Ascorbic acid inhibits antitumor activity of bortezomib in vivo

Department of Medical Oncology, LeBow Institute for Myeloma Therapeutics and Jerome Lipper Myeloma Center, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K (Impact Factor: 10.43). 05/2009; 23(9):1679-86. DOI: 10.1038/leu.2009.83
Source: PubMed


Earlier studies have shown that ascorbic acid (vitamin C) inhibits bortezomib-induced cytotoxicity against cancer cells in vitro. However, the clinical significance of vitamin C on bortezomib treatment is unclear. In this study, we examined whether daily oral intake of vitamin C inhibits antimultiple myeloma (MM) activities of bortezomib. Vitamin C, at orally achievable concentrations, inhibited in vitro MM cell cytotoxicity of bortezomib and blocked its inhibitory effect on 20S proteasome activity. Specifically, plasma collected from healthy volunteers taking 1 g/day vitamin C reduced bortezomib-induced MM cell death in vitro. This antagonistic effect of vitamin C against proteasome inhibitors is limited to the boronate class of inhibitors (bortezomib and MG262). In vivo activity of this combination treatment was then evaluated using our xenograft model of human MM in SCID (severe combined immune-deficient) mice. Bortezomib (0.1 mg/kg twice a week for 4 weeks) significantly inhibits in vivo MM cell growth, which was blocked by oral vitamin C (40 mg/kg/day). Therefore, our results for the first time show that vitamin C can significantly reduce the activity of bortezomib treatment in vivo; and importantly, suggest that patients receiving treatment with bortezomib should avoid taking vitamin C dietary supplements.

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Available from: Gullu Gorgun, Jul 09, 2014
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    • "We hope to inspire the discussion about the safety of any herbal formulas in combination with cytotoxic therapies and encourage physicians to seek faithful conversations dealing with the use of CAM in cancer patients. There are several reports on the detrimental effects of CAM on the efficacy of chemotherapeutic agents such as St. John’s wort with irinotecan or imatinib [7] or ascorbic acid and green tea with bortezomib [8,9] to name but a few. Therefore, we think that a comprehensive management of our patients should also include education about the risk of interactions with herbal formulas. "
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    ABSTRACT: Complementary and alternative medicine is often used by patients with malignant glioma. Although several interactions of various alternative agents with chemotherapy are known, none has been described for temozolomide so far. We report the case of severe liver toxicity with jaundice during radiochemotherapy with temozolomide likely due to interaction with a popular Chinese herbal formula after surgery for glioblastoma. After cessation of the herbal formula as well as the chemotherapy liver enzymes slowly normalized. Due to tumor progression the patient was retreated with temozolomide for 5 cycles without toxicity. Because of further progression combination treatment of bevacizumab and irinotecan was started and again no liver toxicity was observed. We conclude that the observed toxicity with jaundice was probably caused by an interaction of this popular Chinese formula and temozolomide. This is the first report about a relevant interaction of temozolomide and any herbal formula.
    BMC Complementary and Alternative Medicine 03/2014; 14(1):115. DOI:10.1186/1472-6882-14-115 · 2.02 Impact Factor
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    • "Bortezomib has also shown poor efficacy in the treatment of chronic lymphocytic leukemia (CLL), despite potent in vitro activity4,5. Recently, it was found that some of dietary flavonoids and vitamin C have antagonistic interaction with bortezomib which affects the anti-cancer property of this drug6-9. According to that 77% of patients use vitamins or herbs concurrently with conventional anticancer treatment10, here we review current knowledge concerning how dietary intake could counteract chemotherapy with bortezomib. "
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    ABSTRACT: Eat more 'green' or eat 'five a day' is one of the most important healthy lifestyle behaviours in the 21 century. Aiming to fight cancer effectively, more than half patients use vitamins or herbs concurrently with conventional anticancer treatment. Flavonoids or polyphenols existing in vegetables, fruits and green tea are common plant pigments with antioxidant properties and considered acting as cancer preventing or anti-cancer agents. Recently it was found that some flavonoids and vitamin C in diet or supplements have antagonistic effect with the anti-cancer drug bortezomib. Bortezomib is a specific inhibitor for proteasome and is currently used for treatment of relapsed and refractory multiple myeloma. Despite its successful rates in treating multiple myeloma and other solid tumors, it is unable to kill leukemic cells in the blood. It was recently revealed that some flavonoids and vitamin C present in green leaves and green teas in the blood can neutralize bortezomib by directly interaction between two chemicals. Here we summarize why dietary flavonoids should be avoided in patients who take bortezomib as chemotherapeutic drug.
    Cancer Biology and Medicine 12/2013; 10(4):206-213. DOI:10.7497/j.issn.2095-3941.2013.04.004
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    • "In vivo studies in mouse xenograft models of human MM have also suggested that oral administration of EGCG at 25 or 50 mg/kg and vitamin C at 40 mg/kg/day inhibits the antitumor effects of bortezomib dosed intraperitoneally (i.p.) at 0.5 mg/kg and intravenously (IV) at 0.1 mg/kg, respectively [8, 9]. The findings led the authors to conclude that patients receiving bortezomib treatment should avoid consuming green tea or vitamin C [8, 9], both of which have purported benefits for patients undergoing cancer treatment. "
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    ABSTRACT: To investigate whether clinically relevant levels of epigallocatechin gallate (EGCG, a component of green tea) or vitamin C (ascorbic acid) could antagonize bortezomib antitumor activity in CWR22 human prostate xenograft tumors. The pharmacokinetics (PK) of EGCG and ascorbic acid were determined in immunocompromised mice and compared with concentrations measured in human PK studies of dietary supplements. Antitumor activity of bortezomib in combination with EGCG or ascorbic acid was determined using several dosing regimens to evaluate different target plasma concentrations of EGCG and ascorbic acid. Bortezomib dosed twice-weekly at 0.8 mg/kg IV demonstrated tumor growth inhibition (TGI) of 53.9-58.9%. However, when combined with EGCG such that the plasma concentrations of EGCG were >200 μM at the time of bortezomib dosing, all antitumor activity was abrogated (TGI = -17.7%). A lower concentration of EGCG (11-16 μM), which is severalfold higher than measured clinically in humans taking EGCG supplements (0.6-3 μM), was not antagonistic to bortezomib (TGI 63.5%). Pharmacodynamic studies of proteasome inhibition reflected these findings. Ascorbic acid (40 and 500 mg/kg PO daily) was evaluated under a similar study design and did not antagonize bortezomib antitumor activity (TGI 57.2 and 72.2%). No antagonism of bortezomib is seen in preclinical in vivo experiments, where EGCG or ascorbic acid plasma concentrations are commensurate with dietary or supplemental intake. The data suggest that patients receiving bortezomib treatment do not need to avoid normal dietary consumption of green tea, vitamin C-containing foods, or EGCG or vitamin C dietary supplements.
    Cancer Chemotherapy and Pharmacology 03/2011; 68(5):1145-54. DOI:10.1007/s00280-011-1591-2 · 2.77 Impact Factor
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