Publications

  • Journal of alternative and complementary medicine (New York, N.Y.) 05/2014; 20(5):A2-3. · 1.69 Impact Factor
  • Journal of alternative and complementary medicine (New York, N.Y.) 05/2014; 20(5):A2. · 1.69 Impact Factor
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    ABSTRACT: Ascorbate (vitamin C) was an early, unorthodox therapy for cancer, with an outstanding safety profile and anecdotal clinical benefit. Because oral ascorbate was ineffective in two cancer clinical trials, ascorbate was abandoned by conventional oncology but continued to be used in complementary and alternative medicine. Recent studies provide rationale for reexamining ascorbate treatment. Because of marked pharmacokinetic differences, intravenous, but not oral, ascorbate produces millimolar concentrations both in blood and in tissues, killing cancer cells without harming normal tissues. In the interstitial fluid surrounding tumor cells, millimolar concentrations of ascorbate exert local pro-oxidant effects by mediating hydrogen peroxide (H2O2) formation, which kills cancer cells. We investigated downstream mechanisms of ascorbate-induced cell death. Data show that millimolar ascorbate, acting as a pro-oxidant, induced DNA damage and depleted cellular adenosine triphosphate (ATP), activated the ataxia telangiectasia mutated (ATM)/adenosine monophosphate-activated protein kinase (AMPK) pathway, and resulted in mammalian target of rapamycin (mTOR) inhibition and death in ovarian cancer cells. The combination of parenteral ascorbate with the conventional chemotherapeutic agents carboplatin and paclitaxel synergistically inhibited ovarian cancer in mouse models and reduced chemotherapy-associated toxicity in patients with ovarian cancer. On the basis of its potential benefit and minimal toxicity, examination of intravenous ascorbate in combination with standard chemotherapy is justified in larger clinical trials.
    Science translational medicine 02/2014; 6(222):222ra18. · 10.76 Impact Factor
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    ABSTRACT: Disodium ethylene diamine tetraacetic acid (EDTA) reduced adverse cardiac outcomes in a factorial trial also testing oral vitamins. Objective This report describes the intent-to-treat comparison of the 4 factorial groups overall and in patients with diabetes. Methods Double-blind placebo-controlled 2 x 2 factorial multicenter randomized trial of 1708 post-MI patients ≥ 50 years and creatinine ≤2.0 mg/dL randomized to receive 40 EDTA chelation or placebo infusions plus 6 caplets daily of a 28-component multivitamin-multimineral mixture or placebo. Primary endpoint was a composite of total mortality, MI, stroke, coronary revascularization, or hospitalization for angina. Results Median age was 65 years, 18% female, 94% Caucasian, 37% diabetic, 83% prior coronary revascularization, and 73% on statins. Five-year Kaplan-Meier estimates for the primary endpoint in the chelation + high-dose vitamin group was 31.9%, in the chelation + placebo vitamin group 33.7%, in the placebo infusion + active vitamin group 36.6%, and in the placebo infusions + placebo vitamin group 40.2 %. The reduction in primary endpoint by double active treatment compared with double placebo was significant (HR 0.74, 95% CI (0.57,0.95); p=0.016). In patients with diabetes, the primary endpoint reduction of double active compared with double placebo was more pronounced (HR 0.49, 95% CI (0.33,0.75), p<0.001). Conclusions In stable post- MI patients on evidence-based medical therapy, the combination of oral high-dose vitamins and chelation therapy compared with double placebo reduced clinically important cardiovascular events to an extent that was both statistically significant and of potential clinical relevance.
