Doxorubicin and Borscht: a recipe to improve chemotherapy outcome
August 7, 2013
Jacob Schor, ND, FABNO
The chemotherapy drug doxorubicin (also known as adriamycin) is used to treat a wide range of cancers. It is an anthracycline antibiotic and works by intercalating DNA. The most serious side effect, which can be life-threatening, is heart damage. Doxorubicin is still used to treat a wide range of cancers, including breast cancer, hematological malignancies, many types of carcinoma, and soft tissue sarcomas.
For those of you who enjoy historic context, you may find it interesting to know that this drug was isolated from a soil-based microbe isolated in the 1950s by an Italian company, Farmitalia, from soil that surrounds the Castel del Monte, a 13th century castle. A group of French researchers isolated the same compound at the same time the Italian’s did so both research groups contributed to the compound’s name. It was named after the Dauni, a pre-Roman tribe that occupied the area of Italy where the compound was found, combined with the French word for ruby that describes the compounds bright red color. I don’t know how Dauni got changed to Doxo so don’t ask.
Doxorubicin can cause significant heart damage especially if the cumulative dose exceeds 550 mg/square meter body surface. There are a number of approaches to preventing this drug’s cardiotoxicity. The most common is to take co Q-10 during and after treatment. Several recent papers suggest another, rather novel possible co-treatment that may both reduce doxorubicin cardiotoxicity and at the same time increase its effectiveness at killing cancer cells. Novel and peculiar treatment, red beetroot (Beta vulgaris), those things we make borscht with.
In 2011, Kapadia et al from Howard University reported on a study in which they compared the ability of a beet extract against doxorubicin in killing androgen-independent human prostate cancer cells (PC-3) and also estrogen receptor-positive human breast cancer cells (MCF-7). The chemical betanin found in beets that give them their red color is similar in structure to doxorubicin, which as already mentioned is also quite red in color. Both the beets and the doxorubicin killed the cancer cells, though the drug was much more effective.
The beet extract decreased the growth rate of the prostate cancer cells (3.7% in 3 days vs. 12.5% in 7 days) when tested at the concentration of 29 µg/ml. Similar effects were seen with skin cancer cells and liver cancer cells. The beet would have a moderate impact while the drug would kill 100% of the cell.
In May 2012, Xi et al from Virginia Commonwealth University reported that inorganic nitrate offers protection against doxorubicin caused heart damage. This form of nitrate is reduced to nitrite and nitric oxide in the body and has a therapeutic impact against heart disease. These researchers propose a “novel concept of using dietary supplementation of inorganic nitrate to reduce [doxorubicin] …-induced cardiac cellular damage and dysfunction,” basing this suggestion on studies they had conducted on mice.
They suggested that nitrates supplied at just four times the World Health Organizations Acceptable Daily Intake (ADI) “… alleviated [doxorubicin]-induced left ventricular dysfunction and mitochondrial respiratory chain damage.”
Beets are such an excellent food source for inorganic nitrate that in research papers the terms beet juice and inorganic nitrate are used interchangeably.
June 2013: Synergistic cytotoxicity of red beetroot (Beta vulgaris L.) extract with doxorubicin in human pancreatic, breast and prostate cancer cell lines
In June 2013 Kapadia’s group in a second paper looking at beets and doxorubicin reported that a combination of the two had a synergistic effect inhibiting the growth of pancreatic, breast and prostate cancer cell lines, suggesting the “potential of red beetroot extract-doxorubicin combination ”.
Beet juice and beet juice crystals have been substances of considerable interest over the last few years; athletes use them to increase endurance, heart patients to reduce blood pressure and men with erectile dysfunction, well use them as a kind of natural Viagra. All these effects stem from beets being a source of nitrate with which the body can make nitric oxide.
