A new potential chemotherapy for the treatment of hepatocellular carcinoma and its relation to kidney function

 Corresponding author: Asmaa E. AbdElgalil. Copyright © 2025 Author(s) retain the copyright of this article. This article is published under the terms of the Creative Commons Attribution Liscense 4.0. A new potential chemotherapy for the treatment of hepatocellular carcinoma and its relation to kidney function Asmaa E. AbdElgalil 1, *, Shoman AE 2, Ibrahim A.M. El-Safty 3, Arafa A.M. Belal 4, Ekrami A. Hassan 5 and ElSherbiny H. ElSayed 4 1 Department of Chemistry (Biochemistry division), Faculty of Science, Port Said University, Egypt. 2 Department of Community, Environmental and Occupational Medicine. Ain Shams University. 3 Department of Chemistry, Faculty of Education, Ain Shams University, Egypt. 4 Department of Chemistry, Faculty of Science, Port Said University, Egypt. 5 Department of Biochemistry, Faculty of Science, Ain Shams University, Egypt. World Journal of Biology Pharmacy and Health Sciences, 2025, 21(03), 636-641 Publication history: Received on 10 February 2025; revised on 21 March 2025; accepted on 24 March 2025 Article DOI: https://doi.org/10.30574/wjbphs.2025.21.3.0307 Abstract Background: liver cancer has many complications; one of these complications is acute kidney injury. So, the treatment of hepatocellular carcinoma may enhance kidney functions. Cisplatin is one of the most successful chemotherapies used to treat hepatocellular carcinoma with bad side effects and to overcome these side effects; we hybrid it with Laurel nobilis leaves aqueous extract to treat hepatocellular carcinoma so the aim of this study is to determine the effect of the treatment of hepatocellular carcinoma with hybrid compound on kidney injury. Methods: Blood Sample were collected from 36 adult Swiss albino rats. Alanine amino-transferase (ALT), aspartate aminotransferase (AST) and albumin (Alb) were assayed as good indicators for liver health and closely related to liver functions; also, creatinine and urea were also measured for kidney health. Results: ALT, AST and albumin were significantly decreased in HCC rats treated with hybrid compound more than cisplatin treated animals and both of them were significant (P≤0.00) and so creatinine and urea were significantly decrease in hybrid compound more than cisplatin treated animals and both of them were significant (P≤0.001) compared to HCC group. In Conclusion: The kidney functions increase with hepatocellular carcinoma and more enhancements in liver healthy the more enhancements in kidney function. Keywords: Hepatocellular Carcinoma; Acute Kidney Injury; Laurus nobilis L. Leaves; Chemotherapy; Hybrid Compound; Cisplatin 1. Introduction Liver cancer is a global problem as it’s the fourth most common cause of death. It accounts for about 90% of primary liver cancers [1]. The treatment plan depends on tumor size and location, body general health, if liver is cirrhotic or not and stage of cancer [2]. Liver surgical resection and transplantation offer the only cures but their application is limited and the main factors defined the restriction are liver function and tumor size and there are another HCC therapies like radiotherapy, ablation, immunotherapy, systemic therapy etc [2]. Complications in hepatocellular carcinoma patients are common; these complications include acute kidney injury, portal hypertension, ascites, and variceal bleedings. World Journal of Biology Pharmacy and Health Sciences, 2025, 21(03), 636-641 637 Management of complications is essential to maintain physical performance and quality of life in these patients given the limitations in the effectiveness of current treatment options for end stage HCC [3]. One of the most successful treatment for hepatocellular carcinoma is cisplatin which is administered intravenously in normal saline as a chemotherapy medication used to treat a number of cancers like testicular, ovarian, bladder, lung, liver cancer and brain tumors by interferes with DNA replication, which kills the fastest proliferating cancer cells [4] but it has serious bad side effects like nerve disease kidney toxicity, nausea, vomiting, temporary hair loss, loss in the ability to taste food and dry mouth [5]. Acute kidney injury (AKI) is one of the most common complications in cancer patients or due to effect of treatment. t refers to a rapid (hours to days) deterioration of kidney function, leading to failure to excrete waste and maintain fluid balance, which may be severe enough to require renal replacement therapy (RRT) so the enhancement in liver cancer leading to enhance kidney function [6]. Nephrotoxicity is one of bad side effects of cisplatin so there is a need for hybrid cisplatin with another material to avoid this side effect as renal dysfunction makes hepatocellular carcinoma treatment more difficult and may negatively affect treatment outcomes [7]. Hepatorenal syndrome (HRS), with or without cirrhosis, is the leading cause of chronic kidney disease in patients with HCC [7]. The widespread availability and accessibility of Laurus nobilis Leaves is expected to help educate and introduce Laurel leaves as an herbal alternative for