Curcumin Derivatives Verify the Essentiality of ROS Upregulation in Tumor Suppression
Ikuko Nakamae,
Tsumoru Morimoto,
Hiroki Shima,
Masafumi Shionyu,
Hisayo Fujiki,
Noriko Yoneda-Kato,
Takashi Yokoyama,
Shigehiko Kanaya,
Kiyomi Kakiuchi,
Tsuyoshi Shirai,
Edy Meiyanto,
Jun-ya Kato
Affiliations
Ikuko Nakamae
Laboratory of Tumor Cell Biology, Division of Biological Science, Graduate School of Science and Technology, Nara Institute of Science and Technology, Nara 630-0192, Ikoma, Japan
Tsumoru Morimoto
Laboratory of Synthetic Organic Chemistry, Division of Materials Science, Graduate School of Science and Technology, Nara Institute of Science and Technology, Nara 630-0192, Ikoma, Japan
Hiroki Shima
Laboratory of Synthetic Organic Chemistry, Division of Materials Science, Graduate School of Science and Technology, Nara Institute of Science and Technology, Nara 630-0192, Ikoma, Japan
Masafumi Shionyu
Nagahama Institute of Bio-Science and Technology, Nagahama 526-0829, Shiga, Japan
Hisayo Fujiki
Laboratory of Synthetic Organic Chemistry, Division of Materials Science, Graduate School of Science and Technology, Nara Institute of Science and Technology, Nara 630-0192, Ikoma, Japan
Noriko Yoneda-Kato
Laboratory of Tumor Cell Biology, Division of Biological Science, Graduate School of Science and Technology, Nara Institute of Science and Technology, Nara 630-0192, Ikoma, Japan
Takashi Yokoyama
Laboratory of Tumor Cell Biology, Division of Biological Science, Graduate School of Science and Technology, Nara Institute of Science and Technology, Nara 630-0192, Ikoma, Japan
Shigehiko Kanaya
Laboratory of Computational Systems Biology, Division of Information Science, Graduate School of Science and Technology, Nara Institute of Science and Technology, Nara 630-0192, Ikoma, Japan
Kiyomi Kakiuchi
Laboratory of Synthetic Organic Chemistry, Division of Materials Science, Graduate School of Science and Technology, Nara Institute of Science and Technology, Nara 630-0192, Ikoma, Japan
Tsuyoshi Shirai
Nagahama Institute of Bio-Science and Technology, Nagahama 526-0829, Shiga, Japan
Edy Meiyanto
Cancer Chemoprevention Research Center, Faculty of Pharmacy, Universitas Gadjah Mada, Sekip Utara, Yogyakarta 55281, Indonesia
Jun-ya Kato
Laboratory of Tumor Cell Biology, Division of Biological Science, Graduate School of Science and Technology, Nara Institute of Science and Technology, Nara 630-0192, Ikoma, Japan
Background: Curcumin has been shown to exert pleiotropic biological effects, including anti-tumorigenic activity. We previously showed that curcumin controls reactive oxygen species (ROS) levels through the ROS metabolic enzymes, to prevent tumor cell growth. In this study, we synthesized 39 novel curcumin derivatives and examined their anti-proliferative and anti-tumorigenic properties. Methods and Results: Thirty-nine derivatives exhibited anti-proliferative activity toward human cancer cell lines, including CML-derived K562 leukemic cells, in a manner sensitive to an antioxidant, N-acetyl-cysteine (NAC). Some compounds exhibited lower GI50 values than curcumin, some efficiently induced cell senescence, and others markedly increased ROS levels, efficiently induced cell death and suppressed tumor formation in a xenograft mouse model, without any detectable side effects. A clustering analysis of the selected compounds and their measurement variables revealed that anti-tumorigenic activity was most well-correlated with an increase in ROS levels. Pulldown assays and a molecular docking analysis showed that curcumin derivatives competed with co-enzymes to bind to the respective ROS metabolic enzymes and inhibited their enzymatic activities. Conclusions: The analysis of novel curcumin derivatives established the importance of ROS upregulation in suppression of tumorigenesis, and these compounds are potentially useful for the development of an anti-cancer drug with few side effects.