    American Heart Journal. 01/2014;
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    ABSTRACT: Whether high-dose multivitamins are effective for secondary prevention of atherosclerotic disease is unknown. To assess whether oral multivitamins reduce cardiovascular events and are safe. Double-blind, placebo-controlled, 2 x 2 factorial, multicenter, randomized trial. (ClinicalTrials.gov: NCT00044213) SETTING: 134 U.S. and Canadian academic and clinical sites. 1708 patients aged 50 years or older who had myocardial infarction (MI) at least 6 weeks earlier and had serum creatinine levels of 176.8 mol/L (2.0 mg/dL) or less. Intervention: Patients were randomly assigned to an oral, 28-component, high-dose multivitamin and multimineral mixture or placebo. The primary end point was time to total death, recurrent MI, stroke, coronary revascularization, or hospitalization for angina. The median age was 65 years, and 18% of patients were women. The qualifying MI occurred a median of 4.6 years (interquartile range [IQR], 1.6 to 9.2 years) before enrollment. Median follow-up was 55 months (IQR, 26 to 60 months). Patients received vitamins for a median of 31 months (IQR, 13 to 59 months) in the vitamin group and 35 months (IQR, 13 to 60 months) in the placebo group (P = 0.65). Totals of 645 (76%) and 646 (76%) patients in the vitamin and placebo groups, respectively, completed at least 1 year of oral therapy (P = 0.98), and 400 (47%) and 426 (50%) patients, respectively, completed at least 3 years (P = 0.23). Totals of 394 (46%) and 390 (46%) patients in the vitamin and placebo groups, respectively, discontinued the vitamin regimen (P = 0.67), and 17% of patients withdrew from the study. The primary end point occurred in 230 (27%) patients in the vitamin group and 253 (30%) in the placebo group (hazard ratio, 0.89 [95% CI, 0.75 to 1.07]; P = 0.21). No evidence suggested harm from vitamin therapy in any category of adverse events. There was considerable nonadherence and withdrawal, limiting the ability to draw firm conclusions (particularly about safety). High-dose oral multivitamins and multiminerals did not statistically significantly reduce cardiovascular events in patients after MI who received standard medications. However, this conclusion is tempered by the nonadherence rate. National Institutes of Health.
    Annals of internal medicine 12/2013; 159(12):797-805. · 13.98 Impact Factor
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    Jun Yu, Yan Ma, Jeanne Drisko, Qi Chen
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    ABSTRACT: Background Tumor resistance to platinum-based drugs has been an obstacle to the treatment of ovarian cancer. Extract of the plant Rauwolfia vomitoria has long been used by cancer patients. However, there have not been systematic studies of its anticancer activity.Objective In an effort to enhance the effectiveness of platinum-based drugs, we investigated the anticancer effect of a Rauwolfia vomitoria extract (Rau), both alone and in combination with carboplatin (Cp).Methods In vitro cytotoxicity and colony formation were evaluated in several ovarian cancer cell lines. In vivo effects were evaluated in an intraperitoneal ovarian cancer mouse model. The combination of Rau and Cp was assessed using Chou-Talalay’s constant ratio design and median effect analysis based on the isobologram principle to determine the combination index values.ResultsRau decreased cell growth in all 3 tested ovarian cancer cell lines dose dependently and completely inhibited formation of colonies in soft agar. Apoptosis was induced in a time- and dose-dependent manner and was the predominant form of Rau-induced cell death. Synergy of Rau with Cp was detected, with combination index values <1 and dose reduction index values for Cp ranging from 1.7- to 7-fold. Tumor growth in mice was significantly suppressed by 36% or 66% with Rau treatment alone at a low (20 mg/kg) or a high dose (50 mg/kg), respectively, an effect comparable to that of Cp alone. The volume of ascitic fluid and the number of nonblood cells in ascites were also significantly decreased. Combining Rau with Cp remarkably enhanced the effect of Cp and reduced tumor burden by 87% to 90% and ascites volume by 89% to 97%.Conclusions Rau has potent antitumor activity and in combination significantly enhances the effect of Cp against ovarian cancer.
    Current Therapeutic Research 11/2013; 75:8–14. · 0.45 Impact Factor
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    ABSTRACT: Objective: A simple method of using fingerstick blood glucose (FSBG) monitors to estimate blood ascorbate values after high-dose intravenous (IV) ascorbate infusion is evaluated as a substitution for high-performance liquid chromatography (HPLC) measurement. Methods: In 33 participants, readings from FSBG monitors were taken before and after IV ascorbate infusions at various time points, with the postinfusion FSBG readings subtracted from the baseline glucose readings. The results of the subtractions (AAFSBG) were correlated with ascorbate concentrations detected by HPLC (AAHPLC). Results: A linear regression was found between ascorbate concentrations detected by the fingerstick method (AAFSBG) and by HPLC (AAHPLC). The linear correlations were identical in healthy subjects, diabetic subjects, and cancer patients. Analysis of variance obtained an AAFSBG/AAHPLC ratio of 0.90, with a 90% confidence interval of (0.69, 1.20). The corrections of AAFSBG improved similarity to AAHPLC but did not significantly differ from the uncorrected values. Conclusion: The FSBG method can be used as an approximate estimation of high blood ascorbate concentration after IV ascorbate (>50 mg/dL, or 2.8 mM) without correction. However, this measurement is not accurate in detecting lower or baseline blood ascorbate. It is also important to highlight that in regard to glucose monitoring, FSBG readings will be erroneously elevated following IV ascorbate use and insulin should not be administered to patients based on these readings.
