Antitumor Activity of Americanin A Isolated from the Seeds of Phytolacca americana by Regulating the ATM/ATR Signaling Pathway and the Skp2-p27 Axis in Human Colon Cancer Cells

J Nat Prod. 2015 Dec 24;78(12):2983-93. doi: 10.1021/acs.jnatprod.5b00743. Epub 2015 Nov 23.


The antiproliferative and antitumor activities of americanin A (1), a neolignan isolated from the seeds of Phytolacca americana, were investigated in human colon cancer cells. Compound 1 inhibited the proliferation of HCT116 human colon cancer cells both in vitro and in vivo. The induction of G2/M cell-cycle arrest by 1 was concomitant with regulation of the ataxia telangiectasia-mutated/ATM and Rad3-related (ATM/ATR) signaling pathway. Treatment with 1 activated ATM and ATR, initiating the subsequent signal transduction cascades that include checkpoint kinase 1 (Chk1), checkpoint kinase 2 (Chk2), and tumor suppressor p53. Another line of evidence underlined the significance of 1 in regulation of the S phase kinase-associated protein 2 (Skp2)-p27 axis. Compound 1 targeted selectively Skp2 for degradation and thereby stabilized p27. Therefore, compound 1 suppressed the activity of cyclin B1 and its partner cell division cycle 2 (cdc2) to prevent entry into mitosis. Furthermore, prolonged treatment with 1 induced apoptosis by producing excessive reactive oxygen species. The intraperitoneal administration of 1 inhibited the growth of HCT116 tumor xenografts in nude mice without any overt toxicity. Modulation of the ATM/ATR signaling pathway and the Skp2-p27 axis might be plausible mechanisms of action for the antiproliferative and antitumor activities of 1 in human colon cancer cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents, Phytogenic / chemistry
  • Antineoplastic Agents, Phytogenic / isolation & purification*
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Apoptosis
  • CDC2 Protein Kinase / metabolism
  • Checkpoint Kinase 1
  • Checkpoint Kinase 2 / metabolism
  • Colonic Neoplasms
  • Dioxins / chemistry
  • Dioxins / isolation & purification*
  • Dioxins / pharmacology*
  • G2 Phase Cell Cycle Checkpoints / drug effects
  • HCT116 Cells
  • Humans
  • Mice
  • Mice, Nude
  • Molecular Structure
  • Phytolacca americana / chemistry*
  • Protein Kinases / metabolism
  • Seeds / chemistry
  • Signal Transduction
  • Tumor Suppressor Protein p53 / metabolism


  • Antineoplastic Agents, Phytogenic
  • Dioxins
  • Tumor Suppressor Protein p53
  • americanin A
  • Protein Kinases
  • Checkpoint Kinase 2
  • CHEK1 protein, human
  • Checkpoint Kinase 1
  • Chek1 protein, mouse
  • CDC2 Protein Kinase