Modified Citrus Pectin Detailed Scientific Review
Overview
Background
Citrus pectin is contained in the peel and membrane of citrus and other fruits such as apples and plums, but it is most concentrated in citrus fruits. It is widely used in the manufacture of foods, drugs and cosmetics, but is best known as the jelling agent in marmalades and jellies1.
Ordinary citrus pectin is largely undigested because of its long branched chains of complex sugars (polysaccharides). Modified citrus pectin (MCP) has been changed by acidity and heat so that these polysaccharides are split into smaller, non-branched chains of the simple sugar galactose that are digestible2.
Proposed Mechanism of Action
Invasive primary tumors can shed metastatic cells into the blood stream. These cells may subsequently adhere to each other or to normal cells forming clumps (emboli). The tendency of tumor cells to adhere has been correlated with their metastatic potential. Larger emboli (clumps) may be subsequently trapped in capillaries where they begin to grow while smaller emboli and even single cells may develop into larger clumps by adhering to circulating lymphocytes, platelets or cells lining the blood vessels (endothelial cells)3.
This tendency of any cells to interact with and adhere to other cells is thought to be due to certain carbohydrate-binding proteins (lectins) on the cell wall surfaces of both normal and tumor cells3,4. One of the carbohydrates with which lectins interact is the sugar, galactose which yields the carbohydrate binding proteins known as galectins. When interactions occur between galectins expressed on the surface of metastatic cells and galectin receptors expressed on endothelial cells, the resulting complex (ligand) may then interact with additional cells to yield a growing metastatic colony of cells or contribute to the development of a vascular blood supply for a new tumor5,6,7.
Modified citrus pectin appears to bind to one of the galectins thus blocking the tumor cells from adhering to each other and to the walls of blood vessels5,8. Binding to melanoma cells7 and human breast carcinoma cells6 has been demonstrated in vitro. Inhibition of lung metastasis has been demonstrated in rats7,5. Inhibition of primary tumor growth, angiogenesis and spontaneous metastasis has been demonstrated in mice6. Apoptosis (cell death) has been seen in dexamethasone, melphalan, or doxorubicin resistant multiple myeloma cell lines9.
Toxicity and Side Effects
No reports of adverse events have been published in the literature or found in a search of voluntary reports of adverse events to the USDA Center for Food Safety and Applied Nutrition. Although modified citrus pectin is more easily digested than natural citrus pectin, individuals with allergies or sensitivities to citrus may experience stomach discomfort when taking either type of citrus pectin.
As a natural component of food, citrus pectin (even when modified) is considered to be a dietary supplement rather than a drug. As such, it does not require the approval of the Food and Drug Administration (FDA) for marketing. Further information concerning dietary supplement regulations is provided in the FDA Center for Food Safety and Applied Nutrition Overview.
More information on the science and research in modified citrus pectin therapy is provided in the Summary of Research.
Summary of Research
Amount and Type of Research
An updated search of the Medline database and other sources for articles published between January 1, 2004, and February 1, 2007, identified 16 articles about modified citrus pectin in English. Of these articles, nine concerned cancer or cancer-related factors.
In our previous reviews of the literature and other sources between January 1, 1997, and December 31, 2003, we had identified 14 articles concerning modified citrus pectin that were applicable to cancer. We have retrieved all of the total of 23 applicable articles and classified these references as the following types of information:
Human | Animal | In vitro | Reviews | Other |
|---|---|---|---|---|
2 | 7* | 5 | 0 | 13** |
*Two articles reported both an in vitro and an animal study7,10. Another article reported two animal studies and one in vitro study6. Thus, a total of 14 studies have been reported.
**Two of these were general reference articles concerning citrus pectins11 or galactoside-binding lectins3.
The first study in humans was an unpublished presentation of positive, but non-significant results of a pilot clinical trial at a conference12. Subsequently, a non-randomized pilot Phase II clinical trial was published by some of the same authors. They reported a statistically significant increase in PSA doubling time among 13 patients with prostate cancer treated with modified citrus pectin following surgery and/or androgen-deprivation therapy8.
Seven studies in animals and two in vitro studies have been reported.
Conclusions
Based upon two in vitro studies, seven animal studies and one published pilot study in humans, modified citrus pectin may play a role in the reduction of primary and metastatic growth. However, before definitive conclusions can be reached, these results must be confirmed by larger trials in humans that are randomized and placebo controlled.
Study descriptions and sources for these data are provided in the Annotated Bibliography.
Annotated Bibliography
Human Studies
8Guess BW, Scholz MC, Strum SB, Lam RY, Johnson HJ, Jennrich RI. Modified citrus pectin (MCP) increases the prostate-specific antigen doubling time in men with prostate cancer: a phase II pilot study. Prostate Cancer and Prostatic Diseases 2003;6:301-4.