    Journal of the American College of Nutrition 06/2013; 32(3):187-93. · 1.74 Impact Factor
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    Jun Yu, Jeanne Drisko, Qi Chen
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    ABSTRACT: Lack of effective therapy is a major problem in the treatment of pancreatic cancer. In the present study, we investigated a natural product, the extract of Pao Pereira (Pao), for its anti-pancreatic cancer effect in vitro and in vivo, either alone or in combination with the first-line chemotherapeutic drug gemcitabine (Gem). Pao induced dose-dependent apoptosis to all five tested pancreatic cancer cell lines. The combination of Pao and Gem had a synergistic effect in the inhibition of cell growth, with combination indices (CIs) <1 by Chou-Talalay's median effect analysis based on the isobologram principle. Adding Pao to Gem treatment reduced the concentration of Gem to produce an equitoxic effect on pancreatic cancer cells. In an orthotopic pancreatic xenograft mouse model, mice bearing PACN-1 tumors were treated with Pao and Gem, either alone or in combination. The progression of tumors was monitored longitudinally by imaging of live animals. While Gem did not provide significant inhibition, Pao treatment significantly suppressed tumor growth by 70-72%. Combined Pao and Gem treatment further enhanced the tumor inhibitory effect compared to Gem alone, and markedly reduced metastatic lesions in the peritoneum. Collectively, these data suggest that the extract of Pao possesses anti-pancreatic cancer activity and can enhance the effects of Gem in vitro and in vivo.
    Oncology Reports 05/2013; · 2.30 Impact Factor
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    Dataset: Borst
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    J Yu, J Drisko, Q Chen
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    ABSTRACT: Purpose To evaluate extracts from two medical plants Pao Per-eira (Pao) and Rauwolfia vomitoria (Rau) for their anti-tumor effects in various types of pancreatic cancers and ovarian cancers. Methods Five pancreatic cancer and three ovarian cancer cell lines were tested that exhibited different resistance to the 1st line chemo-drug gemcitabine (Gem, for pancrea-tic cancer), and carboplatin (Cp, for ovarian cancer). Chou-Talalay's method was used to evaluate drug combination. Results Both Rau and Pao extracts induced dose-dependent cytotoxicities in all tested cancer cell lines, despite their inherent resistance to chemo-drugs. IC 50 values for Rau were 140-350µg/ml, and 120-350µg/ml for Pao, depend-ing on the cells tested. Normal epithelial cell MRC-5 was much less affected compared to all the tested cancer cells. The differences of cell viabilities between cancer cells and normal cells were statistically significant (p<0.05), indicating possible low toxicity of these extracts. To test whether the treatments of Rau or Pao could enhance the cells' sensitivities to chemo-drugs, we combined either Rau or Pao with gemcitabine to treat pancreatic cancer cells, and with carboplatin to treat ovarian cancer cells. The combination treatments took Chou-Talalay's constant ratio design, with molar ratio set to IC 50extract : IC 50Chemo . The combined-treatments significantly enhanced cell death in cancer cells which were strongly resistant to gemcitabine or carboplatin (p<0.05). The results showed a left-shift in the dose-response curves of the combination treatments compared to the corresponding curves with either Gem or Cp alone in all tested cancer cells. Combination indices (CIs) were <1, indicating synergistic effects. Conclusion These results pave the way for in vivo studies of the anti-cancer effects of Rauwolfia vomitoria and Pao Per-eira extracts, especially in gemcitabine-resistant pancrea-tic cancers and carboplatin-resistant ovarian cancers. Studies on mechanisms of the anti-cancer actions are also undergoing concerning apoptosis and cell cycle arrests.
