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 language | English |
|---|---|
| Pages (from-to) | 787-793 |
| Number of pages | 7 |
| Journal | Biochemical and Biophysical Research Communications |
| Volume | 505 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - 2018 Nov 2 |
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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 journal › Article
}
TY - JOUR
T1 - A novel derivative (GTN024) from a natural product, komaroviquinone, induced the apoptosis of high-risk myeloma cells via reactive oxygen production and ER stress
AU - Okayama, Mikio
AU - Kitabatake, Shotaro
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
AU - Hattori, Yutaka
PY - 2018/11/2
Y1 - 2018/11/2
N2 - 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.
AB - 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.
KW - Apoptosis
KW - ER stress
KW - Multiple myeloma
KW - Natural product
KW - Reactive oxygen species
UR - http://www.scopus.com/inward/record.url?scp=85054396761&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85054396761&partnerID=8YFLogxK
U2 - 10.1016/j.bbrc.2018.09.177
DO - 10.1016/j.bbrc.2018.09.177
M3 - Article
C2 - 30297108
AN - SCOPUS:85054396761
VL - 505
SP - 787
EP - 793
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
SN - 0006-291X
IS - 3
ER -