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.
Colon cancer (CC) is considered a common cancer worldwide 1. Furthermore, treatment with traditional chemotherapeutic agents is typically ineffective, either due to the progression of drug resistance or severe systemic toxicity 2. The Western way of life is strongly connected to colon cancer. The incidence of colon cancer is affected by lifestyle and dietary habits. Among dietary factors, a high fat and carbohydrate intake raises the risk of developing CC 3, 4. The risk of colorectal cancer may be associated with obesity 5.
One of the potent carcinogens that induce colon tumors is Dimethylhydrazine (DMH) 6. The DMH as well as its azoxymethane (AOM) metabolite are considered carcinogens that develop DNA-reactive products when activated metabolically via N-oxidation and hydroxylation steps forming methyl-azoxy-methanol (MAM) 7, 8.
Orlistat is a saturated lipstatin derivative that is a potent natural pancreatic lipase inhibitor isolated from Streptomyces toxytricini. However, due to its relative simplicity and stability, orlistat was preferred as an anti-obesity drug over lipstatin 9. Orlistat has also been found to inhibit the fatty acid synthase (FAS) thioesterase domain, an enzyme that is involved in cancer cell proliferation but not in normal cells 10. Another anti-obesity medication is HCA, which is a citric acid derivative found in many tropical plants, which grow in Sri Lanka and India as Hibiscus subdariffa and Garcinia cambogia 11. The HCA inhibits lipogenesis, a mechanism in which carbohydrate is transformed to fat in the body 12. The mechanism of the development of CC in obese people is still unknown. Previous research has shown that obesity causes inflammation and extracellular matrix remodeling 13. Different cytokines induce the expression of IL-32, which increase the expression of IL-8, IL-6, IL-1, and TNF-α in various cell types by activating the classic pro-inflammatory mediators as nuclear factor B (NF-B) and p38 constituting angiogenesis and apoptosis 12, 13, 14.
Based on the foregoing, this study aimed to determine the potential chemoprotective effect of anti-obesity drugs including orlistat and hydroxycitrate on colon cancer induced in albino rats.
We used male Wistar rats (200±20 g), obtained from the animal facility (El-Nile Co., Cairo, Egypt), and were housed two weeks before the experiment and during experimentation in the animal facility at the Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt. All experimental animals were housed in cages with food and water (ad libitum) in 12h/12h light/dark cycles.
2.2. Ethical ApprovalThe animal experiment was conducted following the National Research Council (US) Guide for the Care and Use of Laboratory Animals (2011) 15, and approved by an independent ethics committee (No, bio._9med.research_0000009) at the Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt.
2.3. ChemicalsThe DMH solution (Sigma-Aldrich Chemical Co., USA) was administrated to rats at a dose of 40 mg/kg as verified by our pilot study (data not shown). Orlistat (Sigma pharmaceutical industries agency, Quesna, Egypt) and Hydroxycitrate (puritan’s pride, USA) were dissolved in normal saline and administered to rats orally at doses of 32 and 135 mg/kg/day, p.o., respectively. The previous rat doses were equivalent to the human clinical doses for obesity treatment 16, 17 based on body surface area conversion ratios 18. In the present study, we used the following ELISA kits: Cancer embryogenic antigen (CEA) (Roche Diagnostics Co., Basel, Switzerland); rat interleukin-6 (IL-6) (Promokine Co., Heidelberg, Germany); NRF2 transcription factor and rat TNF-α (Abcam UK); cancer antigen 19-9 (CA19-9) (Roche Diagnostics Co., Switzerland); nuclear factor κB P65 (NFκB-P65) (MY-Bio-Source Co., San Diego, USA); Caspase-3 (Biovision, San Francisco, USA).
2.4. Design of the ExperimentWe used one hundred rats (10 groups, 10 rats in each group) as the following:
Group 1: Control group (normal rats,16 weeks).
Group 2: DMH (40 mg/kg i.p., two times/week/16 weeks).
Group 3: HFD (20%, supplied daily for 16 weeks).
Group 4: DMH and HFD in combination as in groups 2 & 3.
Group 5: Orlistat (32 mg/kg/day, p.o.; 16 weeks).
Group 6: DMH and orlistat in combination as in groups 3 & 5.
Group 7: DMH, HFD, and orlistat in combination as in groups 2, 3 & 5.
Group 8: Hydroxycitrate (135 mg/kg/day, p.o.; 16 weeks).
Group 9: DMH and hydroxycitrate in combination as in groups 2 & 8.
Group 10: DMH, HFD, and hydroxycitrate in combination as in groups 2, 3 & 8.
