title: Antitumor Activities of the Novel Isosteviol Derivative 10C Against Liver Cancer.
abstract: Hepatocellular carcinoma (HCC) is the most common type of liver cancer and the fifth most common primary malignancy with worldwide increasing incidence. The current study aimed to investigate the anticancer activities of novel isosteviol derivatives towards human HepG2 hepatocellular cancer cells and in an animal model of hepatocellular carcinoma.
  
  
  
  Twelve isosteviol derivatives were screened for their anti-proliferative activities against HepG2 and IC50was calculated for all designed derivatives. The impact of the potent isosteviol derivative 10C on HepG2 cells was further studied by MTT assay, Annexin V/PI staining, flow cytometry and western blotting. In vivo studies were performed to assess the anticancer effect of isosteviol derivative 10C on Diethyl Nitrosamine-induced liver cancer in female rats by evaluating the physiological processes.
  
  
  
  isosteviol derivative 10C induced growth inhibition with IC50of 2 μM mainly through induction of apoptosis in HepG2 cells. Additionally, isosteviol derivative 10C induced G1phase arrest, which was further confirmed by increased expression of cyclin dependent kinase inhibitor 1A (CDKN1A, p21). It also increased BAX, BID and PARP-1 and while it reduced pro-CASPASE-3 expression and phosphorylation levels of AKT in HepG2 cells. Furthermore, western blotting data showed that E-cadherin, β-catenin, VEGF and COX-2 expressions were suppressed by isosteviol derivative 10C in HepG2 cells. The in vivo study demonstrated that dose-dependent treatment of isosteviol derivative 10C led to significant reduction in tumor size compared to the untreated group after the fourth injection with no significant effects on major physiological processes.
  
  
  
  Taken together, in vitro and in vivo studies revealed that isosteviol derivative 10C induced apoptosis in HepG2 cells, blocked angiogenic signaling and it did not induce any apparent toxicity towards the treated hosts which merits further investigation at clinical level.
authors.affiliation: Biomedical Science Department, Qatar University, Doha, Qatar ahmed.malki@qu.edu.qa.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Malki
authors.affiliation: Biochemistry Department, Alexandria University, Alexandria, Egypt.
authors.forename: Ahmed
authors.initials: A
authors.lastname: El-Sharkawy
authors.affiliation: Biochemistry Department, Alexandria University, Alexandria, Egypt.
authors.forename: Mohamed
authors.initials: M
authors.lastname: El Syaed
authors.affiliation: Department of Chemistry and Biochemistry, Ohio University, Athens, OH, U.S.A.
authors.forename: Stephen
authors.initials: S
authors.lastname: Bergmeier
mesh_terms: D000477:Alkylating Agents / Q000633:toxicity; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D004052:Diethylnitrosamine / Q000633:toxicity; D045786:Diterpenes, Kaurane / Q000737:chemistry*; D005260:Female; D005434:Flow Cytometry; D056945:Hep G2 Cells; D006801:Humans; D007124:Immunoenzyme Techniques; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction
chemical_list: D000477:Alkylating Agents; D000970:Antineoplastic Agents; D045786:Diterpenes, Kaurane; C515747:isosteviol; D004052:Diethylnitrosamine
keywords: Isosteviol; VEGF; in vivo; liver cancer; p21