A novel derivative (GTN024) from a natural product, komaroviquinone, induced the apoptosis of high-risk myeloma cells via reactive oxygen production and ER stress

Mikio Okayama, Shotaro Kitabatake, Mariko Sato, Kota Fujimori, Daijyu Ichikawa, Maiko Matsushita, Yutaka Suto, Genji Iwasaki, Taketo Yamada, Fumiyuki Kiuchi, Maki Hirao, Hisako Kunieda, Makoto Osada, Shinichiro Okamoto, Yutaka Hattori

Research output: Contribution to journalArticle

Abstract

New drugs have significantly improved the survival of patients with multiple myeloma (MM), but the prognosis of MM patients with high-risk cytogenetic changes such as t(4; 14), t(14; 16) or del17p remains very poor. A natural product, komaroviquinone (KQN), was originally isolated from the perennial semi-shrub Dracocephalum komarovi and has anti-protozoal activity against Trypanosoma cruzi, the organism causing Chagas’ disease. Here we demonstrate that a novel KQN-derivative, GTN024, has an anti-MM effect both in vitro and in vivo. GTN024 induced the apoptosis of MM cell lines including those with high-risk cytogenetic changes. GTN024 produced reactive oxygen species (ROS) and increased phosphorylated eIF2α. The ROS production and subsequent endoplasmic reticulum (ER) stress are thought to play a key role in GTN024-induced apoptosis, as the apoptosis was completely abrogated by anti-oxidant treatment. In a mouse xenograft model, an intraperitoneal injection of 20 mg/kg of GTN024 significantly delayed tumor growth. Hematological toxicity and systemic toxicity as indicated by weight loss were not observed. These results suggest that the novel KQN-derivative GTN024 could become a candidate drug for treating high-risk MM.

Original languageEnglish
Pages (from-to)787-793
Number of pages7
JournalBiochemical and Biophysical Research Communications
Volume505
Issue number3
DOIs
Publication statusPublished - 2018 Nov 2

Fingerprint

Endoplasmic Reticulum Stress
Biological Products
Multiple Myeloma
Apoptosis
Oxygen
Derivatives
Toxicity
Reactive Oxygen Species
Heterografts
Oxidants
Cytogenetics
Pharmaceutical Preparations
Tumors
Cells
Chagas Disease
Trypanosoma cruzi
Intraperitoneal Injections
komaroviquinone
Weight Loss
Cell Line

Keywords

  • Apoptosis
  • ER stress
  • Multiple myeloma
  • Natural product
  • Reactive oxygen species

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

A novel derivative (GTN024) from a natural product, komaroviquinone, induced the apoptosis of high-risk myeloma cells via reactive oxygen production and ER stress. / Okayama, Mikio; Kitabatake, Shotaro; Sato, Mariko; Fujimori, Kota; Ichikawa, Daijyu; Matsushita, Maiko; Suto, Yutaka; Iwasaki, Genji; Yamada, Taketo; Kiuchi, Fumiyuki; Hirao, Maki; Kunieda, Hisako; Osada, Makoto; Okamoto, Shinichiro; Hattori, Yutaka.

In: Biochemical and Biophysical Research Communications, Vol. 505, No. 3, 02.11.2018, p. 787-793.

Research output: Contribution to journalArticle

Okayama, Mikio ; Kitabatake, Shotaro ; Sato, Mariko ; Fujimori, Kota ; Ichikawa, Daijyu ; Matsushita, Maiko ; Suto, Yutaka ; Iwasaki, Genji ; Yamada, Taketo ; Kiuchi, Fumiyuki ; Hirao, Maki ; Kunieda, Hisako ; Osada, Makoto ; Okamoto, Shinichiro ; Hattori, Yutaka. / A novel derivative (GTN024) from a natural product, komaroviquinone, induced the apoptosis of high-risk myeloma cells via reactive oxygen production and ER stress. In: Biochemical and Biophysical Research Communications. 2018 ; Vol. 505, No. 3. pp. 787-793.
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AU - Sato, Mariko

AU - Fujimori, Kota

AU - Ichikawa, Daijyu

AU - Matsushita, Maiko

AU - Suto, Yutaka

AU - Iwasaki, Genji

AU - Yamada, Taketo

AU - Kiuchi, Fumiyuki

AU - Hirao, Maki

AU - Kunieda, Hisako

AU - Osada, Makoto

AU - Okamoto, Shinichiro

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