|Year : 2021 | Volume
| Issue : 3 | Page : 144-150
Mitoquinol mesylate ameliorates hematological aberration in cirrhotic-hepatocellular carcinogenic rats
Lateef Adegboyega Sulaimon1, Rahmat Adetutu Adisa1, Fatimah Biade Abdulkareem2
1 Department of Biochemistry, Faculty of Basic Medical Sciences, College of Medicine of University of Lagos, Lagos, Nigeria
2 Department of Anatomic and Molecular Pathology, Faculty of Basic Medical Sciences, College of Medicine of University of Lagos, Lagos, Nigeria
|Date of Submission||13-May-2021|
|Date of Decision||01-Aug-2021|
|Date of Acceptance||05-Aug-2021|
|Date of Web Publication||30-Nov-2021|
Dr. Rahmat Adetutu Adisa
Department of Biochemistry, Faculty of Basic Medical Sciences, Laboratories for Biomembranes and Cancer Research, College of Medicine of University of Lagos, Lagos
Source of Support: None, Conflict of Interest: None
Introduction: Hematological abnormalities such as anemia, neutropenia, and thrombocytopenia experienced by cancer patients undergoing chemotherapy necessitate the need to develop agents that stimulate erythropoiesis and boost immune response in cancer. Aim: The present study investigated the effects of mitoquinol mesylate (MitoQ) on the hematological profile of diethyl nitrosamine (DEN)-induced cirrhotic-hepatocellular carcinogenic (HCC) rats. Materials and Methods: One hundred Wistar strain albino rats were randomly divided into five groups (n = 20) for the experimental period of 20 weeks. Groups A, B, and C received distilled water, 10 mg/kg each of DEN and MitoQ respectively. Animals in Group D were pretreated with 10 mg/kg MitoQ for a week followed by coadministration of 10 mg/kg each of MitoQ and DEN for 20 weeks, while Group E received 10 mg/kg DEN for 8 weeks and then coadministration of 10 mg/kg each of DEN and MitoQ till the end of 20th week. Animals were sacrificed at the end of 12th, 16th, and 20th week. Blood samples were collected into labeled heparinized bottles for hematological analysis. Results: Administration of DEN significantly (P < 0.05) decreased the levels of red blood cell (RBC) count and erythrocytes indices. These erythrogram parameters were continuously deranging from 6.86 ± 0.26 to 2.69 ± 0.01, from 37.40 ± 1.99 to 30.35 ± 0.57, from 12.16 ± 0.97 to 8.90 ± 0.37 in the levels of RBC, packed cell volume, and hemoglobin, respectively, with the progression of HCC from cirrhosis to advanced HCC in Wistar rats. Further, the levels of white blood cells (WBCs, 3.68 ± 0.08), granulocytes (1.30 ± 0.06), lymphocytes (0.63 ± 0.11), and platelets (440.00 ± 22.67) were significantly reduced in the DEN group compared to healthy control (4.46 ± 0.12, 2.14 ± 0.27, 1.70 ± 0.13, and 685.80 ± 15.48 in the levels of WBC, granulocytes, lymphocytes, and platelets, respectively) at the advanced HCC stage. Interestingly, MitoQ interventions significantly (P < 0.05) reversed alterations in hematological indices induced by DEN toxicity. Conclusion: Our findings suggest that MitoQ is safe and capable of normalizing hematological abnormalities associated with cirrhosis and HCC in Wistar rats.
Keywords: Cirrhosis, hematology, hepatocellular carcinoma, mitoquinol mesylate, rats
|How to cite this article:|
Sulaimon LA, Adisa RA, Abdulkareem FB. Mitoquinol mesylate ameliorates hematological aberration in cirrhotic-hepatocellular carcinogenic rats. Niger J Exp Clin Biosci 2021;9:144-50
|How to cite this URL:|
Sulaimon LA, Adisa RA, Abdulkareem FB. Mitoquinol mesylate ameliorates hematological aberration in cirrhotic-hepatocellular carcinogenic rats. Niger J Exp Clin Biosci [serial online] 2021 [cited 2022 Nov 30];9:144-50. Available from: https://www.njecbonline.org/text.asp?2021/9/3/144/331548
| Introduction|| |
A full blood count (FBC) provides important information about the kinds and numbers of cells in the blood, especially erythrocytes, leukocytes, and platelets. FBC helps healthcare providers to check symptoms of a particular disease in a patient; the symptoms include weakness, fatigue, or bleeding. In the management of cancer, FBC is a prerequisite investigation requested from all cancer patients before surgery, use of chemotherapy, and radiotherapy. Poor hematological parameters negatively impact the quality of life of cancer patients. Hematological parameters have been correlated with prognosis of several malignancies, in which the white blood cell (WBC) count (total and differentials) and packed cell volume (PCV) predict disease severity and mortality risk.,,, Blood contains a variety of cells in appropriate proportions in normal persons. Disease or infection has a direct impact on blood parameters, so it is pertinent to study the alteration in hematological parameters in cancer patients, at regular intervals during treatment.