Speaking of Viagra brings us back to a 2004 study by Evig et al from the University of Iowa. These researchers reported that you could increase the effect of doxorubicin by adding nitric oxide to the mix. Breast cancer cells exposed to nitric oxide (NO) 30 minutes before treatment were much more sensitive to doxorubicin. Treatmentwith doxorubicin alone killed 60% of the cancer cells, but pre-treating the cells with NO and then treating with doxorubicin killed 95% of the cancer cells in their experiment.
Simultaneous treatment with both NO and doxorubicin produced only a slight increase in cancer kill over treatment with doxorubicin alone. Giving NO after doxorubicin produced no change at all.
One obvious concern with using NO along with chemotherapy is whether this will increase the drug's toxic effect on healthy tissue. In this same study, the researchers ran healthy rat heart cells through the same protocols of NO pretreatment followed by doxorubicin. No increase in toxicity was seen on the healthy cells.
This suggests that some sort of pretreatment that will increase nitric oxide prior to treatment with doxorubicin might increase the benefit.
The classic method most people are familiar with to increase nitric oxide of course really is Viagra. Viagra belongs to a class of drugs known as phophodiesterase-5- inhibitors (PDE- inhibitors). These drugs slow down the action of an enzyme that breaks down nitric oxide thus increasing its apparent effect.
A 2005 study reported that pre-dosing with Viagra prior to doxorubicin treatment decreased cardiotoxicity while at the same time increasing the damage to the cancer cells. At least it did so in mice.
As exciting as all this might have sounded, we have yet to hear of a medical oncologist dosing Viagra prior to chemo. Which brings us back to beets. A pre-chemo dose of nitrates, aka beet juice may be just the ticket to increase nitric oxide, synergistically increase doxorubicin’s anti-cancer action and at the same time reduce cardiotoxicity. It certainly won’t hurt.
While the research on beets has generally used beet juice, I can’t help but think that a bowl of borscht might also help.
There are a multitude of borscht recipes online. Here’s a decent looking recipe: http://natashaskitchen.com/2010/09/26/classic-russian-borscht-recipe/
(I should probably suggest leaving out the potatoes and carrots from the recipe though I suspect including them makes for a better tasting soup.)
“Beet Juice for Health” http://denvernaturopathic.com/beetjuice.htm
Anticancer Agents Med Chem. 2011 Mar;11(3):280-4.
Cytotoxic effect of the red beetroot (Beta vulgaris L.) extract compared to doxorubicin (Adriamycin) in the human prostate (PC-3) and breast (MCF-7) cancer cell lines.
Kapadia GJ, Azuine MA, Rao GS, Arai T, Iida A, Tokuda H.
Department of Pharmaceutical Sciences, Howard University, Washington, DC 20059, USA. firstname.lastname@example.org
Previous cancer chemoprevention studies from our laboratories and by other investigators have demonstrated that the extract of red beetroot (Beta vulgaris L.), the FDA approved red food color E162, can be effective in suppressing the development of multi-organ tumors in experimental animals. To further explore this finding, we have compared the cytotoxic effect of the red beetroot extract with anticancer drug, doxorubicin (adriamycin) in the androgen-independent human prostate cancer cells (PC-3) and in the well-established estrogen receptor-positive human breast cancer cells (MCF-7). This red colored anticancer antibiotic was selected for comparative cytotoxic study because its chemical structure with a planar configuration of an aromatic chromophore attached to a sugar molecule is remarkably similar to that of betanin, the beetroot extract constituent primarily responsible for its red color. Both doxorubicin and the beetroot extract exhibited a dose-dependent cytotoxic effect in the two cancer cell lines tested. Although the cytotoxicity of the beetroot extract was significantly lower when compared to doxorubicin, it continued to decrease the growth rate of the PC-3 cells (3.7% in 3 days vs. 12.5% in 7 days) when tested at the concentration of 29 µg/ml. In contrast, doxorubicin, at the same concentration level, completely inhibited the growth of the PC-3 cells in three days. Similarly, comparative studies in the normal human skin FC and liver HC cell lines showed that the beetroot extract had significantly lower cytotoxic effect than doxorubicin (8.6% vs. 100%, respectively, at 29 µg/ml concentration of each, three-day test period). The results suggest that betanin, the major betacyanin constituent, may play an important role in the cytotoxicity exhibited by the red beetroot extract. Further studies are needed to evaluate the chemopreventive potentials of the beetroot extract when used alone or in combination with doxorubicin to mitigate the toxic side-effects of the latter.
