Application of curcumin in gastroenterology

Curcumin is the most active ingredient in turmeric and has been described as a substance with anti-inflammatory, antioxidant, immunomodulatory, pro-apoptotic and anti-proliferative effects (1,2).

The potential clinical effects of curcumin arise from various in vitro studija, studija na animalnim modelima, a tijekom posljednjih desetak godina provodi se sve više kliničkih istraživanja u različitim indikacijama – od tegoba iz spektra dispepsije i infekcije H. pylori, preko upalnih bolesti crijeva do karcinoma kolorektuma i pankreasa.

Due to its strong anti-inflammatory and antineoplastic properties, curcumin is often used and researched independently or as a supportive therapy in addition to standard therapies.The early stages of research indicated pharmacological properties, and studies systematically show a good safety profile, harmlessness and easy tolerance during application (3).

Mechanisms of action in inflammatory and malignant diseases

Kurkumin djeluje na višestruke terapijske mete u sklopu kaskade upalnih reakcija i njihovih signalnih puteva (Slika 1.).  Poznato je da inactivates NF-kB (4) – važan faktor transkripcije koji regulira staničnu aktivnost, posebice kada je riječ o stresu i ozljedi te je stoga ključan kod upalnog i imunosnog odgovora. Čini se da je aktivacija NF-kB ključna u odnosu između kronične upale i razvoju karcinoma, što je pokazano na mišjem modelu karcinoma izazvanog kolitisom gdje je delecija IkB iz epitelnih stanica rezultirala povećanom apoptozom i smanjenjem incidencije tumora.

In vitro studije pokazuju da se inaktivacija NF-kB djelovanjem kurkumina vjerojatno zbiva putem različitih mehanizama, uključujući slabljenje IkB uz inhibiciju TNF-ovisne IkBα fosforilacije i degradacije (5). Nadalje, kurkumin inhibira IkB kinazu – bilo izravno ili inhibicijom TNF [6]. Inaktivacija NF-kB vodi smanjenoj ekspresiji cikolooksigenaze-2 (COX-2), slabljenju djelovanja citokina (TNF-α, IL) te kemokina. NF-kB je temeljna molekula važna za rast stanice, diferencijaciju i proliferaciju i „glavni igrač“ u karcinogenezi. Kurkumin inhibira stvaranje TNF-α i dušičnog oksida (NO) in vivo i posljedično smanjuje oštećenja tkiva (7). Obećavajući klinički ishodi koji su vidljivi iz životinjskih modela gdje je kurkumin primjenjivan kod upalnih bolesti crijeva, do sada su u pravilu potvrđeni i ranim rezultatima kliničkih istraživanja (8-11).

Poznato je da kod malignih bolesti dolazi do disregulacije brojnih metaboličkih puteva. Kurkumin može modulirati brojne stanične puteve koji su uključeni u karcinogenezu te se tako ponaša kao biološki aktivni spoj s višestrukim terapijskim metama. Mogućnost utjecaja na različite puteve proširuje terapijske opcije i može smanjiti razvoj rezistencije koja se javlja kada se signalizacija događa alternativnim putevima. Glavnina dokaza o mehanizmu antikarcinogenog djelovanja kurkumina potječe iz in vitro and in vivo studija o adenokarcinomu kolorektuma. Čini se da kurkumin ulazi u interakciju sa svim ključnim putevima vezanim uz sekvencu adenom-adenokarcinom, uključujući APC, TP53, KRAS and c-Myc.

In vivo dokazi ukazuju da kurkumin može prevenirati napredovanje bolesti modulacijom staničnih mehanizama uključenih u proliferaciju, angiogenezu i metastaziranje (12).

Inflammatory bowel diseases

Turmeric root has been used in India for centuries to treat inflammatory disorders (2). Today we know that the pleiotropic effects of curcumin are largely based on the inhibition of the transcription factor NF-κB. Furthermore, curcumin affects both the innate and acquired immune response, and due to these diverse effects, it has been repeatedly investigated in numerous studies on animal models and patients suffering from inflammatory bowel diseases, especially ulcerative colitis.

