title: Targeting of multiple senescence-promoting genes and signaling pathways by triptonide induces complete senescence of acute myeloid leukemia cells.
abstract: Leukemia cells aberrantly overexpress senescence-suppression telomerase reverse transcriptase (TERT) and down-regulate key senescence-promoting genes to escape complete senescence, resulting in immortalization and malignant progression. Accordingly, induction of complete senescence is a sensible strategy for anti-leukemia therapy. However, effective senescence-based anti-leukemia drugs with low toxicity are currently lacking. In this study, we found that triptonide (chemical name diterpene triepoxide), a small molecule derived from the herb Tripterygium wilfordii Hook, strongly induced complete senescence in cultured acute myeloid leukemia (AML) cell lines, and potently inhibited growth and colony formation of U937 and HL-60 AML cell line with IC50values of 7.5 and 12nM, respectively. Strikingly, triptonide (4mg/kg) nearly completely suppressed human leukemia cell tumorigenicity (>99%) without obvious toxicity in a mouse xenograft model. Mechanistic studies showed that triptonide induced senescence followed by apoptosis mainly by suppressing transcription of TERT and oncogenic c-Myc, while concomitantly promoting transcription of senescence-promoting genes p16 and p21 and the pro-apoptotic gene encoding DNA damage-inducible transcript 3. These effects of triptonide are mediated by selective mitogen-activated protein kinase kinase-3/p38 signaling pathway activation. Our study provides a conceptual framework for inducing complete senescence as an effective anti-leukemia therapeutic strategy through a "multiple-hits" model and supports further development of triptonide as an anti-cancer agent.
authors.affiliation: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, 2011 Collaborative Innovation Center of Hematology, Soochow University, Suzhou, Jiangsu 215123, China.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Pan
authors.affiliation: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, 2011 Collaborative Innovation Center of Hematology, Soochow University, Suzhou, Jiangsu 215123, China.
authors.forename: Mei
authors.initials: M
authors.lastname: Meng
authors.affiliation: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, 2011 Collaborative Innovation Center of Hematology, Soochow University, Suzhou, Jiangsu 215123, China.
authors.forename: Nana
authors.initials: N
authors.lastname: Zheng
authors.affiliation: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, 2011 Collaborative Innovation Center of Hematology, Soochow University, Suzhou, Jiangsu 215123, China.
authors.forename: Zhifei
authors.initials: Z
authors.lastname: Cao
authors.affiliation: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, 2011 Collaborative Innovation Center of Hematology, Soochow University, Suzhou, Jiangsu 215123, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Xi
authors.affiliation: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, 2011 Collaborative Innovation Center of Hematology, Soochow University, Suzhou, Jiangsu 215123, China. Electronic address: zhouqs@suda.edu.cn.
authors.forename: Quansheng
authors.initials: Q
authors.lastname: Zhou
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D063646:Carcinogenesis / Q000187:drug effects / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects* / Q000235:genetics; D004354:Drug Screening Assays, Antitumor; D005260:Female; D018922:HL-60 Cells; D006801:Humans; D007942:Leukemia, Experimental / Q000188:drug therapy* / Q000473:pathology; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D015398:Signal Transduction; D029757:Tripterygium / Q000737:chemistry*; D014315:Triterpenes / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D020298:U937 Cells
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D014315:Triterpenes; C084079:triptonide
keywords: Apoptosis; Leukemia; Senescence; TERT; Triptonide