Abstract
Aims: Peiminine has been reported to have various pharmacological properties, including anticancer activity. In this study, we investigated the effect of this alkaloid on osteosarcoma and explored the underlying mechanisms. Methods: To evaluate the antiosteosarcoma effects of peiminine in vitro, cell viability was assessed by CCK-8 and live/dead assays; the effects of the drug on apoptosis and the cell cycle were examined by flow cytometry; the effects on cell migration and invasion were detected by wound healing and Transwell assays, respectively, while its effects on autophagy were observed by transmission electron microscopy and an LC3 fluorescent puncta formation assay. The role of autophagy in the peiminine-mediated effects in osteosarcoma cells was evaluated by CCK-8 assay and western blotting after the application of the autophagy inhibitor chloroquine. The effect of peiminine on reactive oxygen species (ROS) production was analyzed using fluorescence confocal microscopy and spectrophotometry. Additionally, peiminine-treated osteosarcoma cells were exposed to SP600125, a JNK inhibitor, and N-acetylcysteine, a ROS scavenger, after which the contribution of the ROS/JNK signaling pathway to osteosarcoma was assessed using cell viability and LC3 fluorescent puncta formation assays, flow cytometry, and western blotting. A xenograft mouse model of osteosarcoma was generated to determine the antitumor effects of peiminine in vivo. Results: Peiminine suppressed proliferation and metastasis and induced cell cycle arrest, apoptosis, and autophagy in osteosarcoma cells. These anticancer effects of peiminine were found to be dependent on intracellular ROS generation and activation of the JNK pathway. In line with these results, peiminine significantly inhibited xenograft tumor growth in vivo. Conclusions: Peiminine induced G0/G1-phase arrest, apoptosis, and autophagy in human osteosarcoma cells via the ROS/JNK signaling pathway both in vitro and in vivo. Our study may provide an experimental basis for the evaluation of peiminine as an alternative drug for the treatment of osteosarcoma.
Highlights
Osteosarcoma (OS), originating from primitive osteogenic mesenchymal cells, is the most frequently diagnosed primary malignant bone tumor
MG-63 and Saos-2 cells were treated with various concentrations of peiminine for 24, 48, and 72 h, following which cell viability was measured by Cell Counting Kit-8 (CCK-8) assay
The results showed that peiminine significantly inhibited the proliferation of OS cells in vitro in a time- and dose-dependent manner (Figures 1A,B)
Summary
Osteosarcoma (OS), originating from primitive osteogenic mesenchymal cells, is the most frequently diagnosed primary malignant bone tumor. Novel adjuvant chemotherapy regimens and improved surgical techniques have extended the 5-years survival rate of patients to approximately 70% (Liu et al, 2017), the cure rate has remained stagnant over the last 30 years (Wang et al, 2019). This underlines the need to identify new, safer, and more efficient drugs to treat this disease (Chen et al, 2019). Dysregulation of the cell cycle is associated with tumor initiation and progression and is a hallmark of cancer cells (Stewart et al, 2003). Many anticancer drugs can induce G0/ G1-phase arrest by targeting cell cycle-related pathways (Li et al, 2015a; Wang et al, 2016a)
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