Nitric Oxide. 2012 May 15;26(4):274-84. doi: 10.1016/j.niox.2012.03.006. Epub 2012 Apr 5.
Dietary inorganic nitrate alleviates doxorubicin cardiotoxicity: mechanisms and implications.
Xi L, Zhu SG, Das A, Chen Q, Durrant D, Hobbs DC, Lesnefsky EJ, Kukreja RC.
VCU Pauley Heart Center, Division of Cardiology, Virginia Commonwealth University, Richmond, VA 23298-0204, United States. email@example.com
Doxorubicin (DOX) is one of the most powerful and widely prescribed chemotherapeutic agents to treat divergent human cancers. However, the clinical use of DOX is restricted due to its severe cardiotoxic side-effects. There has been ongoing search for cardioprotectants against DOX toxicity. Inorganic nitrate has emerged as a bioactive compound that can be reduced into nitrite and nitric oxide in vivo and in turn plays a therapeutic role in diseases associated with nitric oxide insufficiency or dysregulation. In this review, we describe a novel concept of using dietary supplementation of inorganic nitrate to reduce DOX-induced cardiac cellular damage and dysfunction, based on our recent promising studies in a mouse model of DOX cardiotoxicity. Our data show that chronic oral ingestion of sodium nitrate, at a dose equivalent to ~400% of the Acceptable Daily Intake of the World Health Organization, alleviated DOX-induced left ventricular dysfunction and mitochondrial respiratory chain damage. Such cardioprotective effects were associated with reduction of cardiomyocyte necrosis/apoptosis, tissue lipid peroxidation, and mitochondrial H(2)O(2) generation following DOX treatment. Furthermore, proteomic studies revealed enhanced cardiac expression of mitochondrial antioxidant enzyme - peroxiredoxin 5 in thenitrate-treated animals. These studies suggest that inorganic nitrate could be an inexpensive therapeutic agent for long-term oral administration in preventing DOX-induced cardiac toxicity and myopathy during the prolonged pathological process. Future clinical trials in the cancer patients undergoing DOX chemotherapy are warranted to translate these experimental findings into an effective new therapy in preventing the DOX-induced cardiomyopathy.
Copyright © 2012 Elsevier Inc. All rights reserved.
J Nutr. 2013 Jun;143(6):818-26. doi: 10.3945/jn.112.170233. Epub 2013 Apr 17.
Inorganic nitrate and beetroot juice supplementation reduces blood pressure in adults: a systematic review and meta-analysis.
Siervo M, Lara J, Ogbonmwan I, Mathers JC.
Human Nutrition Research Centre, Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle on Tyne, UK. firstname.lastname@example.org
Diets including food products rich in inorganic nitrate are associated with lower blood pressure (BP). The evidence for the BP-lowering effects of inorganic nitrate and beetroot in randomized clinical trials has not been systematically assessed. The objective was to conduct a systematic review and meta-analysis of randomized clinical trials that examined the effects of inorganic nitrateand beetroot supplementation on BP. Medline, EMBASE, and Scopus databases were searched from inception to February 2013. The specific inclusion criteria were: 1) randomized clinical trials; 2) trials reporting effects on systolic or diastolic BP or both; and 3) trials comparing inorganicnitrate or beetroot juice supplementation with placebo control groups. Random-effects models were used to assess the pooled BP effect sizes. Sixteen trials met the eligibility criteria for the systematic review. All studies had a crossover study design. The trials were conducted between 2006 and 2012 and included a total of 254 participants with 7-30 participants/study. The duration of each intervention ranged from 2 h to 15 d. Inorganic nitrate and beetroot juice consumption were associated with greater changes in systolic BP [-4.4 mm Hg (95% CI: -5.9, -2.8); P < 0.001] than diastolic BP [-1.1 mm Hg (95% CI: -2.2, 0.1); P = 0.06]. The meta-regression showed an association between daily dose of inorganic nitrate and changes in systolic BP (P < 0.05).Inorganic nitrate and beetroot juice supplementation was associated with a significant reduction in systolic BP. These findings need to be tested in long-term trials and in individuals at greater cardiovascular risk.
