Small molecule CP-31398 induces reactive oxygen species-dependent apoptosis in human multiple myeloma

// Yohei Arihara 1, * , Kohichi Takada 1, 2, * , Yusuke Kamihara 1 , Naotaka Hayasaka 1 , Hajime Nakamura 1 , Kazuyuki Murase 1, 2 , Hiroshi Ikeda 2 , Satoshi Iyama 2 , Tsutomu Sato 2 , Koji Miyanishi 1 , Masayoshi Kobune 2 and Junji Kato 1 1 Department of Medical Oncology, Sapporo Medical University School of Medicine, Sapporo, Japan 2 Department of Hematology, Sapporo Medical University School of Medicine, Sapporo, Japan * These authors have contributed equally to this work Correspondence to: Junji Kato, email: jkato@sapmed.ac.jp Keywords: CP-31398, ROS, apoptosis, multiple myeloma Received: December 01, 2016      Accepted: June 29, 2017      Published: July 22, 2017 ABSTRACT 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.