Demystifying Modified Citrus Pectin: What Is the Evidence?

by Christopher Moulton, PhD

Pectin is a complex and heterogeneous aggregation of polysaccharides first isolated from plant matter in 1825 by French chemist and pharmacist Henri Bracconot.¹ Pectin is the major constituent of all plant primary cell walls, contributing to the plant’s structural integrity and providing a barrier to the external environment. Consequently, pectin is a component of all omnivorous diets.

Pectin is known to be a soluble, prebiotic fiber that bypasses human digestion in the small intestine, but is readily metabolized by microbes in the large intestine, stimulating growth of bacteria that promote colonic health such as Bifidobacteria and Lactobacillus.² Furthermore, consumption of pectin is associated with benefits for cholesterol and lipid metabolism, glycemic regulation, and alleviation of dumping syndrome.³

As a water-soluble fiber, home cooks and food scientists have long utilized cooked pectin as a gelling and thickening agent for making jellies and other foods. Modified citrus pectin is typically derived from the pectin-rich peel and pith of citrus fruits (like lemons, limes, and oranges), which is subsequently denatured by heat and/or pH changes. This process aims to generate smaller fragments of the pectin polymer that could potentially be absorbed in the small intestine.⁴

Modified citrus pectin has been considered for potential therapeutic benefits such as heavy metal binding⁵ and particularly for prevention of cancer development or metastasis.⁶ Its origins arise from a theoretical model in which a monosaccharide, galactose, was found to suppress metastasis in cell culture experiments and correspondingly that pectin is a galactose-containing polysaccharide.⁷ In a single-arm trial in men with treatment-resistant prostate cancer, administration of modified citrus pectin for 12 months resulted in an increase in prostate-specific antigen (PSA) doubling time (i.e., slower rise in the PSA biomarker) in 7 of 10 patients,⁸ suggesting that these patients may have been at reduced risk for metastatic progression.⁹ In a separate study, 49 patients with a wide array of advanced solid tumors were given modified citrus pectin for 16 weeks. After treatment, 22% of the treated patients had stable disease as measured by Response Evaluation Criteria In Solid Tumors (RECIST), and 12% of treated patients had stable disease for an additional 8 weeks following treatment.¹⁰ To date, these are the only published trials demonstrating any clinical benefit for cancer patients.

In vitro and rodent model experiments suggest that modified citrus pectin conveys various antitumorigenic and antimetastatic properties, but the results are not universally consistent.¹¹ This may be due to process variations in the production of modified citrus pectin (e.g., variable heat or pH conditions) or the heterogeneous composition of the pectin starting material. One study noted that only heat-treated pectin powder induced apoptosis in human prostate cancer cells, while pH-modified pectin powder had no apoptotic activity.¹² Considering the low-pH environment of the stomach, it is unclear if acidification during digestion affects the in vivo pro-apoptotic potential of heat-treated modified citrus pectin. A related study showed that, due to inherent pectinolytic enzymes, pectin from papaya variably inhibits cancer cell proliferation, depending on the ripeness of the fruit.¹³

It has been proposed that modified citrus pectin confers health benefits through interactions with a class of carbohydrate-binding lectins known as galectins. These are a conserved family of proteins that mediate a wide array of intracellular and extracellular processes including development, differentiation, and communication. Galectins display a high degree of specificity for binding of specific carbohydrate ligands, and they are involved in a wide array of functions such as neovascularization, inflammation, and regulation of immune cell activity.¹⁴ Since pectin is a polymer of heterogeneous polysaccharides, it is feasible that pectin fragments or degradation products could inhibit galectins via glycan-binding domains. Recent cell culture studies suggest that such interactions may occur, specifically with galectin-3.^15,16

However, biochemical analysis revealed that numerous commercially available and laboratory-produced modified citrus pectins fail to bind strongly to the family of galectins, making it unlikely that modified citrus pectins directly inhibit galectin activity in vivo .¹⁷ In vitro experiments demonstrated that citrus pectin fragmented by heat in a laboratory setting can induce apoptosis in human liver and lung carcinoma cells.¹⁸ 4,5-dihydroxy-2-cyclopenten-1-one was identified as a cytotoxic molecule that mediated the effect; additionally, as an experimental control heat-modified galactouronic acid (the primary monosaccharide comprising pectin) also yielded this molecule and equally induced apoptosis.¹⁹ This suggests that the effect may not be unique to modified citrus pectin per se, but rather it may be conferred by heat treatment of any source of galactouronic acid. It is not yet known to what extent 4,5-dihydroxy-2-cyclopenten-1-one is cytotoxic to other cancer or noncancer cell types, and further it is unclear if commercial preparations of modified citrus pectin contain this molecule.