Hepatocellular carcinoma (HCC) is the most common type of primary cancer of the liver and majorly develops in patients with cirrhosis. Since the liver has an extremely important role in the maintenance of blood homeostasis, it is not surprising to see a wide range of hematological abnormalities in liver diseases. Liver acts as a storage depot for iron, folic acid, and Vitamin B12 as well as produces erythropoietin and regulates the blood clotting and anticoagulant system. Liver disease, such as liver cirrhosis, hepatitis, and HCC, can impair the liver's ability to perform its biological function. For instance, patients with advanced HCC have abnormal coagulation and fibrinolysis, which is related to tumor progression. Abnormalities in hematological parameters are common in patients with cirrhosis and HCC. The pathogenesis of abnormal hematological indices in cirrhosis and HCC is multifactorial and includes portal hypertension-induced sequestration (hypersplenism), alterations in bone marrow stimulating factors, and viral- and chemotherapy-induced bone marrow suppression. These abnormalities are associated with an increased risk of complications including bleeding and infection.
Anemia, neutropenia, and thrombocytopenia are the most common and persistent hematological abnormalities in oncology patients. Chemotherapy-induced anemia (CIA) is a consequence of malignant invasion of normal tissue, leading to blood loss, bone marrow infiltration with disruption of erythropoiesis, and functional iron deficiency as a consequence of inflammation. CIA is a resultant effect of chemotherapy and may delay or limit therapy as well as contribute to both fatigue and diminished quality of life in cancer patients. Hematological supportive care strategies such as bone marrow transplant or peripheral blood stem cell support are essential to mitigate the cytotoxic effects of high-dose chemotherapy. While transfusion rates vary in patients with CIA, about 50% of patients with incurable cancer require at least one red blood cell (RBC) transfusion before completing chemotherapy treatment. Although it is known that hemoglobin (HGB) significantly influences survival in patients receiving chemotherapy, it remains controversial whether or not improving HGB by blood transfusion improves treatment response.
Despite the aforementioned indications for the need to ameliorate hematological aberrations in cancer patients, there are currently little or no randomized controlled preclinical trials that evaluate the use of mitochondrial targeted antioxidant, mitoquinol mesylate (MitoQ), to restore hematological profile in cirrhotic-HCC rats. Hence, the present study investigated the effects of MitoQ on hematological profile of cirrhotic-HCC rats. MitoQ is the most widely used mitochondrial targeted antioxidant whose protective role in various disease settings has been studied. Its pharmacological effect is remarkably linked to its antioxidative activity against liver diseases, neurodegenerative diseases, cardiac hypertrophy, and nephropathy. Gonzalez et al. reported selective cytotoxic effects of MitoQ against breast cancer over healthy mammary epithelial cells. The selective cytotoxicity of MitoQ against cancer encouraged us to investigate its beneficial effects on hematological profile of the diethyl nitrosamine (DEN)-induced cirrhotic, early, and advanced HCC in a population of 100 Wistar strain albino rats.
| Materials and Methods|| |
The protocol for this study was approved by the National Health Research Ethics Committee of the College of Medicine, University of Lagos, Federal Ministry of Health, Nigeria, with Approval number: CMUL/HREC/03/19/505.
One hundred male Wistar strain albino rats weighing 120–150 g were procured from the Animal House, College of Medicine of University of Lagos, Nigeria, and were randomly distributed in well-ventilated, clean, and standard plastic cages with five animals per cage. The animal room was maintained at a constant temperature of 25°C ± 2°C and 84% ±4% relative humidity with a 12-h (7:00–19:00) light/dark cycle. The rats were acclimatized for a period of 2 weeks and maintained on oral standard rats' pellets (Pfizer Livestock Feeds, Lagos, Nigeria) and water ad libitum. All the experiments were conducted in accordance with the internationally accepted principles for laboratory animal use and care, as found in the guidelines of the National Institute of Health.
