title: Novel carbocyclic curcumin analog CUR3d modulates genes involved in multiple apoptosis pathways in human hepatocellular carcinoma cells.
abstract: Anticancer activity of a novel curcumin analog (E)-2-(4-hydroxy-3-methoxybenzylidene)-5-((E)-3-(4-hydroxy-3-methoxyphenyl)acryloyl)cyclopentanone (CUR3d) was studied using a human hepatocellular carcinoma cell line (HepG2). The results showed that CUR3d completely inhibits the tumor cell proliferation in a dose- and time-dependent manner. CUR3d at 100 μmol/L activated the pro-apoptotic caspase-3 along with downregulation of anti-apoptotic BIRC5 and Bcl2. CUR3d treatment controlled the cancer cell growth by downregulating the expression of PI3K/Akt (Akt1, Akt2) pathway along with NF-κB. CUR3d down-regulated the members of epidermal growth receptor family (EGFR, ERBB3, ERBB2) and insulin like growth receptors (IGF1, IGF-1R, IGF2). This correlated with the downregulation of G-protein (RHOA, RHOB) and RAS (ATF2, HRAS, KRAS, NRAS) pathway signaling. CUR3d also arrested cell cycle via inhibition of CDK2, CDK4, CDK5, CDK9, MDM2, MDM4 and TERT genes. Cell cycle essential aurora kinases (AURKα, AURKβ) and polo-like kinases (PLK1, PLK2, PLK3) were also modulated by CUR3d. Topoisomerases (TOP2α, TOP2β), important factors in cancer cell immortality, as well as HIF-1α were downregulated following CUR3d treatment. The expression of protein kinase-C family (PRKC-A, PRKC-D, PRKC-E) was also attenuated by CUR3d. The downregulation of histone deacetylases (Class I, II, IV) and PARP I further strengthened the anticancer efficacy of CUR3d. Downregulation of carcinogenic cathepsins (CTSB, CTSD) and heat shock proteins exhibited CUR3d's potency as a potential immunological adjuvant. Finally, the non-toxic manifestation of CUR3d in healthy liver and lung cells along with downregulation of drug resistant gene ABCC1 further warrant need for advance investigations.
authors.affiliation: Department of Environmental Sciences, Faculty of Agriculture, Dalhousie University, Truro, Nova Scotia, B2N 5E3, Canada; Department of Pharmacology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, T6G 2H7, Canada.
authors.forename: Khushwant S
authors.initials: KS
authors.lastname: Bhullar
authors.affiliation: Department of Chemistry, Acadia University, Wolfville, Nova Scotia, B4P 2R6, Canada.
authors.forename: Amitabh
authors.initials: A
authors.lastname: Jha
authors.affiliation: Department of Environmental Sciences, Faculty of Agriculture, Dalhousie University, Truro, Nova Scotia, B2N 5E3, Canada; Department of Pathology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, B3H 4R2, Canada. Electronic address: vrupasinghe@dal.ca.
authors.forename: H P Vasantha
authors.initials: HP
authors.lastname: Rupasinghe
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003474:Curcumin / Q000031:analogs & derivatives* / Q000494:pharmacology; D053938:DNA Fragmentation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056945:Hep G2 Cells / Q000187:drug effects; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051381:Rats
chemical_list: C000607201:2-(4-hydroxy-3-methoxybenzylidene)-5-(3-(4-hydroxy-3-methoxyphenyl)acryloyl)cyclopentanone; D000970:Antineoplastic Agents; D053148:Caspase 3; D003474:Curcumin
keywords: Apoptosis; Cancer; Cell cycle; Curcumin; DNA damage; HepG2