Although the results of human research are not consistent, there are studies that indicate that curcumin is effective in maintaining remission in patients with mild to moderate ulcerative colitis. Also, a less randomized, double-blind clinical study showed that the addition of curcumin to mesalamine therapy more effectively induced patients into clinical and endoscopic remission compared to placebo in combination with mesalamine (13).

Gastritis i infekcija Helicobacter pylori

Tijekom posljednjih godina velik je interes za različitim biljnim pripravcima koji imaju antibakterijski učinak na Helicobacter pylori, a sve se češće u tu svrhu u literaturi spominje kurkumin. Osim antibakterijskog djelovanja, kurkumin ima sposobnost narušavanja biofilma što ukazuje na višestruke uloge u inhibiciji infekcije Helicobacter pylori (14). Nadalje, provedena su istraživanja koja ukazuju na korist primjene kurkumina usporedno s trojnom eradikacijskom terapijom. Primjena te prirodne supstance ima široki spektar djelovanja jer smanjuje kroničnu upalu i prevenira karcinogene promjene u bolesnika s kroničnim gastritisom povezanim s infekcijom H. pylori (15).

Colon cancer

Brojni in vitro i pretklinički dokazi podupiru primjenu kurkumina u spektru neoplazmi kolona. Postoje studije u kojima je kurkumin korišten u kombinaciji sa standardnom kemoterapijom kod karcinoma kolorektuma s pozitivnim učincima. U istraživanjima provedenim na pacijentima s karcinomom kolona, kurkumin je korišten u dozama od 360 mg do 8 g u trajanju od nekoliko tjedana do nekoliko mjeseci.

Other areas of application

Curcumin has been used alone or in combination with gemcitabine in patients with advanced pancreatic cancer. These studies indicated the long-term tolerability of curcumin with advanced malignancy during the administration of potentially toxic chemotherapy. It has also been shown that curcumin can modulate metabolic pathways in the formation of gallstones, and its effectiveness is being investigated in irritable bowel syndrome, hepatitis, pancreatitis and familial adenomatous polyposis (FAP) (3).

What can we conclude?

• Curcumin is a plant compound with multiple beneficial effects in gastrointestinal diseases.
• The safety and harmlessness of the use of curcumin has been investigated by numerous preclinical and clinical studies.
• It is safe and effective for use in addition to standard drug therapy
• When choosing a preparation, it is necessary to give preference to formulations with more effective absorption, since the weak absorption of the native form of curcumin limits the therapeutic effectiveness.

Author: Prof. Dr.Sc. Darija Vranešić Bender, clinical nutritionist

Literature:

1. Ammon HP, Wahl MA. Pharmacology of Curcuma longa. Planta Med 1991; 57: 1-7 [PMID: 2062949 DOI: 10.1055/s-2006-960004]

2. Jain SK. Ethnobotany and research on medicinal plants in India. Ciba Found Symp 1994; 185: 153-164; discussion 164-168 [PMID:7736852]

3. Irving GR, Karmokar A, Berry DP, Brown K, Steward WP. Curcumin: The potential for efficacy in gastrointestinal diseases Best Practice & Research Clinical Gastroenterology 25 (2011) 519–534

4. Joe B, Vijaykumar M, Lokesh BR. Biological properties of curofcumin-cellular and molecular mechanisms of action. Crit Rev Food Sci Nutr 2004; 44: 97-111 [PMID: 15116757 DOI: 10.1080/10408690490424702]

5. Salh B, Assi K, Templeman V, Parhar K, Owen D, Gómez-Muñoz A,Jacobson K. Curcumin attenuates DNB-induced murine colitis. Am J Physiol Gastrointest Liver Physiol 2003; 285: G235-G243 [PMID:12637253 DOI: 10.1152/ajpgi.00449.2002]

6. Aggarwal S, Ichikawa H, Takada Y, Sandur SK, Shishodia S, Aggarwal BB. Curcumin (diferuloylmethane) down-regulates expression of cell proliferation and antiapoptotic and metastatic gene products through suppression of IkappaBalphakinase and Akt activation. Mol Pharmacol 2006;69(1):195–206.

