Orlistat and Hydroxycitrate Ameliorate Colon Cancer in Rats: The Impact of Inflammatory Mediators

Hesham Fathy Hassan Hassan¹, Ahmed Mohamed Mansour¹ and El-Sayed Mohamed El-Sayed^1,

¹Pharmacology and Toxicology Department, Faculty of Pharmacy, Al-Azhar University, Cairo (Boys), Egypt

Cite this paper:
Hesham Fathy Hassan Hassan, Ahmed Mohamed Mansour and El-Sayed Mohamed El-Sayed. Orlistat and Hydroxycitrate Ameliorate Colon Cancer in Rats: The Impact of Inflammatory Mediators. Journal of Food and Nutrition Research. 2022; 10(1):41-49. doi: 10.12691/jfnr-10-1-6

Abstract

Colon cancer (CC) is the third type of cancer worldwide. This study aimed to investigate the possible protective effects of orlistat and hydroxycitrate (HCA) against dimethylhydrazine (DMH) and high-fat diet (HFD)-induced CC in adult male rats. The rats were divided into ten groups including the normal group. The rats were treated with the DMH/HFD, orlistat (32 mg/kg), orlistat/DMH, orlistat/DMH/HFD, HCA (135 mg/kg), HCA/DMH, HCA/DMH/HFD, DMH (40 mg/kg), and HFD (20%) for 16 weeks. Administration of orlistat and HCA improved the measured markers of a colon tumor, inflammatory mediators, oxidative stress, as well as caspase-3 (an apoptotic marker) in the colon tissue compared with the CC group. Furthermore, orlistat and HCA corrected the histopathological lesions in the colon lining. These findings revealed that orlistat and HCA had a positive chemopreventive efficacy and could be viewed as a possible clinical solution for colon cancer.

Keywords:
colon cancer orlistat; hydroxycitrate high-fat diet dimethylhydrazine

This work is licensed under a Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

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References:

[1]	F. Bray, J. Ferlay, I. Soerjomataram, R.L. Siegel, L.A. Torre, A. Jemal, Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries, CA Cancer J. Clin. 68 (2018) 394-424.
[2]	E. Abdalla, T. Bauer, Y. Chun, M. D’Angelica, D. Kooby, W. Jarnagin, Locoregional surgical and interventional therapies for advanced colorectal cancer liver metastases: expert consensus statements, HPB Surg. 15 (2013) 119-130.
[3]	A. Chan, E. Giovannucci, Primary prevention of colorectal cancer, Gastroenterology 138 (2010) 2029-2043.
[4]	R. MacDonald, K. Wagner, Influence of dietary phytochemicals and microbiota on colon cancer risk, J. Agric. Food Chem. 60 (2012) 6728-6735.
[5]	Y. Ma, Y. Yang, F. Wang, P. Zhang, C. Shi, Y. Zou, H. Qin, Obesity and risk of colorectal cancer: A systematic review of prospective studies, Plos One. 8 (2013): article e53916: 16 pages.
[6]	M. Saini, P. Sharma, J. Kaur, S. Sanyal, The cyclooxygenase-2 inhibitor etoricoxib is a potent chemopreventive agent of colon carcinogenesis in the rat model, J. Environ. Pathol. Toxicol. Oncol. 28 (2009) 39-46.
[7]	J. Weisburger, Colon carcinogens: their metabolism and mode of action, Cancer 28 (1971) 60-70.
[8]	E. Fiala, Investigations into the metabolism and mode of action of the colon carcinogens 1, 2-dimethylhydrazine and azoxymethane, Cancer 40 (1977) 2436-2445.
[9]	A. Pommier, J. Pons, P. Kocienski, The first total synthesis of (-)-lipstatin. J Org Chem 60 (1995)7334-7339.
[10]	P. Yang, K. Liu, M. Ngai, M. Lear, M. Wenk, S. Yao, Activity-based proteome profiling of potential cellular targets of Orlistat an FDA-approved drug with anti-tumor activities, J Am Chem Soc 132(2010) 656-666.
[11]	T. Yamada, H. Hida, Y. Yamada, Chemistry, physiological properties, and microbial production of hydroxycitric acid, Appl Microbiol Biotechnol 75 (2007) 977-982.
[12]	R. Raina, D. Mondhe, J. Malik, R. Gupta, Garcinia cambogia, In Nutraceuticals (2016) 669-680, Academic Press.
[13]	V. Catalán, J. Gómez-Ambrosi, A. Rodríguez, B. Ramírez, M. Izaguirre, J. Hernández-Lizoain, J. Baixauli, P. Martí, V. Valentí, R. Moncada, Increased obesity-associated circulating levels of the extracellular matrix proteins osteopontin, chitinase-3 like-1 and tenascin C are associated with colon cancer. PLoS One 11 (2016) e0162189.
[14]	J. Choi, S. Bae, J. Hong, T. Azam, C. Dinarello, E. Her, W. Choi, B. Kim, C. Lee, D. Yoon, et al., Identification of the most active interleukin-32 isoform, Immunology 126 (2009) 535-542.
[15]	National Research Council (US) Committee for the Update of the Guide for the Care and Use of Laboratory Animals (2011) Guide for the Care and Use of Laboratory Animals, eighth edition, Washington, D.C: National Academy Press (US).
[16]	M. Drent, I. Larsson, T. William-Olsson, F. Quaade, F. Czubayko, K. Von Bergmann, W. Strobel, L. Sjöström, E. Van der Veen, Orlistat (Ro 18-0647), a lipase inhibitor, in the treatment of human obesity: a multiple dose study, Int J Obes Relat Metab Disord 19 (1995) 221.
[17]	S. Heymsfield, D. Allison, J. Vasselli, A. Pietrobelli, D. Greenfield, C. Nunez, Garcinia cambogia (hydroxycitric acid) as a potential antiobesity agent: a randomized controlled trial, JAMA 280 (1998) 1596-1600.
[18]	G. Paget, J. Barnes, Interspecies dosage conversion scheme in evaluation of results and quantitative application in different species, Evaluation of drug activities: Pharmacometrics 1 (1964) 160-162.
[19]	E. Engvall, P. Perlmann, Enzyme-linked immunosorbent assay (ELISA) quantitative assay of immunoglobulin G, Immunochemistry 8 (1971) 871-874.
[20]	J. Bancroft, M. Gamble, Theory and practice of histological techniques (2008); Elsevier health sciences.
[21]	H. Zeng, D. Lazarova, Obesity-related colon cancer: dietary factors and their mechanisms of anticancer action, Clin. Exp. Pharmacol. Physiol. 39 (2012) 161-167.
[22]	S. Kawanishi, K. Yamamoto, Mechanism of site-specific DNA damage induced by methylhydrazines in the presence of copper (II) or manganese (III), Biochemistry 30 (1991) 3069-3075.
[23]	B. Pence, Dietary selenium and antioxidant status: toxic effects of 1, 2-dimethylhydrazine in rats, J. Nutr. 121 (1991) 138-144.
[24]	C. Rao, Nitric oxide signaling in colon cancer chemoprevention, Mutat. Res. 555 (2004) 107-119.
[25]	L. Hofseth, S. Hussain, G. Wogan, C. Harris, Nitric oxide in cancer and chemoprevention, Free Radic. Biol. Med. 34 (2003) 955-968.
[26]	D. Shitrit, B. Zingerman, A. Shitrit, D. Shlomi, M. Kramer, Diagnostic value of CYFRA 21-1, CEA, CA 19-9, CA 15-3, and CA 125 assays in pleural effusions: analysis of 116 cases and review of the literature, Oncologist 10 (2005) 501-507.