[PubMed - indexed for MEDLINE]
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J Complement Integr Med. 2013 Jun 26;10(1):1-10. doi: 10.1515/jcim-2013-0007.
Synergistic cytotoxicity of red beetroot (Beta vulgaris L.) extract withdoxorubicin in human pancreatic, breast and prostate cancer cell lines.
Kapadia GJ, Rao GS, Ramachandran C, Iida A, Suzuki N, Tokuda H.
Abstract Although a wide variety of cytotoxic plant extracts and phytochemicals are known to act synergistically with anticancer drug doxorubicin (D), their clinical application is hindered by safety concerns of such combination therapy. Our earlier studies showed that red beetroot (Beta vulgarisL.) extract (B), approved by Food and Drug Administration and European Union as red food color E162, reduced multi-organ tumor formations in various animal models when administered in drinking water. This led us to postulate that a long-term daily exposure to low doses of B through diet might be safe and sufficient to produce cancer chemopreventive effect in humans. Further, our recent comparative cytotoxic investigation with B and D in several human cancer cell lines indicated their potential for synergistic activity. Since B is considered safe for human use with no known toxicity, we conducted the present study to evaluate its synergistic antiproliferative activity with D against pancreatic (PaCa), breast (MCF-7) and prostate (PC-3) tumor cells of human origin. Different concentrations of B and D (0.29-290 μg/ml) and in various combinations (B:D ratio = 1:0, 1:1, 5:1, 1:5 and 0:1) were tested for cytotoxic effects against the three cancer cells. The viability of cells was assessed after 72 h incubation with various combinations of B and D using the trypan-blue staining method. The cytotoxic data were analyzed by the combination index method of Chou and Talalay to establish synergy between B and D. The results indicated that an overall positive reduction in drug concentration was achieved by D when combined with B in its cytotoxicity profile in the three human cancer cells tested. The synergistic cytotoxicity was best when the B:D ratio of 1:5 was used in PaCa cells at IC50, IC75 and IC90 dose levels and in MCF-7 cells at IC90 dose level. These results warrant further studies on the potential of red beetroot extract-doxorubicin combination in treating human cancers.
Nitric Oxide. 2004 May;10(3):119-29.
Endogenous production and exogenous exposure to nitric oxide augmentdoxorubicin cytotoxicity for breast cancer cells but not cardiac myoblasts.
Evig CB, Kelley EE, Weydert CJ, Chu Y, Buettner GR, Burns CP.
Department of Medicine, The University of Iowa Carver College of Medicine and The University of Iowa Holden Comprehensive Cancer Center, Iowa City, IA 52242, USA.
