Validation of citron kinase as a drug target for anti-cancer therapy
One of the hallmarks of cancer is uncontrolled cell proliferation and many cell division regulators are validated targets for the isolation
of novel chemotherapeutic drugs for the treatment of cancer pathologies (1). The family of serine/threonine kinases has become one of the most studied classes of anti-cancer drug targets and
small molecule inhibitors of mitotic kinases such as Aurora and Polo-like kinases are currently undergoing clinical trials (2). There is preliminary evidence in the literature that another
mitotic kinase, the cytokinesis regulator Citron kinase (CIT-K), could be a valid target for the treatment of liver cancer pathologies (3). Moreover, data from the Human Protein Atlas and
Oncomine databases suggests that CIT-K is overexpressed in several cancers, including breast, cervical, malignant glioma, ovarian, pancreatic, skin, thyroid and urothelial cancers. Thus there is
a need to establish if this kinase could be a target for other cancer types. The aim of this proposal is to gain further understanding of the CIT-K inhibition phenotype, disease linkage, cancer
selectivity, and potential clinical applications of CIT-K inactivation.
The objectives of our proposal are:
1. To establish whether CIT-K is misexpressed in diverse cancer cell lines and cancer tissue microarrays (TMAs).
We will generate a CIT-K monoclonal antibody and in collaboration with Dr Paul Edwards (Hutchinson-MRC Centre) will examine CIT-K expression by qPCR and Western blot in cell lines derived from breast, colon, lung and pancreatic carcinomas and compare it to normal immortalised counterparts. In collaboration with Prof Carlos Caldas (CR-UK Cambridge Research Institute) we will also analyse CIT-K expression by immunohistochemistry on TMAs containing about 1,000 invasive breast cancers along with normal breast tissue samples. In parallel, we will also analyse CIT-K expression on commercially available TMAs containing 110 cancer and 55 normal samples covering 11 cancer types: breast, colon, lung, kidney, ovarian, endometrial, stomach, prostate, melanoma, liver, and lymphoma.
2. To investigate the effect of CIT-K knockdown on the proliferation and behaviour of different cancer cell lines.
On the basis of the results obtained from objective 1, we will select a few representative cell lines for each cancer type and test the effects of CIT-K RNAi knockdown on five different processes: cell cycle, cell proliferation, cell division, cell death and ability to form colonies. Moreover, we will analyse the velocity and extent of recovery of some of these cell lines after removal of RNAi inhibition. We will also compare the toxicity of CIT-K RNAi versus knock down of another mitotic kinase, Aurora B, whose inhibitors are currently in clinical trails. Finally, we will test if CIT-K knockdown could reduce the tumourigenicity of xenografts of CIT-K-sensitive cancer cells in nude mice.
Should CIT-K be validated through these experiments, the project could then develop into a drug discovery effort in collaboration with CRT.
1. I. Perez de Castro, et al., Curr Opin Pharmacol 8, 375 (2008).
2. S. M. Lens, et al., Nat Rev Cancer 10, 825 (2010).
3. Y. Fu, et al., Mol Biol Rep, DOI 10.1007/s11033-010-0156-5 (2010).
Pharmacological properties of citrus and their ancient and medieval uses in the Mediterranean region.
Real Jardín Botánico de Madrid, Spain.
This paper reviews the pharmacological properties of Mediterranean-grown citrus species (Citrus L., Rutaceae), including citron (Citrus medica L.), lime (Citrus xauantiifolia [Christm.] Swingle), lemon (Citrus xlimon [L.] Osbeck), bitter orange (Citrus xaurantium L.) and pomelo (Citrus maxima [Burm.] Merr.), as referred to in ancient, medieval and 16th century sources. The virtues of the species reported in these texts were compared to those known to modern science. A much broader spectrum of pharmacological properties was recorded by these early writers than one might expect. The use of the citron and lemon as antidotes for 'poison and venom' is recorded in the very earliest material. According to modern scientific literature the citron and the bitter orange may possess anti-cancer activity, lime may have an immunomodulatory effect in humans, and the pomelo may be useful for treating circulatory problems. Lemons might even ease hangover symptoms. Research is required to confirm these properties.
Modified Citrus Pectin
Other common name(s): citrus pectin, Pecta-Sol®, MCP
Scientific/medical name(s): none
Modified citrus pectin (MCP) is a form of pectin that has been altered so that it can be more easily absorbed by the digestive tract. Pectin is a carbohydrate that is made of hundreds or thousands of sugar molecules chemically linked together. It is found in most plants and is particularly plentiful in the peels of apples, citrus fruits, and plums. In modified citrus pectin, the pectin has been chemically altered to break its molecules into smaller pieces. Pectin in its natural form cannot be absorbed by the body and is considered a type of soluble dietary fiber, whereas modified pectin can be absorbed into the bloodstream.
Animal studies and a couple of uncontrolled human studies have found that MCP may inhibit the spread of prostate cancer and melanoma to other organs. However, there have been no controlled clinical studies to prove this effect in humans.
How is it promoted for use?
Proponents claim that modified citrus pectin slows or stops the growth of melanoma, a dangerous form of skin cancer, and metastatic prostate cancer (prostate cancer that has spread). Some also claim that a compound found in MCP strengthens the cancer cell–killing ability of T-cells, cells that also protect against germs.
What does it involve?
