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, Daiju Ichikawa, Maiko Matsushita, Yutaka Suto, Genji Iwasaki, Taketo Yamada, Fumiyuki Kiuchi, Maki Hirao, Hisako Kunieda, Makoto Osada, Shinichiro Okamoto, Yutaka Hattori

研究成果: Article

2 引用 (Scopus)

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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.

元の言語English
ページ(範囲)787-793
ページ数7
ジャーナルBiochemical and Biophysical Research Communications
505
発行部数3
DOI
出版物ステータスPublished - 2018 11 2

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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