Berberine (Huang Lian, Rhizoma Coptidis) , a natural product, induces G1-phase cell cycle arrest and caspase-3-dependent apoptosis in human prostate carcinoma cells
Sudheer K. Mantena1, Som D. Sharma1 and Santosh K. Katiyar1,2,3,4 Departments of 1 Dermatology, 2 Environmental Health Sciences, 3 Clinical Nutrition Research Center, and 4 Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama
Berberine, a naturally occurring isoquinoline alkaloid, has been shown to possess anti-inflammatory and anti-tumour 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 µmol/L) and time-dependent (24–72 hours) manner. Treatment of non-neoplastic 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 G1-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. Pre-treatment 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.
SUMMARIES OF ABSTRACTS AND TRIALS
Ginseng enhances anti-cancer effect of 5-fluorouracil on human colorectal cancer cells
Wang CZ, Luo X, Zhang B, Song WX, Ni M, Mehendale S; Tang Center for Herbal Medicine Research, The University of Chicago; Cancer Chemotherapy and Pharmacology Journal; 2006 Sep 29; PMID: 17009031 [PubMed - as supplied by publisher]
PURPOSE: Panax notoginseng is a commonly used Chinese herb. Although a few studies have found that notoginseng shows anti-tumor effects, the effect of this herb on colorectal cancer cells has not been investigated. 5-Fluorouracil (5-FU) is a chemotherapeutic agent for the treatment of colorectal cancer that interferes with the growth of cancer cells. CONCLUSIONS: This study demonstrates that the herb can enhance the anti-proliferation effect of 5-FU on HCT-116 human colorectal cancer cells and may decrease the dosage of 5-FU needed for colorectal cancer treatment.
Wogonin sensitizes resistant malignant cells to TNF-alpha- and TRAIL-induced apoptosis
Fas SC, Baumann S, Zhu JY, Giaisi M, Treiber MK, Mahlknecht U, Krammer PH, Li-Weber M; Tumor Immunology Program D030, German Cancer Research Center (DKFZ), Published: Blood, 2006 Dec 1; 1;108(12):3700-6; PMID: 16931628 [PubMed - indexed for MEDLINE]
We show here that wogonin, derived from the popular Chinese herb Huang-Qin, attenuates NF-kappaB activity by shifting TNFalpha-induced free radical .O(2)(-) to a more reduced nonradical product, H(2)O(2), and thereby sensitizes TNFalpha-resistant leukemia cells to TNFalpha-induced apoptosis. Importantly, wogonin does not affect the viability of normal peripheral blood T cells. Wogonin also sensitizes TRAIL-induced apoptosis. Our data suggest a potential use of wogonin as a TNFalpha or TRAIL adjuvant for cancer treatment. Our data also demonstrate how a herbal compound enhances killing of tumor cells with reduced side effects compared with other treatments.
Potent inhibition of Lewis lung cancer growth by heyneanol A from the roots of Vitis amurensis through apoptoic and anti-angiogenic activities
Lee EO, Lee HJ, Hwang HS, Ahn KS - Graduate School of East-West Medical Science, Kyunghee University, Kiheungeup, Yongin 449-701, Republic of Korea. Published: Carcinogenesis, 2006 Oct;27 (10):2059-69; PMID: 16675471 [PubMed - indexed for MEDLINE]
Vitis amurensis Rupr. (Shan Pu Tao) has long been used for the treatment of cancer to this end, we isolated from its root heyneanol A (HA), which is a tetramer of resveratrol (RES), and established the in vivo anti-tumour activity of HA using the Lewis lung carcinoma (LLC) model. Remarkably, HA was fairly stable in cell culture medium and did not undergo intracellular conversion to RES. Therefore, HA is an active anti-cancer compound that induces caspase-mediated cancer cell apoptosis and inhibits angiogenesis rivaling the potency of RES and merits further evaluation for cancer chemoprevention.