[27]	Y. Ogata, H. Murakami, T. Sasatomi, N. Ishibashi, S. Mori, M. Ushijima, Y. Akagi, K. Shirouzu, Elevated preoperative serum carcinoembrionic antigen level may be an effective indicator for needing adjuvant chemotherapy after potentially curative resection of stage II colon cancer, J. Surg. Oncol. 99 (2009) 65–70.
[28]	M. Shibutani, K. Maeda, H. Nagahara, H. Ohtani, K. Sakurai, T. Toyokawa, N. Kubo, H. Tanaka, K. Muguruma, M. Ohira, K. Hirakawa, Significance of CEA and CA19-9 combination as a prognostic indicator and for recurrence monitoring in patients with stage II colorectal cancer, Anticancer Res. 34 (2014) 3753-3758.
[29]	G. Verazin, W. Riley, J. Gregory, C. Tautu, J. Prorok, J. Alhadeff, Serum sialic acid and carcinoembryonic levels in the detection and monitoring of colorectal cancer, Dis. Colon Rectum 33 (1990) 139-142.
[30]	M. Hara, M. Sato, H. Takahashi, S. Takayama, H. Takeyama, Accuracy of monitoring serum carcinoembryonic antigen levels in postoperative stage III colorectal cancer patients is limited to only the first postoperative year, Surg. Today 41 (2011) 1357.
[31]	R. Muthu, M. Vaiyapuri, Synergistic and individual effects of umbelliferone with 5- fluorouracil on tumor markers and antioxidant status of rat treated with 1, 2- dimethylhydrazine, Biomed. Aging Pathol. 3 (2013) 219-227.
[32]	A. Guais, G. Baronzio, E. Sanders, F. Campion, C. Mainini, G. Fiorentini, F. Montagnani, M. Behzadi, L. Schwartz, M. Abolhassani, Adding a combination of hydroxycitrate and lipoic acid (METABLOC™) to chemotherapy improves effectiveness against tumor development: experimental results and case report, Invest New Drugs 30 (2012) 200-211.
[33]	D. Lazarus, S. Al-Busafi, N. Hilzenrat, Chylous ascites secondary to giant liver hemangioma, Case Rep. Gastroenterol 6 (2012) 478-483.
[34]	H. Phung, H. Lee, S. Lee, D. Jang, C. Kim, K. Kang, C. Seo, Y. Choi, Analysis and anticancer effects of active compounds from Spatholobi caulis in human breast cancer cells, Processes 8 (2020) 1193.
[35]	H. Hassan, A. Mansour, A. Abo‐Youssef, B. Elsadek, B. Messiha, Zinc oxide nanoparticles as a novel anticancer approach; in vitro and in vivo evidence, Clin Exper Pharmacol Physiol 44(2017) 235-243.
[36]	P. Termuhlen, B. Sweeney-Gotsch, R. Berman, L. Ellis, C. Bucana, Y. Shen, K. Cleary, D. McConkey, Increased apoptosis in metastatic human colonic adenocarcinomas. Cancer Biol Ther, 1(2002)58-63.
[37]	Y. Yamamoto, R. Gaynor, Therapeutic potential of inhibition of the NF-κB pathway in the treatment of inflammation and cancer, J. Clin. Invest. 107 (2001) 135-142.
[38]	H. Shen, V. Tergaonkar, NFκB signaling in carcinogenesis and as a potential molecular target for cancer therapy, Apoptosis 14(2009) 348-363.
[39]	E. Pikarsky, R. Porat, I. Stein, R. Abramovitch, S. Amit, S. Kasem, E. Gutkovich- Pyest, S. Urieli-Shoval, E. Galun, Y. Ben-Neriah, NF-κB functions as a tumour promoter in inflammation-associated cancer, Nature 431 (2004) 461-466.
[40]	S. Lee, K. Lim, Chemopreventive effect of plant originated glycoprotein on colitis-mediated colorectal cancer in A/J mice, J. Biomed. Sci. 15 (2008) 111-121.
[41]	A. Azzolina, A. Bongiovanni, N. Lampiasi, Substance P induces TNF-α and IL-6 production through NFκB in peritoneal mast cells, Biochim. Biophys. Acta 1643 (2003) 75-83.
[42]	W. Van Grevenstein, L. Hofland, M. Van Rossen, P. Van Koetsveld, J. Jeekel, C. Van Eijck, Inflammatory cytokines stimulate the adhesion of colon carcinoma cells to mesothelial monolayers, Dig. Dis. Sci. 52 (2007) 2775-2783.
[43]	D. Liang, F. Li, Y. Fu, Y. Cao, X. Song, T. Wang, W. Wang, M. Guo, E. Zhou, D. Li, Z. Yang, Thymol inhibits LPS-stimulated inflammatory response via down-regulation of NF-κB and MAPK signaling pathways in mouse mammary epithelial cells, Inflammation 37 (2014) 214-222.
[44]	E. Skrzydlewska, S. Sulkowski, M. Koda, B. Zalewski, L. Kanczuga-Koda, M. Sulkowska, Lipid peroxidation and antioxidant status in colorectal cancer, World J Gastroenterol 11 (2005) 403.
[45]	Z. Othman, L. Noordin, N. Omar, M. NA, M. Mohamaed, Protective Effects of Orlistat on Lipid Profile, Cardiac Oxidative Stress Biomarkers and Histology in High-fat Diet-induced Obese Rats, IIUM Med J Malaysia 18 (2019) 23-28.
[46]	J. Suleiman, V. Nna, Z. Zakaria, Z. Othman, A. Bakar, M. Mohamed, Obesity-induced testicular oxidative stress, inflammation and apoptosis: Protective and therapeutic effects of orlistat, Reprod Toxicol 95(2020)113-122.
[47]	R. Sripradha, M. Sridhar, N. Maithilikarpagaselvi, Hydroxycitric acid ameliorates high-fructose-induced redox imbalance and activation of stress sensitive kinases in male Wistar rats, J Basic Clin Physiol Pharmacol 27(2016) 349-356.