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Dichloroacetate (DCA) as a potential metabolic-targeting therapy for cancer. Michelakis ED, Webster L, Mackey JR. Br J Cancer. 2008 Oct 7;99(7):989-94. Epub 2008 Sep 2. Review. PMID: 18766181 doi:10.1038/sj.bjc.6604554 The unique metabolism of most solid tumours (aerobic glycolysis, i.e., Warburg effect) is not only the basis of diagnosing cancer with metabolic imaging but might also be associated with the resistance to apoptosis that characterises cancer. The glycolytic phenotype in cancer appears to be the common denominator of diverse molecular abnormalities in cancer and may be associated with a (potentially reversible) suppression of mitochondrial function. The generic drug dichloroacetate is an orally available small molecule that, by inhibiting the pyruvate dehydrogenase kinase, increases the flux of pyruvate into the mitochondria, promoting glucose oxidation over glycolysis. This reverses the suppressed mitochondrial apoptosis in cancer and results in suppression of tumour growth in vitro and in vivo. Here, we review the scientific and clinical rationale supporting the rapid translation of this promising metabolic modulator in early-phase cancer clinical trials More than 40 nonrandomised trials of DCA in small cohorts of patients have been reported, but the first two randomised control trials of chronic oral therapy with DCA in congenital mitochondrial diseases were reported in 2006. In the first, a blinded placebo-controlled study was performed with oral DCA administered at 25 mg kg-1 day-1 in 30 patients with MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes) (Kaufmann et al, 2006). Most patients enrolled in the DCA arm developed symptomatic peripheral neuropathy, compared with 4 out of 15 in the placebo arm, leading to the termination of the study. Seventeen out of 19 patients had at least partial resolution of peripheral neurological symptoms by 9 months after discontinuation of DCA. This neurotoxicity res

"HOUSTON - A diet that incorporates a daily dose of pistachios may help reduce the risk of lung and other cancers, according to data presented at the American Association for Cancer Research Frontiers in Cancer Prevention Research Conference, held Dec. 6-9. "It is known that vitamin E provides a degree of protection against certain forms of cancer. Higher intakes of gamma-tocopherol, which is a form of vitamin E, may reduce the risk of lung cancer," said Ladia M. Hernandez, M.S., R.D., L.D., senior research dietitian in the Department of Epidemiology at the University of Texas M. D. Anderson Cancer Center, and doctoral candidate at Texas Woman's University - Houston Center. "Pistachios are a good source of gamma-tocopherol. Eating them increases intake of gamma-tocopherol so pistachios may help to decrease lung cancer risk," she said. Pistachios are known to provide a heart-healthy benefit by producing a cholesterol-lowering effect and providing the antioxidants that are typically found in food products of plant origin. Hernandez and colleagues conducted a six-week, controlled clinical trial to evaluate if the consumption of pistachios would increase dietary intake and serum levels of gamma-tocopherol. A pistachio-rich diet could potentially help reduce the risk of other cancers from developing as well, according to Hernandez. "Because epidemiologic studies suggest gamma-tocopherol is protective against prostate cancer, pistachio intake may help," she said. "Other food sources that are a rich source of gamma-tocopherol include nuts such as peanuts, pecans, walnuts, soybean and corn oils.""

"Cigarette smoking and alcohol consumption before head and neck cancer diagnosis strongly predicts the patient's future risk of death, according to published studies. Now, results of a new study show a similar effect among those who continued these habits after cancer diagnosis. "Most cancer survivors are counseled to quit smoking; despite this, many still smoke. In our study, 21 percent continued to smoke even after their cancer diagnosis, increasing their risk of death," said researcher Susan T. Mayne, Ph.D. "Similarly, we found that continued drinking increases the risk of death.""