Effect of lyceum barbarum polysaccharide on human hepatoma QGY7703 cells: inhibition of proliferation and induction of apoptosis
Zhang M, Chen H, Huang J, Li Z, Zhu C, Zhang S - Department of Food Science and Bioengineering, Tianjin University of Science and Technology, Tianjin; PMID: 15826878 [PubMed - indexed for MEDLINE]
Lycium barbarum polysaccharide (LBP), extracted from Lycium barbarum (Fructus Lycii – Gou Qi Zi and Cortex Lycii – Di Gu Pi) is found to have anticancer activity. In this study, the effect of LBP on the proliferation rate, cell cycle distribution and apoptosis in the human hepatoma QGY7703 cell line were investigated. CONCLUSION: The induction of cell cycle arrest and the increase of intracellular calcium in apoptotic system may participate in the anti-proliferative activity of LBP in QGY7703 cells.
Differential control of growth, cell cycle progression and gene expression in human estrogen receptor positive MCF-7 breast cancer cell by extracts derived form polysacchaaropeptide I’m-Yunity (a mushroom extract) and Dan Shen (Radix Salviae Miltiorrhizae)
Hsieh TC, Wu JM - Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla; Published: International Journal of Oncology, 2006 Nov;29(5):1215-22; PMID: 17016654 [PubMed - indexed for MEDLINE]
In this study, we investigated the effects of 70% ethanolic extracts prepared from medicinal mushroom extract denoted I'm-Yunity and Dan Shen, alone and in combination, using MCF-7 cells as an in vitro model of estrogen receptor positive (ER+), low invasive Breast Cancer. CONCLUSION: Treatment by I'm-Yunity did not affect cell cycle progression in MCF-7 cells; however, it promoted active induction of apoptosis. In addition, treatment with Danshen alone resulted in a pronounced reduction in the expression of Rb, cyclin D1, and p53, and also led to a diminution of p65 and p50 forms of NF-kappaB. The pronounced suppressive effects of Danshen on expression of the aforementioned genes were largely attenuated in cells treated with I'm-Yunity-Plus suggesting that ingredients in Danshen must have interacted with those in I'm-Yunity as to culminate in neutralization of the gene suppressive effects of Danshen. Additional support for such interactions was obtained by targeted cDNA array analysis using human tumor metastasis and BCa/ER signaling gene arrays. Taken together, our results are consistent with the interpretation that interaction exists between Danshen and I'm-Yunity and that I'm-Yunity-Plus may have very good efficacy in the treatment of Breast Cancer, particularly for patients with ER+ status.
Evidence for Oldenlandia diffusa-evoked cancer cell apoptosis through superoxide burst and caspase activation
Yadav SK, Lee SC - Yong Loo Lin School of Medicine, National University of Singapore; Zhong Xi Yi Jie He Xue Bao, 2006 Sep; 4(5):485-9; PMID: 16965742 [PubMed - in process]
BACKGROUND & OBJECTIVE: Various studies using the herb Oldenlandia diffusa (Bai Hua She She Cao) alone or in combination with other therapy plans have evidenced the effectiveness of the herb in the management of cancers of different tissue origin. RESULTS: We found that it dose-dependently inhibited the cancer cell growth in MTT assay. Flow cytometry analysis revealed that it elicited significant production of sub-G(1) population of the cells, indicating the extract-evoked cell apoptotic death. The LD(50) of the ethanol extract was estimated to be approximately 320 microg/ml. Moreover, treatment of the cancer cells with the ethanol component markedly increased the production of superoxide within few hours. Significant elevation in the protease activities of caspases-2 and -3 were detected at as early as 3 and 6 hours respectively. CONCLUSION: Our results show that the ethanol extract of the herb effectively evokes cancer cell apoptosis, possibly through burst-mediated caspase activation.
Chinese Herb/Chemotherapy Interactions in Breast Cancer
University of California, San Francisco, Michael Campbell Ph D, Award: 2003 (Cycle IX) $200,000 #9WB-0042 Innovative Treatment Modalities: Hormone and Chemotherapy Targets – Improving Today’s Arsenal.
Traditional Chinese Medicine (TCM) is a treatment modality that has been used for centuries to treat cancer, prolong life, and increase the quality of life for cancer patients. The lack of evidence-based clinical trials coupled with the proliferation of anecdotal and case report studies of TCM make it an important treatment modality to study. TCM use in the San Francisco Bay Area is widespread and frequently used by our patient population, thus it can be studied using standard research models at our institution. There is a high degree of conformity among TCM practitioners in terms of diagnoses and treatments due to the extensive historically-based documentation of TCM treatment modalities.