Purpose: Disease control
Type of study: Non-randomized Phase II clinical trial (prospective series with self-controls)
Methods: (prostate) Patients (n=13) who had previously received surgery, cryosurgery, radiotherapy were entered into the study. Even though eight patients had previously received androgen-deprivation therapy, the PSA was continuing to rise for all patients. Because PSA had been shown to be a reliable marker of prostate cancer growth, it was proposed that any increase in the doubling time should correlate with decreased tumor growth. Modified citrus pectin was given for 12 months in daily doses of 14.4 grams in three divided doses (18 total capsules per day, each containing 800 mg). Compliance and side effects were monitored every four weeks through the trial. The investigators used a newly developed method of regression analysis to statistically evaluate PSA measurements 13 months before treatment, the 12 months during treatment and five months after the completion of treatment. Patients served as their own controls so that PSA doubling time after 12 months of daily oral doses was compared with its time before therapy for each patient.
Results: There were no serious side effects in any patient, but three patients withdrew from the study due to abdominal cramping or diarrhea. MCP was well tolerated by the remaining 10 evaluable patients. Seven (70%) of these evaluable patients had a significantly increased doubling time of PSA compared with their times before the treatment. PSA did not decrease for any patients.
12Strum S, Scholz M, McDermed J, McCulloch M, Eliaz I. Modified citrus pectin slows PSA doubling time: A Pilot Clinical Trial. International Conference on Diet and Prevention of Cancer. May 1999. Tampere, Finland.
(Abstract only)
Purpose: Disease control
Type of Study: Pilot uncontrolled clinical trial
Methods: Patients who had either relapsed from therapy or the therapy had failed to control the disease were given modified citrus pectin at a dose of 15 grams a day in 3 divided oral doses. The PSA doubling time was then calculated.
Results: PSA doubling time was lengthened by more than 30% in 4/7 (57%) of patients. One patient had a partial response, one patient had stable disease, and one patient did not respond.
Caution Concerning This Report: This report was not published in a peer-reviewed journal; that is, it was not reviewed by experts in the field to determine that there was sufficient data to support the conclusions. Although this study was presented at a conference of peers, only the abstract of that presentation has been published.
Animal Studies
13Glinskii OV, Huxley VH, Glinsky GV, Pienta KJ, et al. Mechanical entrapment is insufficient and intercellular adhesion is essential for metastatic cell arrest in distant organs. Neoplasia, 2005; 7(5):522-527.
Purpose: Mechanism for metastatic cell arrest in distant organs
Type of Animal: Hsdlcr:Ha(ICR)-scid mice; male and female
Type of Cancer: Prostate and breast
Experiment Description:
Methods: Experiment was run in duplicate. Pre-labeled breast and prostate cancer cell lines (and negative control hybridoma cells) were injected into male and female mice (depending on gender-predominant cancer cell type). Three hours post-injection the animals were euthanized, organs removed and four random fields were examined under epifluorescence microscopy and photographed.
Results: Results showed that blocking either Thomsen-Friedenreich glycoantigen (TF antigen) or b-galactoside-binding lectin galectin-3 (galectin 3) and preventing adhesion with monoclonal antibodies inhibits metastatic deposit formation in lungs and bones. Mean and standard deviation results showed anti-TF antigen (99.3 ±1.11%), anti-galectin 3 antibodies (97.5 ±2.26%), the lactulosylo-L-leucine (96.3 ±3.21%) and MCP (92.7 ± 4.88%) inhibited subpleural metastatic deposits in vivo. For prostate and breast cancer cells, 99.8 ±0.32%, 97.6 ±0.96%, 94.8 ±6.65%, 91.7 ± 7.30%, respectively.
10Chen CH, Sheu MT, Chen TF, Wang YC, et al. Suppression of endotoxin-induced proinflammatory responses by citrus pectin through blocking LPS signaling pathways. Biochemical Pharmacology, 2006;72(8):1001-1009.
Purpose: Mechanism for reduction of inflammation response
Type of Animal: BALB/c mice and macrophage cell line RAW264.7
Type of Cancer: All types (reduction of inflammation process)
Experiment Description:
Methods: Experimental mouse and macrophage cells were plated and pre-treated with three types of citrus pectins ( DE30, DE60 and DE90) and LPS (lipopolysaccharide from Escherichia coli 0127:B8) for six to 24 hours followed by a series of molecular assays (i.e., western blot analysis, RT-PCR, LPS binding) on the cells. A second set of experiments focused on DE90 pectin and the expression of iNOS (nitric oxide synthase) and COX-2 (cyclooxygenase-2) protein expression triggered by LPS.