Side Effects and Warnings Berberine has been reported to cause nausea, vomiting, hypertension (high blood pressure), respiratory failure and paresthesias (abnormal sensations such as numbness or tingling); however, clinical evidence of such adverse Effects is not prominent in the literature. Rare adverse Effects including headache, skin irritation, facial flushing, headache, bradycardia (slowed heart rate) have also been reported with the use of berberine. Use cautiously when taking berberine for longer than eight weeks due to theoretical changes in bacterial gut flora. Use cautiously in individuals with diabetes, as both human and animal studies indicate that berberine may decrease blood sugar levels. Also use cautiously in individuals with hypotension (low blood pressure), as berberine may have antihypertensive Effects. Patients with cardiovascular disease should also use caution as berberine has been associated with the development of ventricular arrhythmias in subjects with congestive heart failure. Although not well studied in humans, berberine may also theoretically cause delays in small intestinal transit time or increase the risk of bleeding. Berberine may cause abortion, eye or kidney irritation, nephritis (inflamed kidneys), dyspnea (difficulty breathing), flu-like symptoms, giddiness, lethargy, or liver toxicity. Patients with leukopenia (abnormally low white blood cell count) should use cautiously due to the potential for development of leukopenia symptoms. When injected under the skin, berberine may cause hyperpigmentation in the arm. Use berberine cautiously in individuals with high exposure to sunlight or artificial light due to potential for adverse phototoxic reactions. Avoid in newborns due to potential for increase in free bilirubin, jaundice, and development of kernicterus (brain damage caused by severe newborn jaundice). Use berberine cautiously in children due to a lack of safety information. Pregnancy and Breastfeeding Berberine is not recomme

Developmental toxicity evaluation of berberine in rats and mice. Jahnke GD, Price CJ, Marr MC, Myers CB, George JD. Birth Defects Res B Dev Reprod Toxicol. 2006 Jun;77(3):195-206. PMID: 16634078 DOI: 10.1002/bdrb.20075 BACKGROUND: Berberine, a plant alkaloid, is found in some herbal teas and health-related products. It is a component of goldenseal, an herbal supplement. Berberine chloride dihydrate (BCD) was evaluated for developmental toxicity in rats and mice. METHODS: Berberine chloride dihydrate was administered in the feed to timed-mated Sprague-Dawley (CD) rats (0, 3625, 7250, or 14,500 ppm; on gestational days [GD] 6-20), and Swiss Albino (CD-1) mice (0, 3500, 5250, or 7000 ppm; on GD 6-17). Ingested doses were 0, 282, 531, and 1313 mg/kg/day (rats) and 0, 569, 841, and 1155 mg/kg/day (mice). RESULTS:There were no maternal deaths. The rat maternal lowest observed adverse effect level (LOAEL), based on reduced maternal weight gain, was 7250 ppm. The rat developmental toxicity LOAEL, based on reduced fetal body weight per litter, was 14,500 ppm. In the mouse study, equivocal maternal and developmental toxicity LOAELs were 5250 ppm. Due to scattering of feed in the high dose groups, a gavage study at 1000 mg/kg/day was conducted in both species. CONCLUSIONS: In rats, maternal, but not fetal adverse effects were noted. The maternal toxicity LOAEL remained at 7250 ppm (531 mg/kg/day) based on the feed study and the developmental toxicity NOAEL was raised to 1000 mg/kg/day BCD based on the gavage study. In the mouse, 33% of the treated females died. Surviving animals had increased relative water intake, and average fetal body weight per litter decreased 5-6% with no change in live litter size. The maternal toxicity LOAEL remained at 5250 ppm (841 mg/kg/day) BCD, based on increased water consumption. The developmental toxicity LOAEL was raised to 1000 mg/kg/day BCD based on decreased fetal body weight.