We have recently obtained laboratory data on the effects of over 70 Chinese herbal extracts on the growth of breast cancer cells in culture. These herbs have been traditionally prescribed by TCM practitioners for metastatic breast cancer and other cancer patients. Many of these herbal extracts demonstrated significant inhibitory effects in our initial screening. Since many cancer patients who take these herbs also receive conventional chemotherapy, the objective of this project is to determine what kinds of interactions these herbs have with standard chemotherapeutic agents.
Herbs will be prepared as boiled teas, as they are traditionally prepared. Breast cancer cells growing in tissue culture will be treated with individual herbs, chemotherapeutic drugs, or combinations of an herb with a chemotherapeutic drug. After three days of treatment, the cells will be analyzed for growth/death. Growth curves will be generated from these data and comparisons of the curves from individual herbs, drugs, and their combinations will determine whether the herbs act to enhance the effects of the drugs, inhibit their effects, or have no effect. We will then examine the effects of herb/drug combinations that show greater activity than either alone in a mouse model of breast cancer. Rather than randomly screening thousands of plants for anti-breast cancer activity, we have focused on plants which have been used for hundreds/thousands of years in Chinese medicine. In addition, we are administering these agents as “teas” which is how they are traditionally administered to patients.
Laboratory Testing of Chinese Herbs Used for Breast Cancer
University of California, San Francisco – Dabasish Tripathy MD, Award: 1999 (Cycle V) $85,754 Innovative Award: Creative Drugs.
Traditional Chinese Medicine (TCM) is a treatment modality that has been used for centuries to cure cancer, prolong life, increase the quality of life for cancer patients, and more recently to ameliorate the side effects of Western therapies. The lack of evidence-based clinical trials coupled with the proliferation of anecdotal and case report studies of TCM make it an important treatment modality for further study. TCM use in the Bay Area is widespread and frequently used by our patient population, thus it can be studied using standard research models at our institution. There is a high degree of conformity among TCM practitioners in terms of both diagnoses and treatments due to the extensive historically-based documentation of TCM treatment modalities. We propose to obtain laboratory data on herbs commonly used for breast cancer in order to prioritize herbal formulae for future Phase I/II clinical trials.
We plan to perform laboratory analysis of a number of botanical agents that have been traditionally prescribed by TCM practitioners for metastatic breast cancer (MBC) patients. We have pilot data on a few herbal compounds that show anti-tumour activity, and we will use a similar expanded methodology to screen approximately 50 more botanical agents. We will test for the ability of these compounds to cause breast cancer cells to divide using an MTT assay, to commit suicide (apoptosis) using APO-BRDU and to grow using clonogenic assays. The compounds will be tested for their effects using both pulsed and continuous exposure. For herbal extracts with activity, the responsible components will be identified using salt exchange column and high performance liquid chromatography fractions. Promising herbs or combinations could then be entered into Phase I/II clinical trials using tumor response endpoints.
The Use of Ginger and Turmeric in Cancer Treatments
Vimala, S., et al. Anti-tumour promoter activity in Malaysian ginger rhizobia used in traditional medicine. British Journal of Cancer, Vol. 80, No. 1/2, April 1999, pp. 110-16
Ginger, turmeric and other members of the Zingiberaceae family of rhizomes have a long history of use in Malaysian traditional medicine. Ginger, for example, is widely used in the treatment of stomach problems, nausea, vomiting, epilepsy, sore throat, cough, bruises, wounds, childbirth, sore eyes, liver complaints, rheumatism, asthma, and many other disorders. Researchers at the Forest Research Institute of Malaysia now report that several members of the Zingiberaceae family effectively block the promotion of cancerous tumors. They tested 11 different species and found that seven of them had strong anti-tumor properties. Their test involved a short term assay of the inhibitory effect of extracts of the rhizomes (roots) on human cancer cells. They found that turmeric (Curcuma domestica) extracts (turmeric root extracted with petroleum ether, chloroform or ethanol) completely inhibited further growth of the cancer cells. Ginger (Zingiber officinale) extracts, especially the chloroform extract, also inhibited further growth, but the concentration of extract was more critical than for the turmeric extracts. The researchers conclude that turmeric, ginger and other Zingiberaceae rhizomes may be useful in preventing the promotion of cancer and that populations with high risks of cancer should be encouraged to include them in their diet. Further work is now underway to isolate the active components in the plants.
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