2.5. Induction of Tumor (CC)To induce colon cancer in the experimental animals, the rats were treated with DMH (40 mg/kg two times per week) and/or HFD (20% daily) for 16 weeks. The DMH was freshly prepared. The model was established in our lab in a pilot study (data not shown).
2.6. Serum and Colon Tissue SamplingAnimals were placed under light anesthesia one week after the last dose. Before sacrifice, the retro-orbital plexus blood was centrifuged at 3000 rpm (10-15 min) and the serum was separated and preserved at -80 °C. The rats were sacrificed shortly after blood collection, and the colon tissues were excised, washed in saline, and divided into two sections. For the histopathological study, the first section was fixed in formalin solution (10%). The other section was frozen immediately (-70°C, liquid nitrogen) for ELISA assays and biochemical analysis 19.
2.7. Estimation of Physical Characteristics and Mortality RateThe animals were weighed before and after treatment and then euthanized by cervical dislocation.
The weight gain= Final body mass-Initial body mass.
The growth rate= (Final mass -Initial mass)/ days of the experiment.
Mortality (%) in each group= (The no. of dead animals in each group x 100)/ Total no. of animals in each group.
Aberrant crypt foci (ACF%) incidence (histopathological study) = (Animals with ACF X 100)/The no. of animals examined.
2.8. Biomarkers EstimationWe measured caspase-3 in the colon tissues of the rats and estimates CEA and CA19.9 in the rat sera according to the ELISA kits instructions (sandwich technique). In addition, we used an ELISA assay to measure NRF2 and other oxidative stress parameters, as well as inflammatory parameters (IL-6, TNF-α, and NF-B) in the tissues of the colon. All biomarkers were determined using the methods outlined in the diagnostic kits.
2.9. The Histopathological StudyThe colon tissue samples were fixed, processed, sectioned (4 μm), and stained with Hematoxylin and Eosin (H&E) 20.
2.10. Statistical AnalysisGraphPad Prism version 5.0 was used to perform statistical analyses on the results. For multiple compression between classes, we performed a one-way analysis of variance (ANOVA) test, followed by a post-hoc t-test (Tukey-Kramer). The degree of significance was set at p ≤ 0.05, and the results were expressed as means ± standard deviations (SD).
The rats treated with DMH, HFD, and DMH/HFD show significantly reduced weight gain by 46%, 39%, and 19%, respectively as compared to the control rats. Moreover, Table 1 shows an increased ACF incidence and mortality rate in the previous groups comparing to the control rats. However, the treated rats supplemented for 16 weeks with orlistat (32 mg/kg/day) record an increase in weight gain significantly in comparison with rats treated with DMH only. Furthermore, orlistat and hydroxycitrate (135 mg/kg/day) decreased ACF incidence and mortality rate in the groups treated with DMH and/or HFD.
3.2. Effect of Orlistat and Hydroxycitrate on Serum CEA and CA19-9 Tumor Markers of the Treated Rats (Table 2)The rats treated with DMH and DMH/HFD record an increase in serum CEA levels significantly compared to the control group. On the contrary, the treated rats coadministred with orlistat and hydroxycitrate show significantly reduced serum CEA levels compared to the DMH treated group. Similarly, the treated rats supplemented with orlistat and hydroxycitrate show significantly reduced serum levels of CEA compared to the rats treated with DMH/HFD. In addition, the rats treated with DMH and/or HFD show increase serum levels of CA19-9 significantly compared with control rats. The treated rats supplemented with orlistat and hydroxycitrate, on the other hand, show substantially reduced serum CA19-9 levels compared to the group treated with DMH. Similarly, supplementation with orlistat and hydroxycitrate significantly reduced serum CA19-9 levels compared to the groups treated with DMH and/or HFD.
The rats treated for 16 weeks with DMH and/or HFD recorded a significant increase in caspase-3 content in the tissues of the colon compared with control rats. In contrast, orlistat reduced the caspase-3 content in the tissues of the colon significantly compared with the group treated with DMH only. Also, the treated rats supplemented with orlistat and hydroxycitrate show a decrease in the caspase-3 tissue content in the tissues of the colon significantly compared with the groups treated with DMH/HFD.
The TNF-α content in the tissues of the colon in rats treated with DMH and/or HFD was increased significantly compared with normal control rats. On the contrary, orlistat and hydroxycitrate administration to the treated rats substantially reduced the colonic TNF-α tissue content as compared with the rats treated with DMH/HFD. Similarly, supplementation with orlistat and hydroxycitrate decreased the TNF-α content in the tissues of the colon significantly as compared with the rats treated with DMH/HFD.