Mechanisms of berberine (natural yellow 18)-induced mitochondrial dysfunction: interaction with the adenine nucleotide translocator. Pereira CV, Machado NG, Oliveira PJ. Toxicol Sci. 2008 Oct;105(2):408-17. Epub 2008 Jul 3. PMID: 18599498 doi: 10.1124/jpet.107.128017 The data from the present work appear to show that berberine also presents some degree of toxicity to "nontumor" systems, which should be carefully understood. ANT inhibition in nontumor cells by berberine would be responsible for a decrease in energy production and could also result in MPT induction. To the best of our knowledge, no full toxicity assessment exists for berberine in humans, although its use in several commercially available supplements suggests that the compound may present a relatively wide safety interval. In fact, a study with patients with congestive heart failure treated with 1.2 g/day of oral berberine revealed low toxicity and resulted into an average plasma concentration of 0.11 mg/l which would translate into 0.3µM (Zeng and Zeng, 1999Go). Repeated cumulative treatments, alternative forms of formulation (e.g., topical application vs. injection) or more importantly, active mitochondrial accumulation due to its positive charge would be expected to increase its concentration in cells into the range of concentrations used in this study. Empirical data from nontraditional medicines plus the use of extensive clinical assays would allow the use of berberine as a promising antimelanoma agent while maintaining its safety for humans. In radial/vertical forms of melanoma, a possible topical application of berberine would also be possible, thus minimizing side effects on other organs. In conclusion, the present work identifies the ANT as an important target for berberine, with clear relevance for its proposed antitumor effects.

Mitochondrially targeted effects of berberine [Natural Yellow 18, 5,6-dihydro-9,10-dimethoxybenzo(g)-1,3-benzodioxolo(5,6-a) quinolizinium] on K1735-M2 mouse melanoma cells: comparison with direct effects on isolated mitochondrial fractions. Pereira GC, Branco AF, Matos JA, Pereira SL, Parke D, Perkins EL, Serafim TL, Sardão VA, Santos MS, Moreno AJ, Holy J, Oliveira PJ. J Pharmacol Exp Ther. 2007 Nov;323(2):636-49. Epub 2007 Aug 17. PMID: 17704354 doi: 10.1124/jpet.107.128017 The present work shows that berberine is accumulated by mitochondria of a mouse melanoma cell line, leading to mitochondrial fragmentation and dysfunction, accompanied by decreased cellular energy charge. When the effect was compared with the results obtained on isolated mitochondrial fractions, it is observed that regardless of the system used, berberine is toxic for mitochondria. One major limitation of the present study (as in many others) is the lack of knowledge of the real concentration of berberine that reaches mitochondria in intact cells. Although we do not possess data regarding this aspect, it is wise to speculate that mitochondrial berberine concentrations will be much higher than in the bulk cytosol due to electrophoretic accumulation. We believe that the range of berberine concentrations accumulated by mitochondria in intact cells is within the range of concentrations used on isolated mitochondrial fractions in the present study. The present work not only provides insights on the mechanism by which berberine interferes with tumor cell proliferation, demonstrating previously unknown effects on mitochondrial physiology, but also raises a note of caution on the use of berberine as a nontoxic "natural" over-the-counter medication.

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. PMID: 16505103 doi: 10.1158/1535-7163.MCT-05-0448 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. The evaluation of ancient herbal medicines may indicate novel strategies for the treatment of prostate cancer, which remains the leading cause of cancer-related deaths in American men (1). In our present investigation, we show that a naturally occurring isoquinoline alkaloid, berberine, significantly inhibits the proliferation and reduces the viability of DU145 and PC-3 as well as LNCaP cells (Fig. 1), which suggests that berberine may be an effective chemotherapeutic agent against both androgen-sensitive and androgen-insensitive prostate cancer cells. Importantly, we found that berberine did not exhibit toxicity to nonneoplastic human prostate epithelial cells under the conditions used, except for a moderate reduction in cell viability at higher concentrations when cells were treated in vitro for an extended period of time. In conclusion, the results of the present study indicate that berberine inhibits proliferation and induces G1-phase arrest and apoptosis in human prostate cancer cells but not in normal human prostate epithelial cells. In addition, we provide mechanistic evidence that berberine-induced apoptosis in prostate carcinoma cells, particularly hormone-refractory prostate carcinoma cells, is mediated through enhanced expression of Bax, disruption of the mitochondrial membrane potential, and activation of caspase-3.