Modified citrus pectin is available as a capsule or a powder. The dose suggested by manufacturers for the powder is 5 grams (nearly a fifth of an ounce) mixed with water or juice taken 3 times a day with meals. For capsules, the suggested dose is 800 milligrams (mg) 3 times a day with meals.
What is the history behind it?
Pectin is commonly used as a gelling agent for canning foods and making jellies. It is also used widely in the production of food and cosmetics and as an ingredient in some anti-diarrhea medicines. In the past 10 years, the modified form of pectin has been investigated for anti-cancer properties.
What is the evidence?
Several animal studies found that MCP helped reduce the spread of prostate, breast, and skin cancer. Animals with these types of cancer that were fed MCP had a much lower risk of the tumor spreading to the lungs. For example, one study examined the effects of MCP on lung metastases from melanoma cells. Researchers injected mice with melanoma cells. In the mice that were also given MCP, significantly fewer tumors spread to the lungs than in the mice that did not receive the drug. When lung tumors did develop in the mice treated with MCP, the tumors tended to be smaller than those that formed in untreated animals.
These studies appear to show that MCP makes it difficult for cancer cells that break off from the main tumor to join together and grow in other organs. However, in most animal studies, MCP had no effect on the main tumor, suggesting that it may only be useful for preventing or slowing the growth of metastatic tumors in very early stages of development.
Recent laboratory studies of human and animal cells have provided information on how MCP might slow the spread of cancer. MCP appears to attach to galectin-3, a common chemical in many cells. Galectin-3 is present in abnormally high levels in many cancers and plays an important role in the growth, survival, and spread of cancer cells.
Although animal and cell studies are quite encouraging, very little information is available about whether MCP is effective in humans. In one published clinical trial, 10 men with prostate cancer were treated with MCP after standard treatment failed. In 7 of these men, blood tests found prostate-specific antigen (PSA, a marker of prostate cancer growth). Their PSA doubling time (a measure of how fast PSA goes up) improved in comparison with measurements done before taking MCP, indicating that MCP may have a slowing effect on the cancer's growth. This study had no control group (in this case, a group of men who did not take MCP), which limits the strength of its conclusions on MCP's effectiveness. It also did not measure survival or other important endpoints. However, taken with the information gained from animal studies, it suggests that MCP may have a role in reducing the growth and spread of cancer. Randomized controlled trials looking at larger groups of people must be done before any firmer conclusions can be reached.
Are there any possible problems or complications?
Citrus pectin is categorized as "generally regarded as safe" by the U.S. Food and Drug Administration, When MCP is used as intended, side effects rarely occur. However, some people may experience stomach discomfort after taking MCP. There have been a few case reports in which asthma developed in people after exposure to powdered pectin. Modified citrus pectin may cause serious allergic reactions in those who are allergic to citrus fruits.
Relying on this type of treatment alone and avoiding or delaying conventional medical care for cancer may have serious health consequences.
More information from your American Cancer Society
The following information on complementary and alternative therapies may also be helpful to you. These materials may be found on our Web site (www.cancer.org) or ordered from our toll-free number (1-800-ACS-2345).
Guidelines for Using Complementary and Alternative Therapies
Dietary Supplements: How to Know What Is Safe
The ACS Operational Statement on Complementary and Alternative Methods of Cancer Management
Complementary and Alternative Methods for Cancer Management
Learning About New Ways to Treat Cancer
Learning About New Ways to Prevent Cancer
Baldwin JL, Shah AC. Pectin-induced occupational asthma. Chest. 1993; Dec; 104:1936-1937.
Cohen AJ, Forse MS, Tarlo SM. Occupational asthma caused by pectin inhalation during the manufacture of jam. Chest. 1993;103:309-311.
Ferdman RM, Ong PY, Church JA. Pectin anaphylaxis and possible association with cashew allergy. Ann Allergy Asthma Immunol. 2006; 97:759-760.
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;6:301-304.
Memorial Sloan-Kettering Cancer Center. Pectin. Accessed at: http://www.mskcc.org/mskcc/html/69327.cfm on June 10, 2008.
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;94:1854-1862.
PDRHealth. Modified Citrus Pectin. Accessed at: http://www.pdrhealth.com/drug_info/nmdrugprofiles/nutsupdrugs/mod_0175.shtml
on June 10, 2008.
PDRHealth. Pectin. Accessed at: http://www.pdrhealth.com/drug_info/nmdrugprofiles/nutsupdrugs/pec_0198.shtml on June 10, 2008.
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;87:348-353.
Platt D, Raz A. Modulation of the lung colonization of b16-f1melanoma cells by citrus pectin. J Natl Cancer Inst. 1992;84:438-442.
University of Texas M.D. Anderson Cancer Center, Complementary/Integrative Medicine Education Resources (CIMER). Modified citrus pectin. Accessed at: http://www.mdanderson.org/departments/CIMER/display.cfm?id=89391394-4477-426D-B2BE4320C6952470&method=displayFull&pn=6EB86A59-EBD9-11D4-810100508B603A14 0n June 10, 2008.
Yu LG, Andrews N, Zhao Q, et al. Galectin-3 Interaction with Thomsen-Friedenreich Disaccharide on Cancer-associated MUC1 Causes Increased Cancer Cell Endothelial Adhesion. J Biol Chem. 2007;282:773-781.
Note: This information may not cover all possible claims, uses, actions, precautions, side effects or interactions. It is not intended as medical advice, and should not be relied upon as a substitute for consultation with your doctor, who is familiar with your medical situation.
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