Until a credible mechanism of action is firmly established, and until clinical efficacy is more thoroughly demonstrated in additional trials, perhaps caution is warranted regarding the therapeutic utility of modified citrus pectin. However, due to its favorable effects on gastrointestinal and metabolic health, regular consumption of native pectin from citrus and other foods such as apples, pears, and plums should be encouraged for most individuals.³

References

1. Annales de Chimie et de Physique. 1825.
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4. May CD. Industrial pectins: sources, production and applications. Carbohydrate Polymers. 1990;12(1):79-99.
5. Eliaz I, Hotchkiss AT, Fishman ML, Rode D. The effect of modified citrus pectin on urinary excretion of toxic elements. Phytother Res. 2006;20(10):859-864.
6. Glinsky VV, Raz A. Modified citrus pectin anti-metastatic properties: one bullet, multiple targets. Carbohydr Res. 2009;344(14):1788-1791.
7. Platt D, Raz A. Modulation of the lung colonization of B16-F1 melanoma cells by citrus pectin. J Natl Cancer Inst. 1992;84(6):438-442.
8. 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 Prostatic Dis. 2003;6(4):301-304.
9. Roberts SG, Blute ML, Bergstralh EJ, Slezak JM, Zincke H. PSA doubling time as a predictor of clinical progression after biochemical failure following radical prostatectomy for prostate cancer. Mayo Clinic Proceedings. 2001;76(6):576-581.
10. Azémar M, Hildenbrand B, Haering B, Heim ME, Unger C. Clinical benefit in patients with advanced solid tumors treated with modified citrus pectin: a prospective pilot study. Clinical Medicine Oncology. 2007;1:CMO.S285.
11. Leclere L, Cutsem PV, Michiels C. Anti-cancer activities of pH- or heat-modified pectin. Front Pharmacol. 2013;4.
12. Jackson CL, Dreaden TM, Theobald LK, et al. Pectin induces apoptosis in human prostate cancer cells: correlation of apoptotic function with pectin structure. Glycobiology. 2007;17(8):805-819.
13. Prado SBR do, Ferreira GF, Harazono Y, et al. Ripening-induced chemical modifications of papaya pectin inhibit cancer cell proliferation. Sci Rep. 2017;7(1):16564.
14. Di Lella S, Sundblad V, Cerliani JP, et al. When galectins recognize glycans: from biochemistry to physiology and back again. Biochemistry. 2011;50(37):7842-7857.
15. Gao X, Zhi Y, Zhang T, et al. Analysis of the neutral polysaccharide fraction of MCP and its inhibitory activity on galectin-3. Glycoconj J. 2012;29(4):159-165.
16. Lu Y, Zhang M, Zhao P, et al. Modified citrus pectin inhibits galectin-3 function to reduce atherosclerotic lesions in apoE-deficient mice. Mol Med Rep. 2017;16(1):647-653.
17. Stegmayr J, Lepur A, Kahl-Knutson B, et al. Low or no inhibitory potency of the canonical galectin carbohydrate-binding site by pectins and galactomannans. J Biol Chem. 2016;291(25):13318-13334.
18. Leclere L, Fransolet M, Cote F, et al. Heat-modified citrus pectin induces apoptosis-like cell death and autophagy in HepG2 and A549 cancer cells. PLoS One. 2015;10(3).
19. Leclere L, Fransolet M, Cambier P, et al. Identification of a cytotoxic molecule in heat-modified citrus pectin. Carbohydr Polym. 2016;137:39-51.

Christopher Moulton, PhD

Dr. Moulton endeavors to develop innovative, science-based solutions for practitioners to improve and enhance the well-being of their patients. Relatedly, he engages with the scientific & medical communities to better understand the potential of personalized nutrition to advance health care. Dr. Moulton completed a PhD in Nutritional Sciences at the University of Illinois in Urbana-Champaign. He also holds a Master’s degree in Exercise Physiology and a Bachelor’s degree in Biochemistry. Prior to joining Metagenics, Dr. Moulton managed the Center for Nutrition, Learning, & Memory, a public-private partnership focused at the intersection of nutrition & neuroscience.