Berberine suppresses in vitro migration and invasion of human SCC-4 tongue squamous cancer cells through the inhibitions of FAK, IKK, NF-kappaB, u-PA and MMP-2 and -9. Ho YT, Yang JS, Li TC, Lin JJ, Lin JG, Lai KC, Ma CY, Wood WG, Chung JG. Cancer Lett. 2009 Jul 8;279(2):155-62. Epub 2009 Feb 28. PMID: 19251361 doi:10.1016/j.canlet.2009.01.033 There is increasing evidence that urokinase-type plasminogen activator (u-PA) and matrix metalloproteinases (MMPs) play an important role in cancer metastasis and angiogenesis. Inhibition of u-PA and MMPs could suppress migration and invasion of cancer cells. Berberine, one of the main constituents of the plant Rhizoma coptidis, is a type of isoquinoline alkaloid, reported to have anti-cancer effects in different human cancer cell lines. There is however, no available information on effects of berberine on migration and invasion of human tongue cancer cells. Here, we report that berberine inhibited migration and invasion of human SCC-4 tongue squamous carcinoma cells. This action was mediated by the p-JNK, p-ERK, p-p38, IκK and NF-κB signaling pathways resulting in inhibition of MMP-2 and -9 in human SCC-4 tongue squamous carcinoma cells. Our Western blowing analysis also showed that berberine inhibited the levels of urokinase-plasminogen activator (u-PA). These results suggest that berberine down-regulates u-PA, MMP-2 and -9 expressions in SCC-4 cells through the FAK, IKK and NF-κB mediated pathways and a novel function of berberine is to inhibit the invasive capacity of malignant cells.

Berberine inhibits growth, induces G1 arrest and apoptosis in human epidermoid carcinoma A431 cells by regulating Cdki-Cdk-cyclin cascade, disruption of mitochondrial membrane potential and cleavage of caspase 3 and PARP. Mantena SK, Sharma SD, Katiyar SK. Carcinogenesis. 2006 Oct;27(10):2018-27. Epub 2006 Apr 18. PMID: 16621886 doi:10.1093/carcin/bgl043 In the present investigation, we show that berberine, which is present abundantly in Berberis plant species, significantly inhibits the viability, proliferation and induces cell death in human epidermoid carcinoma A431 cells (Figure 1), but this effect was not found in normal human epidermal keratinocytes under the identical conditions, except for a non-significant reduction in cell viability at higher concentrations of berberine (50 and 75 µM) and treatment of cells for a longer period of time (72 h). These data suggested that berberine may be examined as an effective chemotherapeutic agent against non-melanoma skin cancers. In conclusion, our study indicates that berberine inhibits growth, induces G1 arrest and apoptotic cell death of human epidermoid carcinoma A431 cells. We also provide mechanistic evidences that berberine-induced apoptosis in human epidermoid carcinoma cells is mediated through disruption of mitochondrial membrane potential and activation of caspase 3 pathway, although other pathways may have a role and that require further investigation. Moreover, further in vivo studies are required to determine whether berberine could be an effective chemotherapeutic agent for the prevention of non-melanoma skin cancers.

"Berberine is a bitter-tasting, yellow, plant alkaloid with a long history of medicinal use in Chinese and Ayurvedic medicine. Berberine is present in the roots, rhizomes and stem bark of various plants including Hydrastis canadensis (goldenseal), Coptis chinensis (coptis or goldenthread), Berberis aquifolium (Oregon grape), Berberis vulgaris (barberry), and Berberis aristata (tree turmeric). Berberine has also been used historically as a dye, due to its yellow color. Clinical trials have been conducted using berberine. There is some evidence to support its use in the treatment of trachomas (eye infections), bacterial diarrhea, and leishmaniasis (parasitic disease). Berberine has also shown antimicrobial activity against bacteria, viruses, fungi, protozoans, helminths (worms), and chlamydia (STD). Future clinical research is warranted in these areas, as well as cardiovascular disease, skin disorders, and liver disorders.

