By Stephen B. Strum, MD, FACP
Life Extension has been at the forefront in bringing attention to important advances in medicine over the last 20 years. This month's article by Romy Fox
on modified citrus pectin (MCP) continues in this tradition. This is a thought-provoking article: a must-read. My commentary on this article focuses on MCP and its relationship to the control of cancer. For the reader to understand this aspect of MCP, it is necessary that I first discuss how MCP interacts with specific cell products called carbohydrate-binding proteins or galectins.
Two core concepts - communication and balance - are critical to the worlds of humanity and biology. Communication between healthy or normal cells is vital to their many functions and survival. What needs to be emphasized is that this is also true as it relates to the function and survival of cancer cells. It has become clear that the important strategies that work for the "healthy" cell also are vital strategies for the "enemy" or cancer cell. Cell-to-cell communication, therefore, is critical to cell survival. One key aspect of this interaction relates to the ability of tumor cells to form cohesive groups.燗s in human interactions, there is strength in numbers when it comes to cancer cells. Clusters of tumor cells are able to survive destruction by the body's immune system because immunity functions best when dealing with a low tumor burden, i.e., tiny amounts of tumor.
Specialized proteins detected within cancer cells facilitate cancer cell cohesiveness resulting in cell clumping or clustering.燭his in turn hastens the growth and spread of malignancy, as depicted in the diagrams that accompany the article. These proteins are called carbohydrate-binding proteins or lectins. Of the 14 lectins so far identified, the one that appears most important in the cancer process is galectin-3.
If we can block cancer cells from clumping together and also prevent their sticking to target sites on blood vessel walls, we can develop therapies that affect cancer production, the adhesion, migration, growth, progression, and metastasis of cancer cells, and even cancer cell death (apoptosis).1
The galectins, and especially galectin-3, are intimately involved in many, if not all, of these processes.
An in-depth review of the contemporary medical literature on galectins reveals an exciting but intricate picture. Some publications clearly indicate that increased levels of galectin-3 in the blood or in tissue are associated with the frequency of malignancy and an increased stage of tumor progression.2-14
Some of these articles are of landmark importance because they indicate impressive accuracy when galectin-3 testing is used to establish the presence of malignancy. This is clearly the case with thyroid cancer7-11,15-18
and colon cancer.4,5,17
Physicians and patients must be made aware of such highly significant developments, and commercial laboratory tests need to become available to translate these advances to the care of patients.
Additional medical research has involved the raising or lowering of galectin-3 levels in animal models of cancer. These studies have also established a correlation between higher galectin-3 levels and metastasis.19
Some controversy arises, however, from other articles that point out that just the opposite is seen with other malignancies. In such instances, lower or absent galectin-3 levels are associated with a more aggressive biological behavior of certain cancer types, and higher levels of galectin-3 with more mature (more differentiated) tumors that are less advanced in the stage of the cancer.20-22
For example, in the article by Piantelli et al, a significant correlation was found between higher galectin-3 tumor levels and longer relapse-free survival and overall survival in patients diagnosed with cancer of the larynx.23
Therefore, we must be specific in detailing the type of cancer when discussing the effects of galectin-3 levels on cancer diagnosis, tumor stage, aggressiveness, and survival.
The literature on galectin-3 becomes more exciting in light of research that now reveals multiple functions for this protein. Most of the older literature focuses on the carbohydrate-binding properties of galectin-3. The binding takes place at the end of the molecule called the C-terminal end. The other end of the molecule, called the N-terminal, end, is responsible for another important function - protecting the tumor cell from cell death or apoptosis. When a specific amino acid (serine) in the sixth position from the N-terminal end is activated, a chemical process is begun that triggers an "anti-death" chemical sequence. In this case, the cancer cell is being protected. The cellular mechanism involves protection of the cancer cell mitochondria (the powerplants for both normal and cancer cells) from damage due to oxidation by nitric oxide.25
Thus, galectin-3 works at the N-terminal end to protect the cancer cell from cell death or apoptosis caused by nitric oxide. This cell death pathway is a key mechanism in the action of radiation therapy and also some chemotherapy drugs such as cisplatin.26
To add to the excitement of such a discovery, the galectin-3 protein has also been shown to function as an on-off switch. When the N-terminal end of galectin-3 is activated, it switches off the functioning of the carbohydrate-binding end of the protein.27
When the C-terminal end of the molecule is activated, it switches off the anti-apoptosis function of the N-terminal end.28
Thus, galectin-3 is a multi-tasking protein with one "on" trigger to protect the tumor cell from death or an "off" trigger that allows tumor cells to bind together to form cohesive masses, to invade connective tissue including blood vessels, and to metastasize and grow. This is a key development in our understanding of the cancer process!
