Small molecule CP-31398 induces reactive oxygen species-dependent apoptosis in human multiple myeloma
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Yohei Arihara1,*, Kohichi Takada1,2,*, Yusuke Kamihara1, Naotaka Hayasaka1, Hajime Nakamura1, Kazuyuki Murase1,2, Hiroshi Ikeda2, Satoshi Iyama2, Tsutomu Sato2, Koji Miyanishi1, Masayoshi Kobune2 and Junji Kato1
1Department of Medical Oncology, Sapporo Medical University School of Medicine, Sapporo, Japan
2Department of Hematology, Sapporo Medical University School of Medicine, Sapporo, Japan
*These authors have contributed equally to this work
Junji Kato, email: [email protected]
Keywords: CP-31398, ROS, apoptosis, multiple myeloma
Received: December 01, 2016 Accepted: June 29, 2017 Published: July 22, 2017
Reactive oxygen species (ROS) are normal byproducts of a wide variety of cellular processes. ROS have dual functional roles in cancer cell pathophysiology. At low to moderate levels, ROS act as signaling transducers to activate cell proliferation, migration, invasion, and angiogenesis. In contrast, high levels of ROS induce cell death. In multiple myeloma (MM), ROS overproduction is the trigger for apoptosis induced by several anticancer compounds, including proteasome inhibitors. However, no drugs for which oxidative stress is the main mechanism of action are currently used for treatment of MM in clinical situations. In this study, we demonstrate that the p53-activating small molecule CP-31398 (CP) effectively inhibits the growth of MM cell lines and primary MM isolates from patients. CP also suppresses the growth of MM xenografts in mice. Mechanistically, CP was found to induce intrinsic apoptosis in MM cells via increasing ROS production. Interestingly, CP-induced apoptosis occurs regardless of the p53 status, suggesting that CP has additional mechanisms of action. Our findings thus indicate that CP could be an attractive candidate for treatment of MM patients harboring p53 abnormalities; this satisfies an unmet clinical need, as such individuals currently have a poor prognosis.
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