title: Antitumor activity of a novel oncrasin analogue is mediated by JNK activation and STAT3 inhibition.
abstract: BACKGROUND
  To optimize the antitumor activity of oncrasin-1, a small molecule identified through synthetic lethality screening on isogenic K-Ras mutant tumor cells, we developed several analogues and determined their antitumor activities. Here we investigated in vitro and in vivo antitumor activity of NSC-743380 (1-[(3-chlorophenyl) methyl]-1H-indole-3-methanol, oncrasin-72), one of most potent analogues of oncrasin-1.
  
  
  RESULTS
  In vitro antitumor activity was determined in NCI-60 cancer cell line panel using cell viability assay. In vivo antitumor activity was determined in parallel with NSC-741909 (oncrasin-60) in xenograft tumors established in nude mice from A498, a human renal cancer cell line. Changes in gene expression levels and signaling pathway activities upon treatment with NSC-743380 were analyzed in breast and renal cancer cells by Western blot analysis. Apoptosis was demonstrated by Western blot analysis and flow cytometric analysis. NSC-743380 is highly active against a subset of cancer cell lines derived from human lung, colon, ovary, kidney, and breast cancers. The 50% growth-inhibitory concentration (GI(50)) for eight of the most sensitive cell lines was ≤ 10 nM. In vivo study showed that NSC-743380 has a better safety profile and greater antitumor activity than NSC-741909. Treatment with NSC-743380 caused complete regression of A498 xenograft tumors in nude mice at the tested doses ranging from 67 mg/kg to 150 mg/kg. Mechanistic characterization revealed that NSC-743380 suppressed the phosphorylation of C-terminal domain of RNA polymerase II, induced JNK activation, inhibited JAK2/STAT3 phosphorylation and suppressed cyclin D1 expression in sensitive human cancer cells. Blocking JNK activation or overexpression of constitutively active STAT3 partially blocked NSC-743380-induced antitumor activity.
  
  
  CONCLUSIONS
  NSC-743380 induces antitumor activity through modulation of functions in multiple cancer related pathways and could be a potential anticancer agent for some solid tumors.
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Wei
authors.initials: W
authors.lastname: Guo
authors.forename: Shuhong
authors.initials: S
authors.lastname: Wu
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Wei
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Liu
authors.forename: Ji
authors.initials: J
authors.lastname: Wang
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Lu
authors.forename: Melinda
authors.initials: M
authors.lastname: Hollingshead
authors.forename: Bingliang
authors.initials: B
authors.lastname: Fang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012319:RNA Polymerase II / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D040521:Subcutaneous Tissue / Q000187:drug effects / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: C000595256:1-((3-chlorophenyl)methyl)-1H-indole-3-carbinol; D000970:Antineoplastic Agents; D007211:Indoles; D047428:Protein Kinase Inhibitors; D050796:STAT3 Transcription Factor; C532252:oncrasin-1; D048031:JNK Mitogen-Activated Protein Kinases; D012319:RNA Polymerase II