Results: iNOS and COX-2 expression and mRNA expression were significantly inhibited by the three types of pectin (p<0.01). DE90 was the pectin that most strongly inhibited these proteins (p<0.01). Further results indicated downregulation of iNOS and COX-2 protein expression.
6Nangia-Makker P, Hogan V, Honjo Y, Baccarini S, Tait L, Bresalier R, et al. Inhibition of human cancer cell growth and metastasis in nude mice by oral intake of modified citrus pectin. J of the National Cancer Institute 2002 Dec;94(24):1854-62.
Purpose: Disease control
Type of Animal: NCR nu/nu mice
Type of Cancer: MDA-MB-435 human breast carcinoma cells
Experiment #1:
Methods: Breast carcinoma cells were injected into the mammary fat pads of two groups of 10 experimental and 10 control mice. One week prior to these injections, the experimental group of mice received MCP as a 1% part of their drinking water. After 15 weeks, the mice were killed, autopsied and examined for tumor metastases.
Results: Daily water intake was similar in both groups. All mice developed tumors, but the group that drank the water with MCP had a statistically significant reduction in tumor growth rate compared with the control mice (P = .05, Student’s t test). The number of mice with lung metastases was statistically significantly smaller in the MCP group than in the control group (0 of eight vs. six of nine, respectively).
Experiment #2:
Methods: Human colon carcinoma cells (LSLiM6 cells) were surgically implanted into the cecum of 10 experimental and 10 control nude mice. The experimental group received a 1% MCP solution in water for six weeks while the controls received plain water. All mice were then killed, primary tumors were removed and the incidence of metastasis was recorded.
Results: Daily water intake was similar in both groups. The average weight of primary tumors in the control group was 1.16 g (95% C.I. = 1.13 – 1.19) compared with average weight in the MCP group of 0.65 g (95% C.I. = 0.37 – 0.93). The average intra-abdominal weight was also greater in the control group of 2.0 g (95% C.I. = 1.94 – 2.06) vs. 0.88 g (95% CI = 0.37 – 0.93). Metastases to lymph nodes were present in 100% of the controls (nine of nine) and 25% (two of eight) of the MCP group. Metastases to the liver were present in 60% (six of 10) of control mice and 0% (0 of nine) of the MCP group. Similar results were obtained in repeat experiments.
In Vitro Experiments: In vitro experiments that demonstrated effects of MCP upon the binding of galectin-3 to endothelial cell surfaces and angiogenesis are described in this article.
7Platt D, Raz A. Modulation of the lung colonization of b16-f1 melanoma cells by citrus pectin. Journal of the National Cancer Institute 1992 Mar;84(6):438-42.
Purpose: Disease control
Type of Animal: Eight-week-old female C57BL/6 mice
Type of Cancer: B16-F1 melanoma cells
Methods: (Melanoma) Citrus pectin and modified citrus pectin were incubated with B16-F1 melanoma cells in various concentrations, and the abilities of these concentrations to affect lung colonizations were then analyzed. B16-F1 melanoma cells with and without modified citrus pectin were injected into mice and the effects upon metastatic lung colonization were then observed.
Results: The modified citrus pectin did bind to the surface of the melanoma cells; this binding was inhibited by lactose. When the B16-F1 cell line with natural citrus pectin only was intravenously injected into the mice, a significant increase of up to three-fold in the appearance of tumor colonies in the lung occurred. When pH modified citrus pectin was injected, however, there was a decrease of B16-F1 experimental metastasis (greater than 90%). The authors concluded that galactoside-binding proteins had competed with the natural ligand(s) of the tumor binding protein (gallectin) thereby affecting cellular interaction relevant for metastasis.
5Pienta KJ, Naik H, Akhtar A, Yamazaki K, Replogle TS, Lehr J, et al. Inhibition of spontaneous metastasis in a rat prostate cancer model by oral administration of modified citrus pectin. Journal of the National Cancer Institute 1995 Mar;87(5):348-53.
Purpose: Disease control
Type of Animal: Rats
Type of Cancer: Dunning rat prostate cancer MAT-LyLu cells
Methods: Researchers demonstrated the presence of galectin-3 in rat MAT-LyLu cells and human prostate carcinoma by immunoblotting and immunohistochmistry. 51Cr labeling was used to measure the ability of modified citrus pectin to inhibit the adhesion of MAT-LyLu cells to rat endothelial cells. On day 0, 106 MAT-LyLu cells were injected subcutaneously into the hind limb of male Copenhagen rats. The rats were given 0.0%, 0.01%, 0.1% or 1.0% (wt/vol) modified citrus pectin (MCP) continually via their drinking water from day 4 to day 30 when they were sacrificed. The number of MAT-LyLu tumor colonies in the lungs were then counted.
