Fred Hutchinson Cancer Research Center, Seattle, WA 91809, United States.
Drug Resist Updat. 2012 Feb-Apr;15(1-2):123-31. doi: 10.1016/j.drup.2012.01.002. Epub 2012 Feb 23.
Innate or acquired resistance to cancer therapeutics remains an important area of biomedical investigation that has clear ramifications for improving cancer specific death rates. Importantly, clues to key resistance mechanisms may lie in the well-orchestrated and highly conserved cellular and systemic responses to injury and stress. Many anti-neoplastic therapies typically rely on DNA damage, which engages potent DNA damage response signaling pathways that culminate in apoptosis or growth arrest at checkpoints to allow for damage repair. However, an alternative cellular response, senescence, can also be initiated when challenged with these internal/external pressures and in ideal situations acts as a self-protecting mechanism. Senescence-induction therapies are an attractive concept in that they represent a normal, highly conserved and commonly invoked tumor-suppressing response to overwhelming genotoxic stress or oncogene activation. Yet, such approaches should ensure that senescence by-pass or senescence re-emergence does not occur, as emergent cells appear to have highly drug resistant phenotypes. Further, cell non-autonomous senescence responses may contribute to therapy-resistance in certain circumstances. Here we provide an overview of mechanisms by which cellular senescence plausibly contributes to therapy resistance and concepts by which senescence responses can be influenced to improve cancer treatment outcomes.
先天或获得性对癌症治疗的抵抗力仍然是生物医学研究的一个重要领域，这对提高癌症特异性死亡率有明显的影响。重要的是，关键抵抗机制的线索可能在于对损伤和应激的协调良好且高度保守的细胞和全身反应。许多抗肿瘤疗法通常依赖于 DNA 损伤，这会引发强烈的 DNA 损伤反应信号通路，最终导致细胞凋亡或在检查点处生长停滞，以允许进行损伤修复。然而，当受到这些内部/外部压力的挑战时，细胞也可以启动另一种替代的反应，衰老，并且在理想情况下，衰老作为一种自我保护机制发挥作用。衰老诱导疗法是一个有吸引力的概念，因为它们代表了一种正常的、高度保守的、通常被激活的肿瘤抑制反应，以应对压倒性的遗传毒性应激或致癌基因激活。然而，这种方法应确保不会发生衰老旁路或衰老重新出现，因为出现的细胞似乎具有高度耐药表型。此外，细胞非自主性衰老反应可能在某些情况下导致治疗耐药性。在这里，我们提供了一个概述，说明细胞衰老如何可能有助于治疗耐药性的机制，以及如何影响衰老反应以改善癌症治疗效果的概念。