Compared with control rats, the NF-κB content in the tissues of the colon in rats treated with DMH and/or HFD was increased significantly. In contrast, the groups that received co-treatment of orlistat and hydroxycitrate record a significant reduction in the NF-kB content in the tissues of the colon as compared with the group treated with DMH. In addition, supplementation with orlistat and hydroxycitrate decreased the NF-κB content significantly in the tissues of the colon of the rats as compared with the rats treated with DMH/HFD.
The rats treated for 16 weeks with DMH and/or HFD show a significant increase in the IL-6 content in the tissues of the colon in comparison with the normal rats. The groups that received orlistat and hydroxycitrate, on the other hand, greatly reduced the colonic IL-6 tissue content significantly as compared with the group treated with DMH. Similarly, the treated rats supplemented with orlistat and hydroxycitrate show decreased IL-6 content significantly in the tissues of the colon as compared with the rats treated with DMH/HFD.
In comparison with the normal control rats, the MDA content was increased significantly in the tissues of the colon in groups treated with DMH and/or HFD. The treated rats received orlistat and hydroxycitrate, on the other hand, show a significant reduction in the colonic MDA tissue content as compared with the group treated with DMH. Similarly, the groups supplemented with orlistat and hydroxycitrate show a significant reduction in the colonic MDA tissue content as compared with the rats treated with DMH/HFD.
Meanwhile, the NRF2 content shows a significant reduction in the tissues of the colon in groups administered with DMH and/or HFD as compared with the control group. On the contrary, the treated rats supplemented with orlistat and hydroxycitrate show a significant increase in the colonic NRF2 content as compared to the groups treated with DMH and/or HFD.
Moreover, the CAT, SOD, GSH, and GST contents were significantly decreased in the tissues of the colon in rat groups treated with DMH and/or HFD as compared with the control group. On the contrary, the treated rats supplemented with orlistat and hydroxycitrate show an increase in the colonic CAT content as compared to the groups treated with DMH and/or HFD.
Finally, the total NO content in the tissues of the colon in rats treated with DMH and/or HFD was increased as compared with the normal control rats. In contrast, the treated rats supplemented with orlistat and hydroxycitrate show a significant reduction in the colonic NO content as compared with the group treated with DMH. Similarly, the treated rats supplemented with orlistat and hydroxycitrate show a significant reduction in the colonic NO content as compared with the groups treated with DMH/HFD.
Table 6 and Figure 1 show the histopathological findings in colon tissues. The control colon is shown in Figure 1.1A. In contrast, The DMH-treated rats show a colonic wall with average musculosa, mildly edematous submucosa, and ulcerated mucosa, the colon wall also shows aberrant crypt foci (ACF) which are clusters of abnormal tube-like glands (hyperplastic polyp) and considered as one of the marked changes that lead to cancer as seen in Figure 1.1B which demonstrate adenoma with dysplasia. The group of rats treated with a high-fat diet shows a colon with an average musculosa, submucosa displayed mild edema, and intact mucosa and the colon wall appeared with hyperplastic polyp and show adenoma with dysplasia (ACF) as depicted in Figure 1.1C. In addition, the group of rats treated with the DMH/HFD shows a colon with average musculosa, average submucosa, intact mucosa, and adenoma with dysplasia (ACF) (Figure 1.1D). On the contrary, as shown in Figure 1.2E-J, the tissues of the colon in rats supplied with orlistat and hydroxycitrate reveal improved tissue architecture.
Obese people have a lot of adipose tissue that secretes growth factors and cytokines that can increase the risk of colon cancer 21. Dimethylhydrazine (DMH), potent carcinogen was used as a standard in vivo model to induce malignant neoplasms in rodent colons 8. The DMH undergoes metabolic enhancement, forming free radicals causing oxidative stress and initiates lipid peroxidation cascade 22, 23. The nitric oxide (NO) produced by iNOS, on the other hand, mediates inflammation and induces tumors in the colon 24. Excess NO development suppresses DNA repair and inhibits apoptosis causing induction of colon cancer 25.
The CEA marker is used in the clinical diagnosis and monitoring of colon cancer and is considered as the colon cancer best marker with a well-characterized antigen 26, 27. Furthermore, CA19-9 has been linked to a poor prognosis in colorectal cancer 28. As a result, combining CEA and CA19-9 markers led to a better diagnosis of colorectal cancer 29, 30.
