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Polyphyllin G, a pennogenyl saponin extracted from Paris polyphylla, has been shown to possess antitumor effects. In this study, we demonstrated that doxycycline, an antibiotic medicine, could significantly enhance the sensitivities of osteosarcoma cell lines to polyphyllin G. As the cells were pretreated with doxycycline at non‐toxic concentrations and then co‐exposed to polyphyllin G, this combination could induce a rapid cell death distinct from apoptosis. The non‐apoptotic cell death was characterized by a loss of integrity of plasma membrane without externalization of phosphatidyl serine. Furthermore, this combined treatment resulted in suppression of cell viability and colony‐forming ability, and increased the level of γ‐H2A.X, a critical marker for DNA damage, in osteosarcoma cell lines. When examining the underlying mechanism, it was revealed combination of polyphyllin G and doxycycline triggered an enhanced generation of reactive oxygen species (ROS), and up‐regulated mitochondrial oxidative stress within 0.5 h. Co‐administration of the ROS inhibitor NAC reversed the suppressed cell viability and colony‐forming ability, and abolished the increased level of γ‐H2A.X in the cells with the combined treatment, indicating that the enhanced ROS was involved in the anti‐proliferative effect of the combined treatment. Overall, the results demonstrated that doxycycline may function as chemosensitizers by inducing an acute and lethal ROS production to enhance cytotoxic of polyphyllin G in osteosarcoma cell lines, and the combined use of drugs may provide an alternative thinking for the development of new therapeutic agents. [ABSTRACT FROM AUTHOR]