health. Laurel nobilis is a plant widely used in society as an alternative medicine in treating eructation, epigastric bloating, digestion, and it is a diuretic as It has many analgesic properties, [8]. Also, Laurus nobilis Leaf extract has antioxidant, anti-inflammatory, antimicrobial, antifungal, antidiabetic and anticancer properties. Because of the traditional use and commercial value of L. nobilis leaves, their chemical composition has been studied to more extensively than other parts of this plant [9]. Bilirubin, alanine amino-transferase (ALT), aspartate aminotransferase (AST), albumin (Alb) are liver function indicators that reflect liver health and are closely associated with HCC development. Transaminases are closely associated with hepatitis, and elevated levels of ALT and AST increase the risk of HCC as increased AST, and a less increase in ALT levels are indications of liver dysfunction due to cellular infiltration, and albumin significantly affect the prognosis of liver cancer [10] as malignant hepatocytes of HCC-bearing rats showed more albumin production because they have a lesser ability to control albumin synthesis or because of HCC-linked renal dysfunction [11]. Creatinine and urea are unused metabolic products for kidney which are increased in kidney diseases. Creatinine and urea are produced and secreted in urine every day and Serum creatinine and urea levels are considered as indicators to determine renal function damage [12]. In this regard, this study aims to evaluate the effectiveness of plants have medicinal properties in the pharmaceutical fields. One of these plants; Laurus nobilis L. which is an evergreen tree or shrub. The laurel leaves are traditionally used orally to treat symptoms of gastrointestinal problems, such as epigastric bloating and flatulence and its essential oil and its extracts possess antimicrobial and antioxidant properties. Leaves and fruits have aromatic, stimulant, and narcotic properties. The aqueous extract of its leaves is important in the treatment of liver cancer cells so enhancement the kidney functions [13]. 2. Material and methods 2.1. Study Approval and patients, consent The study protocol conformed by the ethical guidelines of the ethical committee of Port Said University, Faculty of Science, Port Said, Egypt (ERN: PSU.Sci.9). 2.2. Chemicals Cisplatin [cisplatin Cl2 (NH3)2] was obtained from Oncotec Pharma Production GmbH as solution for infusion in vial of 10 ml Cisplatin (1mg/ml). 2.3. Laurus nobilis L. leaves extraction Laurus nobilis L. leaves were purchased from traditional herbal markets. After washing the leaves, they dried in the shade and ground to powder by electric grinder. Approximately 20 g of the leaf powder added to 100 ml of distilled water in conical flask. The mixture boiled for 10 min and cooled to room temperature. Then, the crude extracts were filtered, and dried using Lyophilized. This Preparation of extracts was done by following the method of Rizwana et al. World Journal of Biology Pharmacy and Health Sciences, 2025, 21(03), 636-641 638 2.4. Preparation of Cisplatin hybrid compound 20 ml of Cisplatin (1mg/ml) were added to the Laurus nobilis L. leaves suspension prepared (20 ml), with continuous stirring for two hours. Then this hybrid compound stored in a clean sealed bottle. 2.5. Animals This study was conducted on 36 adult Swiss albino rats weighing between 150-200 g which was obtained from the animal house of animal department Port Said University, Cairo, Egypt. They were maintained on a standard pellet diet and tap water. The animals were housed in suitable cages in conditioned atmosphere (20 - 22°C) and kept on a standard diet. The animals were allowed 10 days for adaptation [14]. These rats were divided into the following groups as 6 rats/ group: • Rats with normal control group (G1) • Rats with induced hepatocellular carcinoma (HCC) group that injected intraperitoneal (IP) by DEN (G2). • Normal rats intraperitoneally injected with cisplatin (G3) (0.64mg/kg body weight/day). • Normal rats intraperitoneally injected with Laurus nobilis L. extract (G4) (250 mg/kg). • Rats with induced HCC treated with cisplatin (G5) (0.64mg/kg body weight/day). • Rats with induced HCC treated with Laurus nobilis L. extract loaded cisplatin (G6) (250 mg/kg). 2.6. Blood Samples At the end of the experiment; blood samples were collected from rats under diethyl ether anesthesia by heart puncture. Blood samples were collected, centrifuged at 3000 rpm for 10 minutes. Serum was then obtained for biochemical analysis. 2.7. Biochemical investigations: The following were measured in the serum of each HCC rat and control subject rat. They include alanine amino-transferase (ALT), aspartate aminotransferase (AST), albumin (Alb), creatinine and urea. These parameters were assayed using automated Biochemistry analyzer (A15; Biosystem, Barcelona, Spain). 2.8. Statistical analysis All statistical analyses were performed by SPSS software. Continuous variables were expressed as mean ± standard deviation (SD). A value of P < 0.05 was considered statistically significant. 