"Berberine is a plant alkaloid isolated from the roots and bark of several herbs. Some of these herbs include: Barberry (Berberis vulgaris), Berberis integerrima. Berbamine and berberine are found in the plant barberry. Coptis chinensis or Berberis aristata Goldenseal (Hydrastis canadensis) Oregon Grape (Berberis aquifolium) Phellodendron Amurense Yerba mansa (Anemopsis californica). The berberine alkaloid can be found in the roots, rhizomes, stem, and bark of the plants. Berberine-containing plants are used medicinally in many traditional medical systems, including Ayurvedic herbal and Chinese herbal medicine. Coptis chinensis rhizome -- Golden Thread -- Huang Lian -- Intense yellow color most likely due to high content of berberine, which is very bitter in taste"

"Berberine is a quaternary ammonium salt from the group of isoquinoline alkaloids. It is found in such plants as Berberis, goldenseal (Hydrastis canadensis), and Coptis chinensis, usually in the roots, rhizomes, stems, and bark. Berberine is strongly yellow colored, which is why in earlier times berberis species were used to dye wool, leather and wood. Wool is still today dyed with berberine in Northern India Berberine (BBR) is a natural compound with up-regulating activity on both low-density-lipoprotein receptor (LDLR) and insulin receptor (InsR). This one-drug-multiple-target characteristic might be suitable for the treatment of metabolic syndrome.[12] Berberine has been tested and used successfully in experimental[13] and human diabetes mellitus.[14][15][16] Berberine has been shown to lower elevated blood glucose as effectively as metformin.[17] The mechanisms include inhibition of aldose reductase,[18] inducing glycolysis,[19] preventing insulin resistance[20] through increasing insulin receptor expression[14] and acting like incretins. Berberine has drawn extensive attention towards its antineoplastic effects.[43][44] It seems to suppress the growth of a wide variety of tumor cells including breast cancer,[45] leukemia, melanoma,[46] epidermoid carcinoma, hepatoma, oral carcinoma, tongue carcinoma,[47] glioblastoma, prostate carcinoma, gastric carcinoma.[48][49] Animal studies have shown that berberine can suppress chemical-induced carcinogenesis, tumor promotion, tumor invasion,[50][51][52][53][54] prostate cancer,[55][56][57][58] neuroblastoma,[59][60] and leukemia.[34][61] It is a radiosensitzer of tumor cells but not of normal cells

Berberine and Coptidis rhizoma as novel antineoplastic agents: a review of traditional use and biomedical investigations. Tang J, Feng Y, Tsao S, Wang N, Curtain R, Wang Y. J Ethnopharmacol. 2009 Oct 29;126(1):5-17. Epub 2009 Aug 15. PMID: 19686830 doi:10.1016/j.jep.2009.08.009 Conclusions The modern evidences of treating cancer with Huanglian and berberine have a strong linkage with traditional concept and rules of using Huanglian in CM practice. As anticancer candidates with low toxicity, berberine and its altered structure, as well as Huanglian and its formulae, will attract scientists to pursue the potential anticancer effects and the mechanisms by using technologies of genomics, proteomics and other advanced approaches. On the other hand, relatively few in vivo studies have been conducted on anticancer effects of Huanglian and berberine. The clinical application of berberine or Huanglian as novel cancer therapeutic agents requires in vivo validations and further investigations of their anticancer mechanisms.

A phase 2 trial exploring the effects of high-dose (10,000 IU/day) vitamin D(3) in breast cancer patients with bone metastases. Amir E, Simmons CE, Freedman OC, Dranitsaris G, Cole DE, Vieth R, Ooi WS, Clemons M. Cancer. 2009 Nov 13. [Epub ahead of print] PMID: 19918922 DOI: 10.1002/cncr.24749 METHODS: Patients with bone metastases treated with bisphosphonates were enrolled into this single-arm phase 2 study. Patients received 10,000 IU of vitamin D3 and 1000 mg of calcium supplementation each day for 4 months. The effect of this treatment on palliation, bone resorption markers, calcium metabolism, and toxicity were evaluated at baseline and monthly thereafter. CONCLUSIONS: Daily doses of 10,000 IU vitamin D3 for 4 months appear safe in patients without comorbid conditions causing hypersensitivity to vitamin D. Treatment reduced inappropriately elevated parathyroid hormone levels, presumably caused by long-term bisphosphonate use. There did not appear to be a significant palliative benefit nor any significant change in bone resorption. Cancer 2010. © 2009 American Cancer Society.

