title: Synthesis and cytotoxic activity of novel A-ring cleaved ursolic acid derivatives in human non-small cell lung cancer cells.
abstract: Ursolic acid (UA) is a pentacyclic triterpenoid with recognized anticancer properties. We prepared a series of new A-ring cleaved UA derivatives and evaluated their antiproliferative activity in non-small cell lung cancer (NSCLC) cell lines using 2D and 3D culture models. Compound 17, bearing a cleaved A-ring with a secondary amide at C3, was found to be the most active compound, with potency in 2D systems. Importantly, even in 3D systems, the effect was maintained albeit a slight increase in the IC50. The molecular mechanism underlying the anticancer activity was further investigated. Compound 17 induced apoptosis via activation of caspase-8 and caspase-7 and via decrease of Bcl-2. Moreover, induction of autophagy was also detected with increased levels of Beclin-1 and LC3A/B-II and decreased levels of mTOR and p62. DNA synthetic capacity and cell cycle profiles were not affected by the drug, but total RNA synthesis was modestly but significantly decreased. Given its activity and mechanism of action, compound 17 might represent a potential candidate for further cancer research.
authors.affiliation: Laboratory of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Coimbra, 3000-548, Coimbra, Portugal; Center for Neuroscience and Cell Biology, Coimbra, Portugal.
authors.forename: Vanessa I S
authors.initials: VIS
authors.lastname: Mendes
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Geoffrey A
authors.initials: GA
authors.lastname: Bartholomeusz
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Ayres
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: vgandhi@mdanderson.org.
authors.forename: Varsha
authors.initials: V
authors.lastname: Gandhi
authors.affiliation: Laboratory of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Coimbra, 3000-548, Coimbra, Portugal; Center for Neuroscience and Cell Biology, Coimbra, Portugal. Electronic address: salvador@ci.uc.pt.
authors.forename: Jorge A R
authors.initials: JAR
authors.lastname: Salvador
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology*; D045744:Cell Line, Tumor; D060326:Chemistry Techniques, Synthetic; D004247:DNA / Q000096:biosynthesis; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology*; D014176:Protein Biosynthesis / Q000187:drug effects; D012313:RNA / Q000096:biosynthesis; D014315:Triterpenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000097245:Ursolic Acid
chemical_list: D000970:Antineoplastic Agents; D004247:DNA; D012313:RNA; D014315:Triterpenes; D000097245:Ursolic Acid
keywords: Apoptosis; Autophagy; Lung cancer; Spheroid; Triterpenoids; Ursolic acid