The present results showed increased plasma levels of CEA and CA 19-9 in the groups treated with DMH and/or HFD as compared with the control group, this was owing to increased development in the malignant cells. These results agreed with a previous study 31. The treated groups supplied with orlistat and HCA record a significant decrease in the levels of the plasma CEA and CA 19-9 as compared to the groups treated with DMH and/or HFD only as approved in other studies 32, 33, 34. These findings indicate the anticancer activity of orlistat and/or HCA, as indicated by the marked reduction in the levels of CEA, and CA 19-9.
The present study records significantly the increased caspase-3 content in the colon tissue of groups treated with DMH and/or HFD comparing to the control group, which indicate an apoptosis-induction process 22, 29. Caspase-3 is an important apoptotic marker enzyme in the apoptosis process 24. These data are in approval with Hassan et al. (2017) 35 who found that caspase-3 is elevated in DENA-induced hepatocellular carcinoma in rats. on other hand, supplementation of animals with orlistat, HCA, and thymol led to a reduction in the colon caspase-3 content in comparison with rat groups treated with DMH and/or HFD and did not receive the previous supplementation. In addition, our results are consistent with previous work that reported increased apoptosis in isogenic human colon adenocarcinoma cell lines 36.
The NF-κB and TNF-α are considered inflammatory mediators that create a positive feedback loop causing cellular and DNA damage in the sites of inflammation and share in cancer progression 37. NF-κB control genes are involved in inflammation, proliferation, and apoptosis 38. There is substantial evidence that NF-κB regulates inducible enzymes as well as TNF-α, IL-2, and IL-6 expression 39, 40. The NF-κB response genes in the groups treated with DMH and/or HFD may share in the process of inflammation and tumor growth as recorded in the present study. As a result, the anti-inflammatory activity of orlistat and HCA is the key mechanism that may be associated with the reduced expression of NF-κB in the groups treated with DMH and/or HFD that may cause the prevention of colorectal cancer.
It has been documented that the chronic inflammation's long duration is produced due to activation of NF-B that leads to increased expression of NF-κB and IL-6 41. As a result, treatment of colon cancer is associated with the blocking or suppression of TNF-α and IL-6 genes 42. The present data record that orlistat and HCA can inhibit the activity of NF-B and modulate the inflammatory processes by suppressing inflammation in the groups of rats treated with DMH and/or HFD, which is consistent with previous research 43.
In the present study, the treatment with DMH significantly increases the lipid peroxidation as indicated by increased MDA concentration (tumor promoter) which leads to a state of oxidative stress 43. Colorectal cancer can develop due to DNA mutation and cell proliferation caused by lipid peroxidation 44.
The current study records significantly increased levels of MDA and NO in the colon tissues in groups of animals treated with DMH and/or HFD as compared with the control group. The administration of DMH causes the release of the ROS that react with the cell membrane lipid bilayers and start a cascade of peroxidation that release products as MDA causing disintegration in the cell membranes and mutations that favor cancer growth 45, 46.
Furthermore, rats treated with DMH recorded a significant decrease in the antioxidant parameters (SOD, CAT, GSH, GST, and NRF2). The current study also recorded that the supplementation of the treated rats with orlistat and HCA causes a significant reduction in the colon MDA and NO in contrast to a significant increase in the colonic SOD, CAT, GSH, GST, and NRF2 antioxidant contents. This indicates that orlistat and HCA have antioxidant effects as they can scavenge free radicals and prevent lipid peroxidation 45, 47. Finally, the histopathological analysis of the colon lining shows that the groups of animals treated with DMH and/or HFD recorded marked cancerous features which were ameliorated in the groups supplemented with orlistat and HCA.
Our results in the present study evidenced that the use of orlistat and hydroxycitrate can potentially ameliorate the pathological lesions in the colon and reducing oxidative stress, inflammation, and apoptosis which are considered critical mechanisms for preventing colon cancer caused by DMH and/or HFD.
We are profoundly grateful to Prof. Dr. Sayed Abdel Raheem, Professor of Histopathology, Al- Azhar Faculty of Medicine, Cairo for his kind help during the histopathological investigation of colon tissues. A special thanks are given to Dr. Abdallah Hussien Fathy (Ph D), Laboratory Animal Facility Managing Director, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt for his great efforts in checking the plagiarism of our current manuscript.
The authors declare that they do not have any conflict of interest.
The authors declare that they do not have any source of funding.
The animal experiments were conducted in accordance with the Guide for the Care and Use of Laboratory Animals (National Research Council (US) Committee for the Update of the Guide for the Care and Use of Laboratory Animals, 2011) and the use of animals was reviewed and approved by an independent ethics committee of the Faculty of Pharmacy, Al-Azhar University in Cairo, Egypt, with the reference number “bio._9med.research_0000009”.
The data and materials are available with the corresponding author at any time you request.
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