    · 2.08 Impact Factor
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    ABSTRACT: TACT is an National Institutes of Health-sponsored, randomized, double-blind, placebo-controlled, 2 × 2 factorial clinical trial testing the benefits and risks of 40 infusions of a multicomponent disodium EDTA chelation solution compared with placebo and of an oral, high-dose multivitamin and mineral supplement. TACT has randomized and will follow up 1,708 patients for an average of approximately 4 years. The primary end point is a composite of all-cause mortality, myocardial infarction, stroke, coronary revascularization, and hospitalization for angina. A 900-patient substudy will examine quality-of-life outcomes. The trial is designed to have >85% power to detect a 25% relative reduction in the primary end point for each treatment factor. Enrollment began in September 2003 and was completed in October 2010.
    American heart journal 01/2012; 163(1):7-12. · 4.65 Impact Factor
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    ABSTRACT: Recent studies have revealed the scientific basis for the use of intravenous (i.v.) vitamin C or ascorbic acid (ascorbate) in treating cancers, and raised the possibility of using i.v. ascorbate as a prooxidant anticancer therapy. Through the production of H2O2, pharmacologic ascorbate can induce some cancer cell death in vitro and inhibit a number of types of tumor growth in animal models. However, the mechanism of cell death triggered by ascorbate is not well understood. In this study, we investigated the cytotoxicity of pharmacological concentrations of ascorbate to human prostate cancer cells and the mechanisms involved. The results showed that ascorbate in the millimolar range induced cytotoxicity in five of the six tested prostate cancer cell lines. The IC50 values in the sensitive prostate cancer cells ranged from 1.9 to 3.5 mmol/l, concentrations clinically achievable with i.v. ascorbate use. All tested androgen-independent cells were sensitive to ascorbate treatment. The ascorbate-insensitive cell line LaPC4 is hormonally dependent. Whereas the reasons for sensitivity/resistance to ascorbate treatment need to be investigated further, cell death in sensitive cells was dependent on H2O2. Ascorbate treatment depleted ATP and induced autophagy in sensitive prostate cancer cells, resulting in cell death. Taken together with previous studies, high-dose ascorbate has the potential to be a novel treatment option to hormone-refractory prostate cancer.
    Anti-cancer drugs 12/2011; 23(4):437-44. · 2.23 Impact Factor
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    ABSTRACT: This article provides an overview of imaging modalities that aid in diagnosing, staging, and assessing therapeutic response in prostate cancer. Prostate cancer is the second most common type of cancer in American men and the second leading cause of cancer death among men. Prostate cancer is difficult to diagnose in early stages, and advanced disease often recurs after treatment. To localize sites of recurrence many imaging modalities have been used with varying success. This article presents case studies of PET scanning using carbon 11 acetate and discusses intravenously infused ascorbate, a complementary and alternative medicine therapy for prostate cancer.
    Urologic Clinics of North America 08/2011; 38(3):343-57. · 1.39 Impact Factor
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    ABSTRACT: Two popular complementary, alternative, and integrative medicine therapies, high-dose intravenous ascorbic acid (AA) and intravenous glutathione (GSH), are often coadministered to cancer patients with unclear efficacy and drug-drug interaction. In this study we provide the first survey evidence for clinical use of iv GSH with iv AA. To address questions of efficacy and drug-drug interaction, we tested 10 cancer cell lines with AA, GSH, and their combination. The results showed that pharmacologic AA induced cytotoxicity in all tested cancer cells, with IC(50) less than 4 mM, a concentration easily achievable in humans. GSH reduced cytotoxicity by 10-95% by attenuating AA-induced H(2)O(2) production. Treatment in mouse pancreatic cancer xenografts showed that intraperitoneal AA at 4 g/kg daily reduced tumor volume by 42%. Addition of intraperitoneal GSH inhibited the AA-induced tumor volume reduction. Although all treatments (AA, GSH, and AA+GSH) improved survival rate, AA+GSH inhibited the cytotoxic effect of AA alone and failed to provide further survival benefit. These data confirm the pro-oxidative anti-cancer mechanism of pharmacologic AA and suggest that AA and GSH administered together provide no additional benefit compared with AA alone. There is an antagonism between ascorbate and glutathione in treating cancer, and therefore iv AA and iv GSH should not be coadministered to cancer patients on the same day.