Modified citrus pectin enters the picture and ties up the C-terminal end of the protein blocking the tumor cells' ability to adhere and form cohesive masses or cancer cells. Modified citrus pectin, in studies by Strum et al and Guess et al, slowed the prostate-specific antigen (PSA) doubling time in men with prostate cancer.29,30
This could be simply due to turning off PSA production without affecting tumor cell proliferation. Other studies have shown, however, that modified citrus pectin actually decreases tumor cell growth,31
and that it is able to bind to galectin-3 and decrease cell adhesiveness, invasion, and metastasis.32-34
The central question is whether MCP, at the time it affects the functions noted above, is able to turn off the switch at the N-terminal end of the galectin-3 protein, thus weakening the tumor cell's ability to protect itself from destruction by radiation or chemotherapy. Additional studies are badly needed because of the potentially great benefit of MCP in the treatment of a multitude of malignancies. The diagnostic and staging implications for galectin-3 and other galectins and the therapeutic implications for MCP are of such magnitude as to warrant major conferences and further funding on this exciting development.
In conclusion, modified citrus pectin appears to be an important mitigating factor in cancer cell control and death.References
1. Bresalier RS, Byrd JC, Brodt P, et al. Liver metastasis and adhesion to the sinusoidal endothelium by human colon cancer cells is related to mucin carbohydrate chain length. Int J Cancer. 1998 May 18;76(4):556-62.
2. Iurisci I, Tinari N, Natoli C, Angelucci D, Cianchetti E, Iacobelli S. Concentrations of galectin-3 in the sera of normal controls and cancer patients. Clin Cancer Res. 2000 Apr;6(4):1389-93.
3. Irimura T, Matsushita Y, Sutton RC, et al. Increased content of an endogenous lactose-binding lectin in human colorectal carcinoma progressed to metastatic stages. Cancer Res. 1991 Jan 1;51(1):387-93.
4. Lotan R, Matsushita Y, Ohannesian D, et al. Lactose-binding lectin expression in human colorectal carcinomas. Relation to tumor progression. Carbohydr Res. 1991 Jun 25; 213:47-57.
5. Schoeppner HL, Raz A, Ho SB, Bresalier RS. Expression of an endogenous galactose-binding lectin correlates with neoplastic progression in the colon. Cancer. 1995 Jun 15;75(12):2818-26.
6. Lotan R, Ito H, Yasui W, Yokozaki H, Lotan D, Tahara E. Expression of a 31-kDa lactoside-binding lectin in normal human gastric mucosa and in primary and metastatic gastric carcinomas. Int J Cancer. 1994 Feb 15;56(4):474-80.
7. Xu XC, el-Naggar AK, Lotan R. Differential expression of galectin-1 and galectin-3 in thyroid tumors. Potential diagnostic implications. Am J Pathol. 1995 Sep;147(3):815-22.
8. Orlandi F, Saggiorato E, Pivano G, et al. Galectin-3 is a presurgical marker of human thyroid carcinoma. Cancer Res. 1998 Jul 15;58(14):3015-20.
9. Bartolazzi A, Gasbarri A, Papotti M, et al. Application of an immunodiagnostic method for improving preoperative diagnosis of nodular thyroid lesions. Lancet. 2001 May 26;357(9269):1644-50.
10. Papotti M, Volante M, Saggiorato E, Deandreis D, Veltri A, Orlandi F. Role of galectin-3 immunodetection in the cytological diagnosis of thyroid cystic papillary carcinoma. Eur J Endocrinol. 2002 Oct;147(4):515-21.
11. Inohara H, Honjo Y, Yoshii T, et al. Expression of galectin-3 in fine-needle aspirates as a diagnostic marker differentiating benign from malignant thyroid neoplasms. Cancer. 1999 Jun 1;85(11):2475-84.
12. Bresalier RS, Byrd JC, Wang L, Raz A. Colon cancer mucin: a new ligand for the beta-galactoside-binding protein galectin-3. Cancer Res. 1996 Oct 1;56(19):4354-7.
13. Bresalier RS, Yan PS, Byrd JC, Lotan R, Raz A. Expression of the endogenous galactose-binding protein galectin-3 correlates with the malignant potential of tumors in the central nervous system. Cancer. 1997 Aug 15;80(4):776-87.
14. Honjo Y, Inohara H, Akahani S, et al. Expression of cytoplasmic galectin-3 as a prognostic marker in tongue carcinoma. Clin Cancer Res. 2000 Dec;6(12):4635-40.
15. Bartolazzi A, Papotti M, Orlandi F. Methodological considerations regarding the use of galectin-3 expression analysis in preoperative evaluation of thyroid nodules. J Clin Endocrinol Metab. 2003 Feb;88(2):950; author reply 950-1.
