Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences building, Indian Institute of Technology Madras, Chennai, 600036, India.
Department of Chemical Engineering, Indian Institute of Technology Madras, Chennai, 600036, India.
Sci Rep. 2019 Mar 4;9(1):3347. doi: 10.1038/s41598-019-40017-7.
Reactive oxygen species (ROS) are primary effectors of cytotoxicity induced by many anti-cancer drugs. Rhythms in the pseudo-steady-state (PSS) levels of particular intracellular ROS in cancer cells and their relevance to drug effectiveness are unknown thus far. We report that the PSS levels of intracellular superoxide (SOX), an important ROS, exhibit an inherent rhythm in HCT116 colon cancer cells, which is entrained (reset) by the SOX inducer, menadione (MD). This reset was dependent on the expression of p53, and it doubled the sensitivity of the cells to MD. The period of oscillation was found to have a linear correlation with MD concentration, given by the equation, T, in h = 23.52 - 1.05 [MD concentration in µM]. Further, we developed a mathematical model to better understand the molecular mechanisms involved in rhythm reset. Biologically meaningful parameters were obtained through parameter estimation techniques; the model can predict experimental profiles of SOX, establish qualitative relations between interacting species in the system and serves as an important tool to understand the profiles of various species. The model was also able to successfully predict the rhythm reset in MD treated hepatoma cell line, HepG2.
活性氧 (ROS) 是许多抗癌药物诱导细胞毒性的主要效应物。迄今为止，癌细胞中特定细胞内 ROS 的准稳态 (PSS) 水平的波动及其与药物有效性的相关性尚不清楚。我们报告称，内源性超氧阴离子 (SOX) 的 PSS 水平在 HCT116 结肠癌细胞中表现出固有节律，SOX 诱导剂甲萘醌 (MD) 可使该节律重设（重置）。这种重设依赖于 p53 的表达，并使细胞对 MD 的敏感性提高一倍。发现振荡的周期与 MD 浓度呈线性相关，方程为 T，以 h 为单位=23.52-1.05[µM 中的 MD 浓度]。此外，我们开发了一个数学模型来更好地理解涉及节律重置的分子机制。通过参数估计技术获得了生物学意义上的参数；该模型可以预测 SOX 的实验曲线，建立系统中相互作用物质之间的定性关系，并作为理解各种物质曲线的重要工具。该模型还能够成功预测 MD 处理的肝癌细胞系 HepG2 中的节律重置。