Meta-analysis of vitamin D, calcium and the prevention of breast cancer. Chen P, Hu P, Xie D, Qin Y, Wang F, Wang H. Breast Cancer Res Treat. 2009 Oct 23. [Epub ahead of print] PMID: 19851861 These results provide strong evidence that vitamin D and calcium have a chemopreventive effect against breast cancer.

Relationship between low ultraviolet B irradiance and higher breast cancer risk in 107 countries. Mohr SB, Garland CF, Gorham ED, Grant WB, Garland FC. Breast J. 2008 May-Jun;14(3):255-60. Epub 2008 Apr 17. PMID: 18422861 DOI: 10.1111/j.1524-4741.2008.00571.x There was a protective effect of UVB irradiance on risk of breast cancer that was independent of fertility rate, proportion of the population overweight, alcohol intake, animal energy intake, and other covariates.

Association between plasma 25-hydroxyvitamin D and breast cancer risk. Crew KD, Gammon MD, Steck SE, Hershman DL, Cremers S, Dworakowski E, Shane E, Terry MB, Desai M, Teitelbaum SL, Neugut AI, Santella RM. Cancer Prev Res (Phila Pa). 2009 Jun;2(6):598-604. Epub 2009 May 26. PMID: 19470790 In summary, these results add to a growing body of evidence that adequate vitamin D stores may prevent breast cancer development. Whereas circulating 25-OHD levels of >32 ng/mL are associated with normal bone mineral metabolism, our data suggest that the optimal level for breast cancer prevention is ≥40 ng/mL. Well-designed clinical trials are urgently needed to determine whether vitamin D supplementation is effective for breast cancer chemoprevention.

The role of vitamin D in cancer prevention. Garland CF, Garland FC, Gorham ED, Lipkin M, Newmark H, Mohr SB, Holick MF. Am J Public Health. 2006 Feb;96(2):252-61. Epub 2005 Dec 27. Review. PMID: 16380576 DOI: 10.2105/AJPH.2004.045260 Vitamin D status differs by latitude and race, with residents of the northeastern United States and individuals with more skin pigmentation being at increased risk of deficiency. A PubMed database search yielded 63 observational studies of vitamin D status in relation to cancer risk, including 30 of colon, 13 of breast, 26 of prostate, and 7 of ovarian cancer, and several that assessed the association of vitamin D receptor genotype with cancer risk. The majority of studies found a protective relationship between sufficient vitamin D status and lower risk of cancer. The evidence suggests that efforts to improve vitamin D status, for example by vitamin D supplementation, could reduce cancer incidence and mortality at low cost, with few or no adverse effects.

Serum 25-hydroxyvitamin D and colon cancer: eight-year prospective study. Garland CF, Comstock GW, Garland FC, Helsing KJ, Shaw EK, Gorham ED. Lancet. 1989 Nov 18;2(8673):1176-8. PMID: 2572900 Blood samples taken in 1974 in Washington County, Maryland, from 25 620 volunteers were used to investigate the relation of serum 25-hydroxyvitamin D (25-OHD) with subsequent risk of getting colon cancer. 34 cases of colon cancer diagnosed between August, 1975, and January, 1983, were matched to 67 controls by age, race, sex, and month blood was taken. Risk of colon cancer was reduced by 75% in the third quintile (27-32 ng/ml) and by 80% in the fourth quintile (33-41 ng/ml) of serum 25-OHD. Risk of getting colon cancer decreased three-fold in people with a serum 25-OHD concentration of 20 ng/ml or more. The results are consistent with a protective effect of serum 25-OHD on colon cancer.