16. Cvejic D, Savin S, Golubovic S, Paunovic I, Tatic S, Havelka M. Galectin-3 and carcinoembryonic antigen expression in medullary thyroid carcinoma: possible relation to tumour progression. Histopathology. 2000 Dec;37(6):530-5.
17. Miyazaki J, Hokari R, Kato S, et al. Increased expression of galectin-3 in primary gastric cancer and the metastatic lymph nodes. Oncol Rep. 2002 Nov-Dec;9(6):1307-12.
18. Saggiorato E, Cappia S, De Giuli P, et al. Galectin-3 as a presurgical immunocytodiagnostic marker of minimally invasive follicular thyroid carcinoma. J Clin Endocrinol Metab. 2001 Nov;86(11):5152-8.
19. Bresalier RS, Mazurek N, Sternberg LR, et al. Metastasis of human colon cancer is altered by modifying expression of the betagalactoside-binding protein galectin 3. Gastroenterology. 1998 Aug;115(2):287-96.
20. van den Brule FA, Buicu C, Sobel ME, Liu FT, Castronovo V. Galectin-3, a laminin binding protein, fails to modulate adhesion of human melanoma cells to laminin. Neoplasma. 1995;42(5):215-9.
21. van den Brule FA, Price J, Sobel ME, Lambotte R, Castronovo V. Inverse expres- sion of two laminin binding proteins, 67LR and galectin-3, correlates with the invasive phenotype of trophoblastic tissue. Biochem Biophys Res Commun. 1994 May 30;201(1):388-93.
22. van den Brule FA, Berchuck A, Bast RC, et al. Differential expression of the 67-kD laminin receptor and 31-kD human laminin-binding protein in human ovarian carcinomas. Eur J Cancer. 1994;30A(8):1096-9.
23. Piantelli M, Iacobelli S, Almadori G, et al. Lack of expression of galectin-3 is associated with a poor outcome in node-negative patients with laryngeal squamous-cell carcinoma. J Clin Oncol. 2002 Sep 15;20(18):3850-6.
24. van den Brule FA, Waltregny D, Liu FT, Castronovo V. Alteration of the cytoplasmic/nuclear expression pattern of galectin-3 correlates with prostate carcinoma progression. Int J Cancer. 2000 Jul 20;89(4):361-7.
25. Moon BK, Lee YJ, Battle P, Jessup JM, Raz A, Kim HR. Galectin-3 protects human breast carcinoma cells against nitric oxide- induced apoptosis: implication of galectin-3 function during metastasis. Am J Pathol. 2001 Sep;159(3):1055-60.
26. Akahani S, Nangia-Makker P, Inohara H, Kim HR, Raz A. Galectin-3: a novel anti-apoptotic molecule with a functional BH1 (NWGR) domain of Bcl-2 family. Cancer Res. 1997 Dec 1;57(23):5272-6.
27. Mazurek N, Conklin J, Byrd JC, Raz A, Bresalier RS. Phosphorylation of the beta-galactoside-binding protein galectin-3 modulates binding to its ligands. J Biol Chem. 2000 Nov 17;275(46):36311-5.
28. Yoshii T, Fukumori T, Honjo Y, Inohara H, Kim HR, Raz A. Galectin-3 phosphorylation is required for its anti-apoptotic function and cell cycle arrest. J Biol Chem. 2002 Mar 1;277(9):6852-7. Epub 2001 Nov 27.
29. Strum SB, Scholz M, McDermed J, McCulloch M, Eliaz I. Modified citrus pectin slows PSA doubling time: a pilot clinical trial. Paper presented at: International Conference on Diet and Prevention of Cancer; May 1999; Tampere, Finland.
30. Guess BW, Scholz MC, Strum SB, Lam RY, Johnson HJ, Jenrich 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):301-4.
31. Hayashi A, Gillen AC, Lott JR. Effects of daily oral administration of quercetin chalcone and modified citrus pectin. Altern Med Rev. 2000 Dec;5(6):546-52.
32. Inohara H, Raz A. Effects of natural complex carbohydrate (citrus pectin) on murine melanoma cell properties related to galectin-3 functions. Glycoconj J. 1994 Dec;11(6):527-32.
33. Nangia-Makker P, Hogan V, Honjo Y, et al. Inhibition of human cancer cell growth and metastasis in nude mice by oral intake of modified citrus pectin. J Natl Cancer Inst. 2002 Dec 18;94(24):1854-62.
34. Pienta KJ, Naik H, Akhtar A, et al. Inhibition of spontaneous metastasis in a rat prostate cancer model by oral administration of modified citrus pectin. J Natl Cancer Inst. 1995 Mar 1;87(5):348-53.