Invenio Therapeutics, Case Western Reserve University, Cleveland, Ohio 44106, USA.
J Biol Chem. 2012 Jul 6;287(28):23635-43. doi: 10.1074/jbc.M111.312801. Epub 2012 May 23.
Despite advances in oncology drug development, most commonly used cancer therapeutics exhibit serious adverse effects. Often the toxicities of chemotherapeutics are due to the induction of significant DNA damage that is necessary for their ability to kill cancer cells. In some clinical situations, the direct induction of significant cytotoxicity is not a requirement to meet clinical goals. For example, differentiation, growth arrest, and/or senescence is a valuable outcome in some cases. In fact, in the case of acute myeloid leukemia (AML), the use of the differentiation agent all-trans-retinoic acid (ATRA) has revolutionized the therapy for a subset of leukemia patients and led to a dramatic survival improvement. Remarkably, this therapeutic approach is possible even in many elderly patients, who would not be able to tolerate therapy with traditional cytotoxic chemotherapy. Because of the success of ATRA, there is widespread interest in identifying differentiation strategies that may be effective for the 90-95% of AML patients who do not clinically respond to ATRA. Utilizing an AML differentiation agent that is in development, we found that AML differentiation can be induced through ATP depletion and the subsequent activation of DNA damage signaling through an ATR/Chk1-dependent and p53-independent pathway. This study not only reveals mechanisms of AML differentiation but also suggests that further investigation is warranted to investigate the potential clinical use of low dose chemotherapeutics to induce differentiation instead of cytotoxicity. This therapeutic approach may be of particular benefit to patients, such as elderly AML patients, who often cannot tolerate traditional AML chemotherapy.
尽管肿瘤药物研发取得了进展，但大多数常用的癌症治疗药物都存在严重的不良反应。化疗药物的毒性通常是由于诱导了大量的 DNA 损伤，而这些损伤是它们杀死癌细胞的必要条件。在某些临床情况下，直接诱导显著的细胞毒性并不是达到临床目标的要求。例如，分化、生长停滞和/或衰老在某些情况下是有价值的结果。事实上，在急性髓细胞白血病（AML）的情况下，使用分化剂全反式维甲酸（ATRA）已经彻底改变了一部分白血病患者的治疗方法，并导致了显著的生存改善。值得注意的是，即使是许多不能耐受传统细胞毒性化疗的老年患者，也可以采用这种治疗方法。由于 ATRA 的成功，人们广泛关注寻找可能对 90-95%的 AML 患者有效的分化策略，这些患者对 ATRA 没有临床反应。我们利用正在开发的 AML 分化剂发现，通过 ATP 耗竭和随后通过 ATR/Chk1 依赖性和 p53 非依赖性途径激活 DNA 损伤信号，可以诱导 AML 分化。这项研究不仅揭示了 AML 分化的机制，还表明有必要进一步研究低剂量化疗药物诱导分化而不是细胞毒性的潜在临床应用。这种治疗方法可能对老年 AML 患者等患者特别有益，这些患者通常不能耐受传统的 AML 化疗。
