promoting effect of teleocidin on skin tumor formation in mice initiated with 7,12-dimethylbenz[a]anthracene.
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