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    • br Conclusion This is the first report to

    2024-04-16


    Conclusion This is the first report to show that treatment of lung cancer cell lines, A549 and H1299, with ovatodiolid stimulates intracellular reactive oxygen species generation and induces DNA damage. Subsequently activates ATM/ATR and CHK1/2 signaling pathway, inhibits CDC25C and p21WAF1/CIP1, suppresses CDK1/Cyclin B1 complex activity, and ultimately resulting in Rottlerin arrest in G2/M phase. At the same time, reactive oxygen species activates ATM/ATR and CHK1/2 signaling pathway, leading to decrease anti-apoptotic molecule Bcl-2 and Mcl-1 expression, and increase pro-apoptotic molecule PUMA, Bax, DR5, eventually provokes both intrinsic and extrinsic apoptotic cell death by activating caspase-3, caspase-8, and caspase-9 (Fig. 7), which are regardless of p53 gene status in lung cancer cells. Overall, our observation provides a mechanistic role of ovatodiolide in inhibiting lung cancer cell growth and inducing cell death in vitro and supports a basis for further study of ovatodiolide in vivo to characterize its preventive and therapeutic potential for lung cancer.
    Competing interests
    Introduction Low-dose hyper-radiosensitivity (HRS) is a phenomenon discovered by Marples and Joiner in 1993 that mammalian cells exhibit enhanced sensitivity to low doses (<0.5Gy) of ionizing radiation (IR), which is followed by an induced radioresistance (IRR) to larger doses (above 0.5Gy) [1]. The studies of HRS/IRR effects were mainly carried out using sparsely ionizing radiation, such as X- or γ-rays with the endpoint of analysis being the cellular survival. HRS/IRR responses can be observed in both normal and malignant cell lines [2], [3], [4], [5], [6], [7]. Recently, more and more work has been done to identify the underlying mechanism, which may be related to the DNA double strand break (DSB) repair, checkpoint regulation or apoptosis [3], [4], [5], [8], [9], [10], of which the link between G2/M checkpoint and HRS/IRR effects is the best studied. It is well established that there are two molecularly distinct G2/M checkpoints induced by irradiation. The accumulation of cells in G2 phase measured only several hours after irradiation, is ataxia telangiectasia mutated (ATM)-independent, dose dependent, and represents the arrest of cells that were in G1 or S phases at the time of irradiation. In contrast, the ‘early’ G2/M checkpoint, which occurs at the very early periods after irradiation, is transient and ATM-dependent, representing the failure of cells that were in G2 phase at the time of irradiation to progress into mitosis [11]. Studies have shown that the ‘early’ G2/M checkpoint is the main determinant that matches the transition in cell survival from HRS to IRR [3], [5], [12]. To date, little work has been done on the HRS phenomenon with radiation of high linear energy transfer (LET). It is well-known that biological effects of ionizing radiation vary with LET [13]. High-LET heavy ions produce dense ionization along their trajectories and cause complex and irreparable clustered DNA damage, which is generally more genotoxic and cytotoxic to irradiated cells than photons. HRS/IRR responses have also been observed in V79 and human cells under different types of particle radiation [14], [15], [16]. We previously reported that normal human skin fibroblast cells, GM0639 exhibited HRS at ∼0.2Gy of carbon ions (70keV/μm), monitoring survival and mutation induction as the endpoints. Using the specific ATM inhibitor and stimulator, we showed that the ATM-dependent early G2/M checkpoint and DNA repair were involved in the occurrence of HRS/IRR, which seems to be identical to that arising after exposure to low LET radiation [16]. More work is needed to explore whether there is a specific mechanism that functions for heavy ion beams.
    Materials and methods
    Results
    Discussion Compared with low LET radiation, fewer reports have been published on the HRS/IRR effects under high LET radiation. We and other researchers reported the existence of an HRS/IRR response following exposure to protons, alpha particles and heavier particles of high LET [14], [15], [16], [30], [31], [32]. To date, a full understanding of the mechanism encompassing an analysis of DSB repair, cell cycle regulation and apoptosis, has not been undertaken. Around 2003, Marples et al. proposed and investigated the hypothesis that after exposure to X-rays, the phenomen of HRS is a manifestation of the absence of checkpoint arrest in cells irradiated at low doses in the G2 phase of the cell cycle [8], [9]. Subsequently, extensive studies were performed to substantiate the link between early G2/M arrest and HRS [3], [5], [12], [33], which is now the most widely accepted underlying mechanisms. We also confirm this relationship using carbon ion beams through enrichment of the cell population in G2 phase with the thymidine block technique, and an Aurora kinase inhibitor to attenuate the G2–M transition following low dose radiation. In this way, the early G2/M checkpoint was shown to also represent an important factor underlying the HRS/IRR response after heavy ion beam exposure. As we showed previously, ATM is important for HRS following sparsely ionizing or charged radiation [16].