title: 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.
abstract: 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.
authors.affiliation: College of Pharmacy, Natural Products Research Institute, Seoul National University , Seoul 151-742, Korea.
authors.forename: Cholomi
authors.initials: C
authors.lastname: Jung
authors.affiliation: College of Pharmacy, Natural Products Research Institute, Seoul National University , Seoul 151-742, Korea.
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Hong
authors.affiliation: College of Pharmacy, Natural Products Research Institute, Seoul National University , Seoul 151-742, Korea.
authors.forename: Song Yi
authors.initials: SY
authors.lastname: Bae
authors.affiliation: College of Pharmacy, Natural Products Research Institute, Seoul National University , Seoul 151-742, Korea.
authors.forename: Sam Sik
authors.initials: SS
authors.lastname: Kang
authors.affiliation: College of Pharmacy, Natural Products Research Institute, Seoul National University , Seoul 151-742, Korea.
authors.forename: Hyen Joo
authors.initials: HJ
authors.lastname: Park
authors.affiliation: College of Pharmacy, Natural Products Research Institute, Seoul National University , Seoul 151-742, Korea.
authors.forename: Sang Kook
authors.initials: SK
authors.lastname: Lee
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D017209:Apoptosis; D016203:CDC2 Protein Kinase / Q000378:metabolism; D000071877:Checkpoint Kinase 1; D064447:Checkpoint Kinase 2 / Q000378:metabolism; D003110:Colonic Neoplasms; D004147:Dioxins / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D029604:Phytolacca americana / Q000737:chemistry*; D011494:Protein Kinases / Q000378:metabolism; D012639:Seeds / Q000737:chemistry; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004147:Dioxins; D016159:Tumor Suppressor Protein p53; C055021:americanin A; D011494:Protein Kinases; D064447:Checkpoint Kinase 2; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse; D016203:CDC2 Protein Kinase