الفهرس 
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Abstract
Hepatocellular carcinoma is the sixth most prevailed cancer worldwide, and the fourth cause of cancer related death, it is the first cancer related death in Egypt. HCC is considered one of the malicious cancers for many reasons: First, high level of diagnosis in late stages where it is advanced and uncurable. Second, chemotherapy failed in HCC due to accelerated resistance mechanisms and that in most cases liver cannot tolerate chemotherapy specially when majority of patients suffer from cirrhosis and compromised liver functions. Thirdly, cirrhosis renders surgical resection or other curative treatments impossible. Another reason is that HCC lack specific addiction to clearly identified pathways or oncogene, which until recently hindered therapeutic specific targeted options limited.
HCC has many risk factors that could be environmental infectious such as hepatitis viruses HBV and HCV which are considered major risk factors for HCC development. Aflatoxins and some chemicals used in fertilizers are dangerous HCC risk factor especially in rural areas. Other host dependant factors such as obesity, smoking, genetic or metabolic diseases such as hemochromatosis, NAFLD, or autoimmune hepatitis also pose risk factors for HCC.
Hepatocarcinogenesis is a convoluted process, its initiation cannot be tracked even if the chief reason is known such as HBV. Nevertheless, some altered pathways, genomic alterations and tumor microenvironment factors can be traced to study this process. In most of the cases HCC has underlying liver disease that cause constituent inflammation that led to tumor formation.
Many genomic alterations occur in HCC pathogenesis, all of them serve mainly to increase cell survival and evade death. It could be somatic, copy number variation, insertion mutations or epigenetic mutations. Dysregulated signalling pathways contribute to hepatocarcinogenesis, many signalling pathways are altered in HCC initiation, progression of the diseases and even in resistance to treatments. The most altered pathways in HCC are growth factors related signalling pathways specially VEGF/VEGFR pathway, HGF/ c-MF.1 pathway. Intracellular pathways such as MAPK pathway. PI3K/Akt/mTOR pathways that regulate many aspects in tumorigenesis including cell survival, angiogenesis, proliferation, migration, apoptosis evasion. Inflammatory regulating pathways also plays a pivotal role in HCC progression such as NF-kB pathway, among others.
This study objective is to find a combinatorial approach to target these pathways, as a hallmark of cancer dysregulation of one pathway led to activation of others and may raise resistance. Regorafenib is the second line of treatment for HCC, it is a multikinase inhibitor and fluoro-derivative of sorafenib. It can inhibit angiogenic and stromal kinases on tumor cells and epithelial cells such as angiopoietin, Tie-2 system, VEGFR1/3, PDGFR-p, FGFR1, mutant kinases such as KIT, RET, and intracellular RAF kinases. Berberine is a small molecule with multitargets, it has antioxidant, anti-inflammatory and anti-tumorigenic effects, molecular docking techniques showed direct interaction with binding site of crucial kinases.
In current study, HepG2 cell line was used to evaluate effect of regorafenib, berberine each alone or in combination. Cytotoxic effect of both was evaluated utilizing MTT assay where IC50 of each was determined, regorafenib IC50 was 12.027 pM and that of berberine was 261.104 pM after 72h incubation at 37°C and 5% C02, combination used the same IC50 for each drug alone (12.027 pM regorafenib+ 261.104 pM berberine). The combination index was 0.918 at 50% growth inhibition indicating synergistic effect. The combination decreased the dose required for berberine 4.2-fold, and for regorafenib 1.46-fold decreasing doses so potential side effects.