This research is a laboratory based pre-clinical study, designed according to the method of Ke-Qin et al. with slight modification. In this study, we adopted the use of water as a delivery vehicle for DEN and MitoQ instead of corn oil used in the referenced study since both DEN and MitoQ are soluble in water. After acclimatization, the animals were randomly divided into five groups of 20 animals per group. Exactly 10 mg/kg each of distilled water, DEN, and MitoQ was orally administered separately to Group A, Group B, and Group C, respectively, for a period of 12, 16, and 20 weeks. Animals in Group D were pretreated with 10 mg/kg MitoQ for a week followed by coadministration of 10 mg/kg each of MitoQ and DEN for 12, 16, and 20 weeks, while Group E received 10 mg/kg DEN for 8 weeks and then coadministration of 10 mg/kg each of DEN and MitoQ till the end of 12th, 16th, and 20th week. The body weight of each animal was measured weekly, and the doses of DEN and MitoQ were varied accordingly. Furthermore, the body weight of each animal was recorded before sacrifice at the end of 12th, 16th, and 20th week, which represent cirrhotic, early, and advanced HCC stages, respectively. The rats were fasted overnight before they were sacrificed by cervical dislocation.
Whole blood samples were obtained by retro-orbital puncture using capillary tubes just before sacrifice. The samples were collected in labeled lithium heparinized bottles for hematological profile analysis.
Hematological parameters including RBC count, WBC count, PCV, and HGB concentration were determined using the BC-3200 Auto Hematology Analyzer, (Mindray Medical International Ltd., Shenzhen, China).
Data were statistically computed using GraphPad Prism 6 Software (GraphPad Software Inc., CA, USA) and expressed as mean ± standard error of the mean values. Differences between mean values were determined by one-way analysis of variance and further analyzed using Tukey's honest significant difference test and P < 0.05 was considered statistically significant.
| Results|| |
The data presented in [Table 1], [Table 2], [Table 3] indicate that RBC, PCV, HGB, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and MCH concentration (MCHC) were significantly (P < 0.05) lower in the DEN-administered group compared to the healthy control. Furthermore, these RBC parameters gradually decreased with stages of HCC in the DEN group. Interestingly, administration of MitoQ (MitoQ, MitoQ + DEN, DEN + MitoQ) significantly (P < 0.05) elevated the levels of RBC, PCV, HGB, MCV, MCH, and MCHC to the near basal level at all stages of HCC. It is noteworthy to mention that the restoration is more pronounced in rats pretreated with MitoQ (MitoQ + DEN) and the group-administered MitoQ alone. However, there was no significant (P > 0.05) difference in the levels of PCV and HGB at cirrhosis [Table 1], RBC count at early HCC [Table 2], and MCV at advanced HCC [Table 3], when comparing the DEN and DEN + MitoQ groups.
|Table 1: Effect of mitoquinol mesylate on erythrogram of cirrhotic rats after 12 weeks of oral administration of mitoquinol mesylate and diethyl nitrosamine|
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|Table 2: Effect of mitoquinol mesylate on erythrogram of early hepatocellular carcinoma rats after 16 weeks of oral administration of mitoquinol mesylate and diethyl nitrosamine|
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|Table 3: Effect of mitoquinol mesylate on erythrogram of advanced hepatocellular carcinoma rats after 20 weeks of oral administration of mitoquinol mesylate and diethyl nitrosamine|
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Administration of DEN (DEN group) significantly increased WBC count, lymphocytes, granulocytes, and platelets in cirrhotic rats [Table 4] while increasing monocytes and granulocytes counts at early HCC stage [Table 5] compared to healthy control. On the contrary, the levels of WBCs, granulocytes, lymphocytes, and platelets were significantly reduced in the DEN group compared to healthy control at the advanced HCC stage [Table 6]. The DEN-administered group exhibited a progressive increase in monocytes count, while the levels of WBCs, lymphocytes, and platelets were continuously deranged with progression of HCC in Wistar rats [Table 4], [Table 5], [Table 6]. The MitoQ-administered groups (MitoQ, MitoQ + DEN, DEN + MitoQ) showed a reversal of the alterations in white blood indices caused by the DEN administration. However, a very high level of platelets was observed in the group posttreated with MitoQ (DEN + MitoQ) at cirrhotic stage [Table 4].
