title: p53-independent structure-activity relationships of 3-ring mesogenic compounds' activity as cytotoxic effects against human non-small cell lung cancer lines.
abstract: We recently demonstrated the cytotoxicity of liquid crystal precursors (hereafter referred to as "mesogenic compounds") in the human non-small cell lung cancer (NSCLC) cell line A549 which carry wild-type p53. p53 mutations are observed in 50 % of NSCLC and contribute to their resistance to chemotherapy. To develop more effective and cancer-specific agents, in this study, we investigated the structure-activity relationships of mesogenic compounds with cytotoxic effects against multiple NSCLC cells.
  
  
  
  The pharmacological effects of mesogenic compounds were examined in human NSCLC cells (A549, LU99, EBC-1, and H1299) and normal WI-38 human fibroblast. Analyses of the cell cycle, cell-death induction, and capsases expression were performed.
  
  
  
  The 3-ring compounds possessing terminal alkyl and hydroxyl groups (compounds C1-C5) showed cytotoxicity in NSCLC cells regardless of the p53 status. The compounds C1 and C3, which possess a pyrimidine at the center of the core, induced G2/M arrest, while the compounds without a pyrimidine (C2, C4, and C5) caused G1 arrest; all compounds produced caspase-mediated cell death. These events occurred in a p53-independent manner. Furthermore, it was suggested that compounds induced cell death through p53-independent DNA damage-signaling pathway. Compounds C2, C4, and C5 did not show strong cytotoxicity in WI-38 cells, whereas C1 and C3 did. However, the cytotoxicity of compound C1 against WI-38 cells was improved by modulating the terminal alkyl chain lengths of the compound.
  
  
  
  We showed the p53-indepdent structure-activity relationships of mesogenic compounds related to the cytotoxic effects. These structure-activity relationships will be helpful in the development of more effective and cancer-specific agents.
authors.affiliation: Department of Frontier Materials Chemistry, Graduate School of Science and Technology, Hirosaki University, 3 Bunkyo-cho, Hirosaki, Aomori, 036-8561, Japan.
authors.forename: Saori
authors.initials: S
authors.lastname: Fukushi
authors.affiliation: Department of Radiation Science, Hirosaki University Graduate School of Health Sciences, 66-1 Hon-cho, Hirosaki, Aomori, 036-8564, Japan.
authors.forename: Hironori
authors.initials: H
authors.lastname: Yoshino
authors.affiliation: Department of Frontier Materials Chemistry, Graduate School of Science and Technology, Hirosaki University, 3 Bunkyo-cho, Hirosaki, Aomori, 036-8561, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Yoshizawa
authors.affiliation: Department of Radiation Science, Hirosaki University Graduate School of Health Sciences, 66-1 Hon-cho, Hirosaki, Aomori, 036-8564, Japan. ikashi@hirosaki-u.ac.jp.
authors.forename: Ikuo
authors.initials: I
authors.lastname: Kashiwakura
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D045744:Cell Line, Tumor; D004249:DNA Damage; D004354:Drug Screening Assays, Antitumor; D059565:G2 Phase Cell Cycle Checkpoints; D006571:Heterocyclic Compounds / Q000494:pharmacology; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
chemical_list: D000970:Antineoplastic Agents; D006571:Heterocyclic Compounds; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53
keywords: Alkyl chain length; Caspase; Cell death; DNA damage-signaling pathway; G1 arrest; G2/M arrest; Non-small cell lung cancer; Structure–activity relationship; p53