title: Activation of the c-Jun N-terminal kinase/activating transcription factor 3 (ATF3) pathway characterizes effective arylated diazeniumdiolate-based nitric oxide-releasing anticancer prodrugs.
abstract: Improved therapies are needed for nonsmall cell lung cancer. Diazeniumdiolate-based nitric oxide (NO)-releasing prodrugs are a growing class of promising NO-based therapeutics. Recently, we have shown that O(2)-(2,4-dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate (JS-K, 1) is effective against nonsmall cell lung cancer (NSCLC) cells in culture and in vivo. Here we report mechanistic studies with compound 1 and its homopiperazine analogue and structural modification of these into more stable prodrugs. Compound 1 and its homopiperazine analogue were potent cytotoxic agents against NSCLC cells in vitro and in vivo, concomitant with activation of the SAPK/JNK stress pathway and upregulation of its downstream effector ATF3. Apoptosis followed these events. An aryl-substituted analogue, despite extended half-life in the presence of glutathione, did not activate JNK or have antitumor activity. The data suggest that rate of reactivity with glutathione and activation of JNK/ATF3 are determinants of cancer cell killing by these prodrugs.
authors: SAIC-Frederick, Inc. , National Cancer Institute, Frederick, Maryland 21702, United States.
authors: Anna E
authors: AE
authors: Maciag
authors: Rahul S
authors: RS
authors: Nandurdikar
authors: Sam Y
authors: SY
authors: Hong
authors: Harinath
authors: H
authors: Chakrapani
authors: Bhalchandra
authors: B
authors: Diwan
authors: Nicole L
authors: NL
authors: Morris
authors: Paul J
authors: PJ
authors: Shami
authors: Yih-Horng
authors: YH
authors: Shiao
authors: Lucy M
authors: LM
authors: Anderson
authors: Larry K
authors: LK
authors: Keefer
authors: Joseph E
authors: JE
authors: Saavedra
mesh_terms: D051700:Activating Transcription Factor 3 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000473:pathology; D059447:Cell Cycle Checkpoints; D002455:Cell Division; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D016195:G2 Phase; D020868:Gene Silencing; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D020030:Nitric Oxide Donors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
chemical_list: D051700:Activating Transcription Factor 3; D000970:Antineoplastic Agents; D020030:Nitric Oxide Donors; D010879:Piperazines; D011355:Prodrugs; D048031:JNK Mitogen-Activated Protein Kinases