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      Comparative Study between the 3D‐Liver Spheroid Models Developed from HepG2 and Immortalized Hepatocyte‐Like Cells with Primary Hepatic Stellate Coculture for Drug Metabolism Analysis and Anticancer Drug Screening

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          Abstract

          Liver spheroids may be the best alternative models for evaluating efficacy and toxicity of the new anticancer candidates and diagnostics for hepatocellular carcinoma (HCC). Here, novel 3D‐liver spheroid models are constructed from human hepatoma cells (HepG2)/ immortalized human hepatocyte‐like cells (imHCs) with primary hepatic stellate cells (HSCs) coculture using the ultralow attachment technique. Spheroid morphology, HSC distribution, metabolic activity, protein expressions, and drug penetration are evaluated. All developed 3D spheroid models exhibit in spherical shape with narrow size distribution, diameter between 639–743 (HepG2‐10%HSC) and 519–631 (imHC‐10%HSC) µm. Both imHC mono and coculture models significantly express normal liver biomarkers at the higher level than HepG2 models. While 3D‐HepG2 models significantly exhibit HCC biomarkers at the higher level than imHC models. HepG2 and imHC spheroids express basal cytochrom P450 (CYP450) enzymes at different levels depending on cell types, culture period, and ratio of coculture. Their metabolic activities for dextromethorphan (CYP2D6) tolbutamide (CYP2C9) and midazolam (CYP3A4) are routinely evaluated. For midazolam metabolism, imHC models allow the detection of phase II metabolic enzymes (UGT2B4 and UGT2B7). The presence of HSC in HepG2‐HSC model increases biological barrier for doxorubicin (DOX) penetration, and escalates IC 50 of DOX from 61.4 to 127.2 µg mL −1.

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          Most cited references64

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          Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries

          This article provides an update on the global cancer burden using the GLOBOCAN 2020 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer. Worldwide, an estimated 19.3 million new cancer cases (18.1 million excluding nonmelanoma skin cancer) and almost 10.0 million cancer deaths (9.9 million excluding nonmelanoma skin cancer) occurred in 2020. Female breast cancer has surpassed lung cancer as the most commonly diagnosed cancer, with an estimated 2.3 million new cases (11.7%), followed by lung (11.4%), colorectal (10.0 %), prostate (7.3%), and stomach (5.6%) cancers. Lung cancer remained the leading cause of cancer death, with an estimated 1.8 million deaths (18%), followed by colorectal (9.4%), liver (8.3%), stomach (7.7%), and female breast (6.9%) cancers. Overall incidence was from 2-fold to 3-fold higher in transitioned versus transitioning countries for both sexes, whereas mortality varied <2-fold for men and little for women. Death rates for female breast and cervical cancers, however, were considerably higher in transitioning versus transitioned countries (15.0 vs 12.8 per 100,000 and 12.4 vs 5.2 per 100,000, respectively). The global cancer burden is expected to be 28.4 million cases in 2040, a 47% rise from 2020, with a larger increase in transitioning (64% to 95%) versus transitioned (32% to 56%) countries due to demographic changes, although this may be further exacerbated by increasing risk factors associated with globalization and a growing economy. Efforts to build a sustainable infrastructure for the dissemination of cancer prevention measures and provision of cancer care in transitioning countries is critical for global cancer control.
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            EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma

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              Hepatocellular carcinoma

              Liver cancer remains a global health challenge, with an estimated incidence of >1 million cases by 2025. Hepatocellular carcinoma (HCC) is the most common form of liver cancer and accounts for ~90% of cases. Infection by hepatitis B virus and hepatitis C virus are the main risk factors for HCC development, although non-alcoholic steatohepatitis associated with metabolic syndrome or diabetes mellitus is becoming a more frequent risk factor in the West. Moreover, non-alcoholic steatohepatitis-associated HCC has a unique molecular pathogenesis. Approximately 25% of all HCCs present with potentially actionable mutations, which are yet to be translated into the clinical practice. Diagnosis based upon non-invasive criteria is currently challenged by the need for molecular information that requires tissue or liquid biopsies. The current major advancements have impacted the management of patients with advanced HCC. Six systemic therapies have been approved based on phase III trials (atezolizumab plus bevacizumab, sorafenib, lenvatinib, regorafenib, cabozantinib and ramucirumab) and three additional therapies have obtained accelerated FDA approval owing to evidence of efficacy. New trials are exploring combination therapies, including checkpoint inhibitors and tyrosine kinase inhibitors or anti-VEGF therapies, or even combinations of two immunotherapy regimens. The outcomes of these trials are expected to change the landscape of HCC management at all evolutionary stages.
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                Author and article information

                Contributors
                (View ORCID Profile)
                Journal
                Advanced Therapeutics
                Advanced Therapeutics
                Wiley
                2366-3987
                2366-3987
                February 2023
                December 14 2022
                February 2023
                : 6
                : 2
                Affiliations
                [1 ] Department of Pharmacy Faculty of Pharmacy Mahidol University 447 Sri‐Ayutthaya Rd Rajathevi Bangkok 10400 Thailand
                [2 ] National Center for Genetic Engineering and Biotechnology (BIOTEC) National Science and Technology Development Agency (NSTDA) Pathum Thani 10200 Thailand
                [3 ] Department of Biochemistry Faculty of Pharmacy Mahidol University 447 Sri‐Ayutthaya Rd Rajathevi Bangkok 10400 Thailand
                [4 ] Department of Surgery and Cancer Imperial College London South Kensington Campus Exhibition Road London SW7 2AZ UK
                [5 ] Department of Materials and London Centre for Nanotechnology Imperial College London Exhibition Road London SW7 2AZ UK
                [6 ] Department of Pediatrics Faculty of Medicine Ramathibodi Hospital Mahidol University Rama VI Rd Rajathevi Bangkok 10400 Thailand
                Article
                10.1002/adtp.202200169
                2ec6dd3f-7704-4aec-9b05-17787c87c230
                © 2023

                http://creativecommons.org/licenses/by-nc-nd/4.0/

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