Abstract：
Radiotherapy leverages ionizing radiation to kill cancer cells through direct and indirect effects, and direct effects are considered to play an equal or greater role. Several photosensitizers have been developed to mimic the direct effects of radiotherapy, generating radical cations in DNA models, but none has been applied in cellular studies. Here, we design a radiomimetic photosensitizer, producing DNA radical cations in cells for the first time. To reduce adverse effects, several redox-inducible precursors are prepared as cancer cells have elevated levels of GSH and H2O2. These precursors respond to GSH or H2O2, releasing the active photosensitizer that captures DNA abasic (AP) sites and generates DNA radical cations upon photolysis, without disrupting the redox state of cells. DNA radical cations migrate freely and are eventually trapped by H2O and O2 to yield DNA lesions, thus triggering DNA damage response. Our study suggests that direct effects of radiotherapy suppress cancer cell proliferation mainly by inducing G2/M phase cell cycle arrest, rather than promoting apoptosis. Synergistic effects of the precursor and chemotherapeutic agents are also observed in combination phototherapy. Beyond highlighting an alternative strategy for phototherapy, this proof-of-concept study affords a facile cellular platform to study the direct effects of radiotherapy.
摘要：
放射治疗利用电离辐射通过直接和间接效应杀死癌细胞，直接效应被认为发挥同等或更大的作用。已经开发了几种光敏剂来模拟放射治疗的直接作用，在DNA模型中产生自由基阳离子，但没有应用于细胞研究。这里,我们设计了一种放射模拟光敏剂,首次在细胞中产生DNA自由基阳离子。为了减少不良影响，当癌细胞的GSH和H2O2水平升高时，制备了几种可氧化还原诱导的前体。这些前体响应GSH或H2O2，释放活性光敏剂，捕获DNA脱碱基（AP）位点，并在光解时产生DNA自由基阳离子，而不会破坏细胞的氧化还原状态。DNA自由基阳离子自由迁移，最终被H2O和O2捕获，产生DNA损伤，从而引发DNA损伤反应。我们的研究表明，放疗的直接作用主要通过诱导G2/M期细胞周期阻滞来抑制癌细胞的增殖。而不是促进细胞凋亡。在组合光疗中也观察到前体和化疗剂的协同作用。除了强调光疗的替代策略，这项概念验证研究为研究放射治疗的直接影响提供了一个简单的细胞平台。