We studied the effect of nitric oxide (*NO) on the anticancer activity of doxorubicin. When MCF-7 human breast cancer cells were exposed to an aqueous solution of *NO delivered as a bolus 30 min prior to doxorubicin, the cytotoxic effect as measured in a clonogenic assay was increased (doxorubicin alone, 40% survival, doxorubicin plus *NO, 5% survival). The *NO donor diethylamine nitric oxide, but not inactivated donor, also yielded an increase in doxorubicincytotoxicity. The sequence was important since the simultaneous application of *NO withdoxorubicin yielded only a small augmentation of effect, and the exposure of the cells todoxorubicin prior to the *NO obliterated the augmentation. Prior depletion of glutathione by incubation of the cells for 24h with D,L-buthionine-S,R-sulfoximine (BSO) further increased thecytotoxicity so that BSO plus *NO plus doxorubicin killed all of the clones. MCF-7 cells transduced with inducible nitric oxide synthase gene (iNOS) through an adenoviral vector overexpressed iNOS and produced increased amounts of nitrite, an indicator of increased *NO production. These iNOS transduced cells were more susceptible to doxorubicin than vector control or wild-type cells. Cell cycle progression of iNOS transduced cells was not different from controls. Likewise, iNOS transduction resulted in no change in cellular glutathione levels. For comparison, we examined the effect of iNOS transduction on the sensitivity of MCF-7 to edelfosine, a membrane-localizing anticancer drug without direct DNA interaction. Insertion of the iNOS had no effect on killing of the MCF-7 cells by this ether lipid class drug. We also tested the effect of iNOS transduction ondoxorubicin sensitivity of H9c2 rat heart-derived myoblasts. We found no augmentation ofcytotoxicity by *NO, and this observation offers potential therapeutic tumor selectivity by using *NO with doxorubicin. Therefore, we conclude that *NO produced intracellularly by iNOS overexpression or delivered as a bolus sensitizes human breast cancer cells in culture todoxorubicin, but not to a cardiac cell line or to edelfosine. This augmentation is not due to a modulation of cell cycle distribution or measurable cellular glutathione resulting from the transduction.
Circulation. 2005 Apr 5;111(13):1601-10.
Phosphodiesterase-5 inhibition with sildenafil attenuates cardiomyocyte apoptosis and left ventricular dysfunction in a chronic model of doxorubicin cardiotoxicity.
Fisher PW, Salloum F, Das A, Hyder H, Kukreja RC.
Department of Internal Medicine, Division of Cardiology, Virginia Commonwealth University Medical Center, Richmond 23298, USA.
Sildenafil, a phosphodiesterase-5 inhibitor, induces cardioprotection against ischemia/reperfusion injury via opening of mitochondrial K(ATP) channels. It is unclear whethersildenafil would provide similar protection from doxorubicin-induced cardiotoxicity.
METHODS AND RESULTS:
Male ICR mice were randomized to 1 of 4 treatments: saline,sildenafil, doxorubicin (5 mg/kg IP), and sildenafil (0.7 mg/kg IP) plus doxorubicin (n=6 per group).Apoptosis was assessed with the use of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling and in situ oligo ligation methods. Desmin distribution was determined via immunofluorescence. Bcl-2 expression was analyzed by Western blot. Left ventricular function was assessed by measuring developed pressure and rate pressure product in Langendorff mode. ECG changes indicative of doxorubicin cardiotoxicity were also measured. For in vitro studies, adult ventricular cardiomyocytes were exposed to doxorubicin (1 micromol/L), sildenafil (1 micromol/L) with or without N(G)-nitro-L-arginine methyl ester (L-NAME) (100 micromol/L), or 5-hydroxydecanoate (100 micromol/L) 1 hour before doxorubicin and incubated for 18 hours.Doxorubicin-treated mice demonstrated increased apoptosis and desmin disruption, which was attenuated in the sildenafil+doxorubicin group. Bcl-2 was decreased in the doxorubicin group but was maintained at basal levels in the sildenafil+doxorubicin group. Left ventricular developed pressure and rate pressure product were significantly depressed in the doxorubicin group but were attenuated in the sildenafil+doxorubicin group. ST interval was significantly increased in thedoxorubicin group over 8 weeks. In the sildenafil+doxorubicin group, ST interval remained unchanged from baseline. Doxorubicin caused a significant increase in apoptosis, caspase-3 activation, and disruption of mitochondrial membrane potential in vitro. In contrast, sildenafilsignificantly protected against doxorubicin cardiotoxicity; however, this protection was abolished by both L-NAME and 5-hydroxydecanoate.
Prophylactic treatment with sildenafil prevented apoptosis and left ventriculardysfunction in a chronic model of doxorubicin-induced cardiomyopathy.
[PubMed - indexed for MEDLINE]
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