7. Sharma S, Kulkarni SK, Agrewala JN, Chopra K. Curcumin attenuates thermal hyperalgesia in a diabetic mouse model of neuropathic pain. Eur J Pharmacol 2006 1;536(3):256–61.

8. Holt PR, Katz S, Kirshoff R. Curcumin therapy in inflammatory bowel disease: a pilot study. Dig Dis Sci 2005 Nov;50(11):2191–3.

9. Billerey-Larmonier C, Uno JK, Larmonier N, Midura AJ, Timmermann B, Ghishan FK, et al.Protective effects of dietary curcumin in mouse model of chemically induced colitis are strain dependent. Inflamm Bowel Dis 2008 Jun;14(6):780–93.

10. Hanai H, Iida T, Takeuchi K, Watanabe F, Maruyama Y, Andoh A, et al. Curcumin maintenance therapy for ulcerative colitis: randomized, multicenter, double-blind, placebo-controlled trial. Clin Gastroenterol Hepatol 2006 Dec;4(12):1502–6.

11. Larmonier CB, Midura-Kiela MT, Ramalingam R, Laubitz D, Janikashvili N, Larmonier N, et al. Modulation of neutrophil motility by curcumin: implications for inflammatory bowel disease. Inflamm Bowel Dis 2011 Feb;17(2):503–15.

12. Li L, Braiteh FS, Kurzrock R. Liposome-encapsulated curcumin: in vitro and in vivo effects on proliferation, apoptosis, signaling, and angiogenesis. Cancer 2005 Sep 15;104(6):1322–31.

13.Lang A, Salomon N, Wu JC, Kopylov U, Lahat A, Har-Noy O, Ching JY, Cheong PK, Avidan B, Gamus D, Kaimakliotis I, Eliakim R, Ng SC, Ben-Horin S. Curcumin in Combination With Mesalamine Induces Remission in Patients With Mild-to-Moderate Ulcerative Colitis in a Randomized Controlled Trial. Clin Gastroenterol Hepatol. 2015;13(8):1444-9.e1.

14. Vetvicka V, Vetvickova J, Fernandez-Botran R. Effects of curcumin on Helicobacter pylori infection.Ann Transl Med. 2016 Dec;4(24):479. doi: 10.21037/atm.2016.12.52.

15. Judaki A, Rahmani A, Feizi J, Asadollahi K, Hafezi Ahmadi MR. Curcumin in combination with triple therapy regimes ameliorates oxidative stress and histopathologic changes in chronic gastritis–associated Helicobacter pylori infection. Arq Gastroenterol. 2017 May 8:0. doi: 10.1590/S0004-2803.201700000-18.

16. McFadden RM, Larmonier CB, Shehab KW, Midura-Kiela M, Ramalingam R, Harrison CA, Besselsen DG, Chase JH, Caporaso JG, Jobin C, Ghishan FK, Kiela PR. The Role of Curcumin in Modulating Colonic Microbiota During Colitis and Colon Cancer Prevention. Inflamm Bowel Dis. 2015;21(11):2483-94.

17. Shen L, Liu L, Ji HF. Regulatory effects of curcumin spice administration on gut microbiota and its pharmacological implications. Food Nutr Res. 2017 Aug 9;61(1):1361780. doi: 10.1080/16546628.2017.1361780.

18. Schiborr C, Kocher A, Behnam D, Jandasek J, Toelstede S, Frank J. The oral bioavailability of curcumin from micronized powder and liquid micelles is significantly increased in healthy humans and differs between sexes. Mol Nutr Food Res. 2014;58(3):516-27.