Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, University of Sydney, Sydney, Australia.
Antioxid Redox Signal. 2019 Mar 10;30(8):1096-1123. doi: 10.1089/ars.2017.7387. Epub 2018 Feb 6.
Nuclear factor kappa B (NF-κB) signaling is essential under physiologically relevant conditions. However, aberrant activation of this pathway plays a pertinent role in tumorigenesis and contributes to resistance. Recent Advances: The importance of the NF-κB pathway means that its targeting must be specific to avoid side effects. For many currently used therapeutics and those under development, the ability to generate reactive oxygen species (ROS) is a promising strategy.
As cancer cells exhibit greater ROS levels than their normal counterparts, they are more sensitive to additional ROS, which may be a potential therapeutic niche. It is known that ROS are involved in (i) the activation of NF-κB signaling, when in sublethal amounts; and (ii) high levels induce cytotoxicity resulting in apoptosis. Indeed, ROS-induced cytotoxicity is valuable for its capabilities in killing cancer cells, but establishing the potency of ROS for effective inhibition of NF-κB signaling is necessary. Indeed, some cancer treatments, currently used, activate NF-κB and may stimulate oncogenesis and confer resistance.
Thus, combinatorial approaches using ROS-generating agents alongside conventional therapeutics may prove an effective tactic to reduce NF-κB activity to kill cancer cells. One strategy is the use of thiosemicarbazones, which form redox-active metal complexes that generate high ROS levels to deliver potent antitumor activity. These agents also upregulate the metastasis suppressor, N-myc downstream regulated gene 1 (NDRG1), which functions as an NF-κB signaling inhibitor. It is proposed that targeting NF-κB signaling may proffer a new therapeutic niche to improve the efficacy of anticancer regimens.
核因子 kappa B（NF-κB）信号在生理相关条件下是必不可少的。然而，该途径的异常激活在肿瘤发生中起着重要作用，并导致耐药性。
NF-κB 途径的重要性意味着其靶向必须是特异性的，以避免副作用。对于许多目前使用的治疗药物和正在开发的药物，生成活性氧物种（ROS）的能力是一种有前途的策略。
由于癌细胞比正常细胞表现出更高的 ROS 水平，它们对额外的 ROS 更敏感，这可能是一个潜在的治疗靶点。已知 ROS 参与（i）NF-κB 信号的激活，当处于亚致死剂量时；（ii）高水平诱导细胞毒性导致细胞凋亡。事实上，ROS 诱导的细胞毒性因其杀死癌细胞的能力而具有价值，但为了有效抑制 NF-κB 信号，必须确定 ROS 的效力。事实上，一些目前使用的癌症治疗方法会激活 NF-κB，并可能刺激肿瘤发生和赋予耐药性。
因此，使用产生 ROS 的剂与常规治疗联合使用的组合方法可能被证明是一种有效策略，可以降低 NF-κB 活性以杀死癌细胞。一种策略是使用硫代氨基甲酸盐，它们形成氧化还原活性金属配合物，产生高水平的 ROS，从而提供有效的抗肿瘤活性。这些药物还上调转移抑制因子 N-myc 下游调节基因 1（NDRG1），它作为 NF-κB 信号抑制剂发挥作用。有人提出，靶向 NF-κB 信号可能提供一个新的治疗靶点，以提高抗癌方案的疗效。