|Table 4: Effect of mitoquinol mesylate on leukogram of cirrhotic rats after 12 weeks of oral administration of mitoquinol mesylate and diethyl nitrosamine|
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|Table 5: Effect of mitoquinol mesylate on leukogram of early hepatocellular carcinoma rats after 16 weeks of oral administration of mitoquinol mesylate and diethyl nitrosamine|
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|Table 6: Effect of mitoquinol mesylate on leukogram of advanced hepatocellular carcinoma rats after 20 weeks of oral administration of mitoquinol mesylate and diethyl nitrosamine|
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| Discussion|| |
Hematological profiling is a routine test that is used by clinicians to diagnose several diseases such as anemia, hemorrhagic states, acute infections, allergic disorders, cancers, and immune disorders. Anemia is common in cancer patients, and its incidence deepens with chemotherapy which necessitates the need for blood transfusion in most cases. Anemia negatively impacts survival and accentuates fatigue in cancer patients. Cancer promotes the production of inflammatory cytokine production, which suppresses erythropoiesis and erythropoietin. Erythropoietin is a glycoprotein hormone that stimulates stem cells in the bone marrow to produce RBCs.
In this study, a significant decrease in the RBC, PCV, and HGB levels in the DEN group at cirrhotic, early, and advanced HCC is indicative of anemia. This is in agreement with earlier findings of Venkatesh and Kalaivani, where administration of DEN induced a decline in the levels of RBC, PCV, and HGB in Wistar rats. RBC, HGB, and PCV are markers of anemia, predicting the increased risk of cancer patients' death due to heart attack., The observed anemia in cirrhotic-HCC rats could be a result of damage of the bone marrow, tumor infiltration, and malignancy. Decreased RBC and HGB levels also indicate the severity of hepatic damage induced by DEN. Decrease in the HGB level might be due to increased catabolism and degradation of HGB, which affects the oxygen-carrying capacity of the blood and the amount of oxygen delivered to the tissues since RBCs and HGB are very important in transporting respiratory oxygen.
RBC indices reflect the size (MCV) and level of HGB content (MCH and MCHC) of the RBCs and are used to evaluate the cause of anemia. The cirrhotic-HCC rats exhibited microcytic hypochromic anemia as their MCV, MCH, and MCHC values were significantly lower compared to the healthy control. This could be attributed to the increased destruction of the RBCs by the DEN beyond the production capacity of the bone marrow as well as the fall in the levels of the body iron content. The anemia caused by the DEN was, however, ameliorated in cirrhotic-HCC rats pre- and post-treated with MitoQ, resulting in the restoration of RBC, PCV, and HGB levels recorded in this study. The increased RBC, PCV, and HGB levels in the MitoQ-administered group suggest polycythemia and positive erythropoiesis.,,
The increased WBC and lymphocytes counts in the DEN-induced cirrhotic rats may be due to immunity response against the invading precancerous cells as well as decreased resistance of the body to toxicity induced by DEN. A change in WBC counts commonly results from an infection, malignancy, chemotherapy, or hematological disease. The continuous decline in WBC and lymphocytes with the progression of HCC could be due to increased levels of proinflammatory cytokines, such as IL-1, IL-6, TNF-α, and INF-δ that induce iron retention by the reticuloendothelial system, gastrointestinal tract, and liver, thereby exerting an inhibitory effect on erythroid precursors. Rana et al. also reported decrease in absolute lymphocyte count with increase in the stage of carcinoma. Ufelle et al. reported significant decrease in all hematological parameters in breast cancer when compared with control. The decreased levels of WBC and lymphocytes of DEN group at the advanced stage may suggest that immune system is overwhelmed by the invading cancer cells. Lymphocytes fight cancer; high lymphocytes count increases the overall survival of the cancer patients while low count of lymphocytes in the blood encourages a relapse and reduces survival rates.
Agents that activate host defense mechanisms in the presence of an impaired immune responsiveness can provide supportive therapy to conventional chemotherapy. MitoQ fulfills this purpose by increasing WBC and the differential leukocytes counts, especially at the advanced HCC stage in the present study. The immune--boosting properties of MitoQ could be linked to its immunostimulatory activity to maintain a disease-free state, and this supports its clinical relevance in the management of immunity-dependent disorders. Studies reported that regulation of proliferating stem cells by granulocyte–macrophage colony stimulating factor is responsible for the production of WBCs., The significant increase in the platelets in advanced HCC rats pre-treated with MitoQ demonstrated the potency of MitoQ in stimulating thrombopoietin production to prevent bruising and bleeding that could result from cancer/chemotherapy induced thrombocytopenia.
| Conclusion|| |
Our findings suggest that oral administration of MitoQ is safe and capable of normalizing hematological abnormalities associated with liver cancer in Wistar rats. It has a positive, beneficial effect against the DEN-induced hepatocarcinogenesis in Wistar rats. However, there is need for more preclinical and clinical studies to evaluate chemopreventive and therapeutic potential of MitoQ in managing cirrhosis and HCC.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]