Pentagamavunon-1 (PGV-1) inhibits ROS metabolic enzymes and suppresses tumor cell growth by inducing M phase (prometaphase) arrest and cell senescence

Sci Rep. 2019 Oct 16;9(1):14867. doi: 10.1038/s41598-019-51244-3.

Abstract

We previously showed that curcumin, a phytopolyphenol found in turmeric (Curcuma longa), targets a series of enzymes in the ROS metabolic pathway, induces irreversible growth arrest, and causes apoptosis. In this study, we tested Pentagamavunon-1 (PGV-1), a molecule related to curcumin, for its inhibitory activity on tumor cells in vitro and in vivo. PGV-1 exhibited 60 times lower GI50 compared to that of curcumin in K562 cells, and inhibited the proliferation of cell lines derived from leukemia, breast adenocarcinoma, cervical cancer, uterine cancer, and pancreatic cancer. The inhibition of growth by PGV-1 remained after its removal from the medium, which suggests that PGV-1 irreversibly prevents proliferation. PGV-1 specifically induced prometaphase arrest in the M phase of the cell cycle, and efficiently induced cell senescence and cell death by increasing intracellular ROS levels through inhibition of ROS-metabolic enzymes. In a xenograft mouse model, PGV-1 had marked anti-tumor activity with little side effects by oral administration, whereas curcumin rarely inhibited tumor formation by this administration. Therefore, PGV-1 is a potential therapeutic to induce tumor cell apoptosis with few side effects and low risk of relapse.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Alcohol Oxidoreductases / antagonists & inhibitors
  • Alcohol Oxidoreductases / genetics
  • Alcohol Oxidoreductases / metabolism
  • Animals
  • Antineoplastic Agents, Phytogenic / chemistry
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Carrier Proteins / antagonists & inhibitors
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Cell Death / drug effects
  • Cell Division / drug effects
  • Cell Division / genetics
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Cellular Senescence / drug effects
  • Curcumin / analogs & derivatives
  • Curcumin / pharmacology*
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Glutathione S-Transferase pi / antagonists & inhibitors
  • Glutathione S-Transferase pi / genetics
  • Glutathione S-Transferase pi / metabolism
  • Glutathione Transferase / antagonists & inhibitors
  • Glutathione Transferase / genetics
  • Glutathione Transferase / metabolism
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • K562 Cells
  • Lactoylglutathione Lyase / antagonists & inhibitors
  • Lactoylglutathione Lyase / genetics
  • Lactoylglutathione Lyase / metabolism
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy*
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology
  • MCF-7 Cells
  • Mice, Nude
  • NAD(P)H Dehydrogenase (Quinone) / antagonists & inhibitors
  • NAD(P)H Dehydrogenase (Quinone) / genetics
  • NAD(P)H Dehydrogenase (Quinone) / metabolism
  • Peroxiredoxins / antagonists & inhibitors
  • Peroxiredoxins / genetics
  • Peroxiredoxins / metabolism
  • Prometaphase / drug effects*
  • Prometaphase / genetics
  • Reactive Oxygen Species / metabolism
  • Tumor Burden / drug effects
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents, Phytogenic
  • Carrier Proteins
  • Gsto1 protein, mouse
  • Reactive Oxygen Species
  • Alcohol Oxidoreductases
  • carbonyl reductase 1, mouse
  • Peroxiredoxins
  • Prdx1 protein, mouse
  • NAD(P)H Dehydrogenase (Quinone)
  • Nqo1 protein, mouse
  • Glutathione S-Transferase pi
  • Glutathione Transferase
  • Gstp1 protein, mouse
  • Glo1 protein, mouse
  • Lactoylglutathione Lyase
  • Curcumin