3. Results 3.1. Diagnosis performance of candidate markers Table 1 Statistical analysis (ONE WAY) for liver function levels in the different groups concerning to mean± standard deviation Groups ALT (U/L) AST (U/L) Albumin (g/dl) Control (N=6) 18.4± 1.3h 29.38± 0.87h 3.99± 0.07 HCC (N=6) 59.03± 0.96c 72.2± 0.73c 4.08± 0.07 Normal + cisplatin(N=6) 25.39± 0.71h, c 45.6± 1.02h, c 4.49± 0.34h, c Normal + extract (N=6) 19.2± 1.24h 40.6± 1.0h, c 4.2± 0.12 Hcc+ cisplatin (N=6) 47.39± 1.08h, c 62.36± 0.9h, c 5.4± 0.24h, c Hcc+ extract+ cisplatin (N=6) 32.46± 1.06h, c 48.3± 0.8h, c 4.55± 0.28h, c Data expressed as mean ± standard deviation (mean ± SD), P value is significant at ≤ 0.05. N (number of sample members), ALT: alanine aminotransferas, AST: aspartate aminotransferase •c significance vs control group. •h significance vs Hcc group. World Journal of Biology Pharmacy and Health Sciences, 2025, 21(03), 636-641 639 Liver biochemical tests (serum alanine amino-transferase (ALT), aspartate aminotransferase (AST) and albumin) were significantly different in various groups (Table1). The activities of ALT and AST and albumin levels were decreased in significant level in hepatocellular cells treated with hybrid compound of Laurus nobilis L. aqueous extract with cisplatin more than hcc rats treated with cisplatin compared to hcc group and also the hybrid compound data on normal cells has no change when compared with normal group (Figure 1). The kidney function tests include creatinine and urea as they are relationship between the health of kidney and HCC. Data in table 2 revealed that creatinine and urea were significantly decrease in cisplatin Laurus nobilis Leaves extract hybrid compound more than cisplatin treated animals and both of them significant (P≤0.001) compared to HCC group while injected normal animals with cisplatin showed significant change (P≤0.001) but injected normal group with hybrid compound showed no significant change (P˃0.01) when compared to control group animals (Figure 1) Table 2 Statistical analysis (ONE WAY) for kidney function levels in the different groups concerning to mean± standard deviation Groups Creatinine (mg/dl) Urea (mg/dl) Control (N=6) 0.65± 0.1h 41.5± 1.2h HCC (N=6) 2.4± 0.15c 97.3± 1.14c Normal + cisplatin (N=6) 0.9± 0.07h, c 56.3± 1.05h, c Normal + extract (N=6) 0.7± 0.08h 42.3± 0.77h Hcc+ cisplatin (N=6) 1.8± 0.12h, c 81.7± 1.2h, c Hcc+ extract+cisplatin (N=6) 1.3± 0.18h, c 53.4± 0.9h, c P value is significant at ≤ 0.05, N (number of sample members). •c significance vs control group, h significance vs Hcc group. Figure 1 The mean of liver and kidney function tests among different groups 4. Discussion Nowadays, attention is being paid to plants containing phenolic compounds for use in the prevention or treatment diseases like cancer, diabetes and hypertension due to its biological importance in human health and pharmacological properities such as anti-inflammatory, antimicrobial, anti-allergic, antidiuretic, anti-cancer and antioxidant activities.one such plants is Laurus nobilis [15]. World Journal of Biology Pharmacy and Health Sciences, 2025, 21(03), 636-641 640 Laurus nobilis Leaves extract has hypoglycemic effects, antioxidant, and properties to enhance lipid metabolism, liver and kidney function [7]. Liver biochemical markers (serum ALT, AST and albumin) are detectors to liver health and HCC development. The present study showed high significant improvements in serum levels of ALT, AST, albumin (P<0.001) in liver cancer cells treated with hybrid compound of Laurus nobilis Leaves extract with cisplatin more than liver cancer cells treated with cisplatin. And there was no significant change in normal cells treated with the hybrid compound proves that no bad effect on normal cells of liver as shown in Table 1. Also, kidney function markers (serum creatinine and urea) showed high significant improvements in serum levels of creatinine and urea (P<0.001) in liver cancer cells treated with hybrid compound of Laurus nobilis Leaves extract with cisplatin more than liver cancer cells treated with cisplatin. And there was no significant change in normal cells treated with the hybrid compound proves that no bad effect on normal cells of liver as shown in Table 2. The data showed that the liver biomarkers were better HCC treated with hybrid compound than in HCC treated with cisplatin. Also, the same was done with kidney function markers. 5. Conclusion Laurus nobilis L. leaves aqueous extract has medicinal properties in cancer cells and in kidney functions and the more enhancements in hepatocellular carcinoma, the more enhancements in kidney function. Compliance with ethical standards Disclosure of conflict of interest No conflict of interest to be disclosed. Statement of ethical approval The study was conducted on rats which were obtained from the animal house of animal department Port Said University, Cairo, Egypt. They were maintained on a standard pellet diet and tap water. The animals were housed in suitable cages in conditioned atmosphere (20 - 22°C) and kept on a standard diet. The study protocol conformed by the ethical guidelines of the ethical committee of Port Said University, Faculty of Science, Port Said, Egypt (ERN: PSU.Sci.9). 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