Results: Fifteen of 16 control rats had lung metastases on day 30 compared with seven of 14 rats in the 0.1% MCP group and nine of 16 rats in the 1.0% MCP group, and these reductions in lung metastases were statistically significant (p<.03 and p<.001, respectively). Further, the 1.0% modified citrus pectin treated group rats had significantly (p<.05) fewer metastatic colonies than control groups (nine colonies in the control groups compared with one colony in the treated group). It should be noted that modified citrus pectin had no effect on the growth of primary tumors.
14Hayashi A, Gillen AC, Lott JR. Effects of daily oral administration of quercetin chalcone and modified citrus pectin on implanted colon-25 tumor growth in balb-c mice. Alternative Medicine Review.5. 2000;5(6):546-52.
Purpose: Disease control
Type of Animal: Balb-c mice
Type of Cancer: Colon-25 tumors
Methods: Tumors were implanted into mice and then doses of 0.8 mg/ml or 1.6 mg/ml of modified citrus pectin were given to the mice orally on the first day that tumors could be palpated (usually the eighth day). The mice were followed until day 20.
Results: The groups given MCP had a significant reduction in the size of primary tumors compared with control mice. Low dose reduction was 38% (Standard Error of the Mean 0.37, p<0.02) and high dose reduction was 69% (Standard Error of the Mean 0.20, p<0.001). The weight of the tumors was slightly increased in the low dose group and decreased in the high dose group, but neither of these differences was significant.
Full citations are available in the Reference List.
Reference List
- Walker M. Anticancer attributes of modified citrus pectin. Townsend Letter for Doctors & Patients 1996 Aug-1996 Sep;82-5.
- Klabin Marketing I. Modified Citrus Pectin brochure.
- Raz A, Lotan R. Endogenous galactoside-binding lectins: a new class of functional tumor cell surface molecules related to metastasis. Cancer and Metastasis Reviews 1987;6:433-52.
- Anonymous. Modified citrus pectin-monograph. Alternative Medicine Review.5. 2000;5(6):573-5.
- Pienta KJ, Naik H, Akhtar A, Yamazaki K, Replogle TS, Lehr J et al. Inhibition of spontaneous metastasis in a rat prostate cancer model by oral administration of modified citrus pectin. Journal of the National Cancer Institute 1995 Mar;87(5):348-53.
- Platt D, Raz A. Modulation of the lung colonization of b16-f1 melanoma cells by citrus pectin. Journal of the National Cancer Institute 1992 Mar;84(6):438-42.
- Guess BW, Scholz MC, Strum SB, Lam RY, Johnson HJ, Jennrich RI. Modified citrus pectin (MCP) increases the prostate-specific antigen doubling time in men with prostate cancer: a phase II pilot study. Prostate Cancer and Prostatic Diseases 2003;6:301-4.
- Nangia-Makker P, Hogan V, Honjo Y, Baccarini S, Tait L, Bresalier R et al. Inhibition of human cancer cell growth and metastasis in nude mice by oral intake of modified citrus pectin. J of the National Cancer Institute 2002 Dec;94(24):1854-62.
- Fennema. Pectic Substances. Food Chemistry 1985;(2nd Ed.):123-5.
- Chauhan D, Li G, Podar K, Hideshima T et al. A novel carbohydrate-based therapeutic GCS-100 overcomes bortezomib resistance and enahances dexamethasone-induced apoptosis in multiple myeloma cells. Cancer Res 2005;65(18):8350-8.
- Chen CH, Sheu MT, Chen TF, Wang YC, Hou WC et al. Suppression of endotoxin-induced proinflammatory responses by citrus pectin through blocking LPS signaling pathways. JBCP 2006;72(8):1001-9.
- Strum S, Scholz M, McDermed J, McCulloch M, Eliaz I. Modified Citrus pectin slows PSA doubling time: A Pilot Clinical Trial. 1999, International Conference on Diet and Prevention of Cancer. Tampere, Finland.
- Glinskii O, Huxley V, Glionsky G, Pienta K, Raz A, Glinsky V. Mechanical entrapment is insufficient and intracellular adhesion is essential for metastatic cell arrest in distant organs. Neoplasia 2005;7(5):522-7.
- Linehan WM. Inhibition of prostate cancer metastasis: A critical challenge ahead. Journal of the National Cancer Institute 1995;87(5):331-2.
- Hayashi A, Gillen AC, Lott JR. Effects of daily oral administration of quercetin chalcone and modified citrus pectin on implanted colon-25 tumor growth in balb-c mice. Alternative Medicine Review.5. 2000;5(6):546-52.