Department of Experimental Medicine, "Sapienza" University of Rome, Italy. Laboratory Affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Italy.
Department of Radiological, Oncological and Pathological Sciences, "Sapienza" University of Rome, Rome, Italy.
Exp Cell Res. 2021 Nov 15;408(2):112879. doi: 10.1016/j.yexcr.2021.112879. Epub 2021 Oct 13.
Colon cancer is one of the most common cancers, currently treated with traditional chemotherapies or alternative therapies. However, these treatments are still not enough effective and induce several side effects, so that the search of new therapeutic strategies is needed. The use of Poly-(ADP-ribose)-polymerase (PARP) inhibitors, although originally approved against BRCA-1 or BRCA-2 mutated cancers, has been extended, particularly in combination with other treatments, to cure cancers that do not display defects in DNA repair signaling pathways. The role of p53 oncosuppressor in the regulating the outcome of PARP inhibitor treatment remains an open issue. In this study, we addressed this topic by using a well-tolerated PARP 1/2/3 inhibitor, namely AZD2461, against colon cancer cell lines with different p53 status. We found that AZD2461 reduced cell proliferation in wtp53 and p53-/- cancer cells by increasing ROS and DNA damage, while R273H mutant (mut) p53 counteracted these effects. Moreover, AZD2461 improved the reduction of cell proliferation by low dose radiation (IR) in wtp53 cancer cells, in which a down-regulation of BRCA-1 occurred. AZD2461 did not affect cell proliferation of mutp53 colon cancer cells also in combination with low dose radiation, suggesting that only wt p53 or p53 null colon cancer cells could benefit AZD2461 treatment.
结肠癌是最常见的癌症之一，目前采用传统化疗或替代疗法进行治疗。然而，这些治疗方法仍然不够有效，并会引起多种副作用，因此需要寻找新的治疗策略。聚（ADP-核糖）聚合酶（PARP）抑制剂的使用，尽管最初是针对 BRCA-1 或 BRCA-2 突变型癌症批准的，但已经得到扩展，特别是与其他治疗方法联合使用，以治愈不显示 DNA 修复信号通路缺陷的癌症。p53 抑癌基因在调节 PARP 抑制剂治疗效果中的作用仍然是一个悬而未决的问题。在这项研究中，我们使用一种耐受性良好的 PARP1/2/3 抑制剂 AZD2461，针对具有不同 p53 状态的结肠癌细胞系来解决这个问题。我们发现，AZD2461 通过增加 ROS 和 DNA 损伤来减少 wtp53 和 p53-/- 癌细胞的增殖，而 R273H 突变（mut）p53 则抵消了这些作用。此外，AZD2461 改善了 wtp53 癌症细胞中低剂量辐射（IR）对细胞增殖的减少，其中 BRCA-1 的表达下调。AZD2461 也不会影响 mutp53 结肠癌细胞的增殖，即使与低剂量辐射联合使用，这表明只有 wt p53 或 p53 缺失的结肠癌细胞才能从 AZD2461 治疗中获益。