    Free Radical Biology & Medicine 05/2011; 51(3):681-7. · 5.27 Impact Factor
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    ABSTRACT: Conventional treatment approaches have had little impact on the course of pancreatic cancer, which has the highest fatality rate among cancers. Gemcitabine, the primary therapeutic agent for pancreatic carcinoma, produces minimal survival benefit as a single agent. Therefore, numerous efforts have focused on gemcitabine combination treatments. Using a ratio design, this study established that combining pharmacologically achievable concentrations of ascorbate with gemcitabine resulted in a synergistic cytotoxic response in eight pancreatic tumor cell lines. Sensitization was evident regardless of inherent gemcitabine resistance and epithelial-mesenchymal phenotype. Our analysis suggested that the promiscuous oxidative actions of H(2)O(2) derived from pharmacologic ascorbate can culminate in synergism independent of the cancer cell's underlying phenotype and resistance to gemcitabine monotherapy. Gemcitabine-ascorbate combinations administered to mice bearing pancreatic tumor xenografts consistently enhanced inhibition of growth compared to gemcitabine alone, produced 50% growth inhibition in a tumor type not responsive to gemcitabine, and demonstrated a gemcitabine dose-sparing effect. These data support the testing of pharmacologic ascorbate in adjunctive treatments for cancers prone to high failure rates with conventional therapeutic regimens, such as pancreatic cancer.
    Free Radical Biology & Medicine 03/2011; 50(11):1610-9. · 5.27 Impact Factor
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    ABSTRACT: Anecdotal information and case reports suggest that intravenously administered vitamin C is used by Complementary and Alternate Medicine (CAM) practitioners. The scale of such use in the U.S. and associated side effects are unknown. We surveyed attendees at annual CAM Conferences in 2006 and 2008, and determined sales of intravenous vitamin C by major U.S. manufacturers/distributors. We also queried practitioners for side effects, compiled published cases, and analyzed FDA's Adverse Events Database. Of 199 survey respondents (out of 550), 172 practitioners administered IV vitamin C to 11,233 patients in 2006 and 8876 patients in 2008. Average dose was 28 grams every 4 days, with 22 total treatments per patient. Estimated yearly doses used (as 25 g/50 ml vials) were 318,539 in 2006 and 354,647 in 2008. Manufacturers' yearly sales were 750,000 and 855,000 vials, respectively. Common reasons for treatment included infection, cancer, and fatigue. Of 9,328 patients for whom data is available, 101 had side effects, mostly minor, including lethargy/fatigue in 59 patients, change in mental status in 21 patients and vein irritation/phlebitis in 6 patients. Publications documented serious adverse events, including 2 deaths in patients known to be at risk for IV vitamin C. Due to confounding causes, the FDA Adverse Events Database was uninformative. Total numbers of patients treated in the US with high dose vitamin C cannot be accurately estimated from this study. High dose IV vitamin C is in unexpectedly wide use by CAM practitioners. Other than the known complications of IV vitamin C in those with renal impairment or glucose 6 phosphate dehydrogenase deficiency, high dose intravenous vitamin C appears to be remarkably safe. Physicians should inquire about IV vitamin C use in patients with cancer, chronic, untreatable, or intractable conditions and be observant of unexpected harm, drug interactions, or benefit.
    PLoS ONE 01/2010; 5(7):e11414. · 3.73 Impact Factor
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    ABSTRACT: Ascorbic acid is an essential nutrient commonly regarded as an antioxidant. In this study, we showed that ascorbate at pharmacologic concentrations was a prooxidant, generating hydrogen-peroxide-dependent cytotoxicity toward a variety of cancer cells in vitro without adversely affecting normal cells. To test this action in vivo, normal oral tight control was bypassed by parenteral ascorbate administration. Real-time microdialysis sampling in mice bearing glioblastoma xenografts showed that a single pharmacologic dose of ascorbate produced sustained ascorbate radical and hydrogen peroxide formation selectively within interstitial fluids of tumors but not in blood. Moreover, a regimen of daily pharmacologic ascorbate treatment significantly decreased growth rates of ovarian (P < 0.005), pancreatic (P < 0.05), and glioblastoma (P < 0.001) tumors established in mice. Similar pharmacologic concentrations were readily achieved in humans given ascorbate intravenously. These data suggest that ascorbate as a prodrug may have benefits in cancers with poor prognosis and limited therapeutic options.
    Proceedings of the National Academy of Sciences 08/2008; 105(32):11105-9. · 9.74 Impact Factor

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