Targeting of multiple senescence-promoting genes and signaling pathways by triptonide induces complete senescence of acute myeloid leukemia cells

Biochem Pharmacol. 2017 Feb 15:126:34-50. doi: 10.1016/j.bcp.2016.11.024. Epub 2016 Nov 28.

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 IC50 values 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.

Keywords: Apoptosis; Leukemia; Senescence; TERT; Triptonide.

MeSH terms

  • Animals
  • Antineoplastic Agents, Phytogenic / chemistry
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Antineoplastic Agents, Phytogenic / therapeutic use
  • Carcinogenesis / drug effects
  • Carcinogenesis / pathology
  • Cell Proliferation / drug effects
  • Cellular Senescence / drug effects*
  • Cellular Senescence / genetics
  • Drug Screening Assays, Antitumor
  • Female
  • HL-60 Cells
  • Humans
  • Leukemia, Experimental / drug therapy*
  • Leukemia, Experimental / pathology
  • Mice, Inbred NOD
  • Mice, SCID
  • Neoplasm Transplantation
  • Signal Transduction
  • Tripterygium / chemistry*
  • Triterpenes / chemistry
  • Triterpenes / pharmacology*
  • Triterpenes / therapeutic use
  • U937 Cells

Substances

  • Antineoplastic Agents, Phytogenic
  • Triterpenes
  • triptonide