Hassen et al. Int J Pharm Pharm Sci, Vol 12, Issue 9, 1-8 1 Original Article THERAPEUTIC EFFECT OF SILVER NANOPARTICLES AGAINST DIETHYL NITROSAMIN AND CARBON TETTRACHLORIDE-INDUCED HEPATOCELLULAR CARCINOMA IN RATS MARWA T. HASSEN 1* , NAJAT JABBAR AHMED 2 , HANAA K. MOHAMED 3 1*,3 Department of Zoology, Faculty of Women for Arts, Science and Education, Ain Shams University, Cairo, Egypt, 2 Erbil Technical Health College, Erbil Polytechnic University, Erbil, Iraq Email: meropinky87@gmail.com Received: 21 Jun 2020, Revised and Accepted: 25 Jul 2020 ABSTRACT Objective: Hepatic cancer is known as primary liver cancer and hepatocellular carcinoma (HCC). Newly silver nanoparticles gained importance due to its advantages and multiple potential such as molecular imaging agent, antimicrobial, wound healing, anti-inflammatory and anticancer activity. The current study deals to assess therapeutic property silver nanoparticles (AgNPs) against diethylnitrosamine (DENA), and carbon tetrachloride (CCL4) induced hepatic cancer. Methods: Thirty male albino rats (200-250g) were distributed into four groups and hepatic cancer was induced with a single intraperitoneal dose of 200 mg/kg body weight of DENA. Two weeks later, animals received subcutaneous injections of CCl4 once a week in a dose of 3 ml/kg body weight for 6weeks. Serum biomarkers, antioxidants enzymes, inflammatory markers were evaluated to find the anti-proliferative potential of silver nanoparticles. Histological evaluation and microscopic reports were also done to document the results of the current work. Results: AgNPs significantly recover the serum marker enzymes of hepatic parameter AST, ALT, ALP, and total bilirubin and also decreased the levels of NO, IL-6 and TNF-α. Histopathological features also exhibited recovery of a hepatic architecture in cancer-induced rats. Moreover, the immunohistochemical investigation demonstrated that the levels of PCNA, and Caspase-3, which are hepatocarcinogenic markers, were significantly improved by AgNPs. Conclusion: These results concluded that AgNPs showed promising curing effects on hepatocellular ailments. Keywords: Hepatocellular carcinoma (HCC), Diethylnitrosoamine (DENA), Carbon tetrachloride (CCL4), Silver nanoparticles (AgNPs), Apoptosis, Interleukin-6(IL-6) © 2020 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/) DOI: http://dx.doi.org/10.22159/ijpps.2020v12i9.38813. Journal homepage: https://innovareacademics.in/journals/index.php/ijpps. INTRODUCTION The liver is the largest solid organ and one of the most vital organs that functions as xenobiotic and drug, energy, protein and amino acid metabolism, storage of glucose in the form of glycogen, storage of vitamins, and regulation of hormonal functions. Ozougwu stated that a total loss of liver function might lead to death within minutes, indicating the liver‘s great importance. Hepatocellular carcinoma (HCC) is a life-threatening neoplasm that originated from hepatocytes, representing approximately 80% of liver cancer and 3 rd most common cancer-related death [1]. HCC is an extremely vascularized and malignant tumor that is responsible for poor survival and rapid recurrence in patients [2]. Human cancers are related to chronic inflammation caused by chemical, biological and, physical factors. The effect of inflammation-fibrosis-carcinoma axis acts as a bridge from inflammation to cancer, and therefore promotes inflamed liver development to fibrosis/cirrhosis and HCC [3]. Upon exposure to risk factors like alcohol, viruses, parasites and, toxic substances, the hepatic injury resulted in the degeneration and inflammation, leading to chronic liver diseases, which may further progress to different stages of fibrosis, cirrhosis, and HCC. HCC is the final stage of this process [3]. Drug-induced liver cancer in rats is an important tool to study primary HCC such as Ethanol, carbon tetrachloride (CCl4), afatoxin, nitrosamines, amino azo dyes, aromatic amine and so on all are used to induce HCC in animal models. Diethylnitrosamine (DENA) is amongst the most essential natural carcinogenic agents, which is known to cause changes in the enzymes required in DNA repair replication and is regularly utilized as a cancer-causing agent to prompt liver carcinogenesis in mouse models [4]. DENA is a well-known potent hepatocarcinogenic agent present in tobacco smoke, water, cured and fried meals, cheddar cheese, agricultural chemicals, cosmetics, and pharmaceutical products [5]. In experimental induction of HCC in animal models, we use the two- stage application of chemicals for the initiation and promotion of hepatocellular tumors. The initiator in this protocol is a single injection of a dose of DENA. Two weeks later, animals received subcutaneous injections of CCl4 for 6 w to promote the carcinogenic effect of DENA. Uehara et al. reported that DENA/CCl4 mouse model differs from animal models utilizing either agent alone in that the resultant chronic liver fibrosis is accompanied by a dramatic increase in the liver tumor incidence, with 100% of the mice in the co-treatment group developing liver tumors by 5 mo of age. The HCC is an extremely vascularized tumor, in which angiogenesis has a critical role in the progression, metastasis, and frequency [6]. One of the angiogenic stimulating factors is oxidative stress/inflammatory cascade. It enhances the vascular permeability and chemokine-mediated enrolment of leukocytes and platelets with major angiogenic cytokines and growth factors release. The most important of these are nitric oxide (NO), vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), interleukin-4 (IL-4), interleukin-8 (IL-8) and tumor necrosis factor-alpha (TNF-α) [7]. Furthermore, dysregulated apoptosis has a crucial role in HCC tumorigenesis and acquired resistance to chemotherapy. Nanotechnology, a concept in the field of science and technology in recent years, has also been likely to grow based on their demand, like other technologies. Nanoparticles are usually a cluster of atoms ranging between 1-100 nm in size and they exhibit new properties based on their size, distribution and morphology [8]. Many materials are synthesized in nanosize for various applications, including medicine, mechanical, biomedical, and electronics. Though the biological method is commonly adopted for the creation of silver nanoparticles, the use of plant extracts is widely spread studied due to its advantages over others [9]. Among the nanoparticles, nanosilver has potential applications in the field of biomedicine since silver has a disinfecting effect and has found International Journal of Pharmacy and Pharmaceutical Sciences Print ISSN: 2656-0097 | Online ISSN: 0975-1491 Vol 12, Issue 9, 2020