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

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.

SUBMITTER: Arihara Y

PROVIDER: S-EPMC5630380 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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

Arihara Yohei Y Takada Kohichi K Kamihara Yusuke Y Hayasaka Naotaka N Nakamura Hajime H Murase Kazuyuki K Ikeda Hiroshi H Iyama Satoshi S Sato Tsutomu T Miyanishi Koji K Kobune Masayoshi M Kato Junji J

Oncotarget 20170722 39

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 dr ...[more]

PMID: 29029480

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Project description:BackgroundLenalidomide, an immunomodulatory drug (IMiD), is an effective therapy for the treatment of multiple myeloma (MM). However, prolonged treatment may be accompanied by toxicity, second primary malignancies, and drug resistance. There is an inherent vulnerability in MM cells that high rates of immunoglobulin synthesis resulting in the high level of reactive oxygen species (ROS). This provides a therapeutic potential for MM.Materials and methodsThe intracellular ROS levels, H2O2 production and glutathione (GSH) levels were measured using detection kit. Cell viability was evaluated using cell-counting kit-8 (CCK-8) and soft agar colony formation assay. Apoptosis was determined in whole living cells using flow cytometry. Chidamide and its anti-myeloma efficacy in combination with lenalidomide were characterized in MM cell lines in vitro and in a mouse xenograft model. Moreover, Western blotting, immunofluorescence and immunohistochemical studies were performed.ResultsROS levels increased in a time- and dose-dependent manner with chidamide treatment. Moreover, the GSH levels were decreased and the mRNA level of SLC7A11 downregulated after chidamide treatment. The co-treatment with chidamide and lenalidomide increased apoptosis and proliferation inhibition, with combination index (CI) in the synergistic range (0.2-0.5) using the Chou-Talalay method. The cooperative anti-myeloma efficacy was confirmed in the murine model, and immunohistochemical studies also supported this potentiation. Chidamide enhanced the effect of lenalidomide-induced degradation of IKZF1 and IKZF3 by elevating H2O2. In addition, co-treatment with chidamide and lenalidomide increased biomarkers of caspase and DNA damage.ConclusionElevated ROS production may constitute a potential biochemical basis for anti-myeloma effects of chidamide plus lenalidomide. The results of this study confirm the synergistic effect of chidamide and lenalidomide against MM and provide a promising therapeutic strategy for MM.

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

Publications

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

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