Discipline of Pharmacology, Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, South Australia, Australia.
School of Health, Medical and Applied Sciences, Central Queensland University, Queensland, Australia; Centre for Personalized Cancer Medicine, Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, South Australia, Australia.
Toxicol In Vitro. 2020 Sep;67:104908. doi: 10.1016/j.tiv.2020.104908. Epub 2020 Jun 2.
Nutlin-3a is a p53 activator and potential cyclotherapy approach that may also mitigate side effects of chemotherapeutic drugs in the treatment of colorectal cancer. We investigated cell proliferation in a panel of colorectal cancer (CRC) cell lines with wild-type or mutant p53, as well as a non-tumorigenic fetal intestinal cell line following Nutlin-3a treatment (10 μM). We then assessed apoptosis at 24 and 48 h following administration of the active irinotecan metabolite, SN-38 (0.001 μM - 1 μM), alone or following pre-treatment with Nutlin-3a (10 μM). Nutlin-3a treatment (10 μM) significantly reduced proliferation in wild-type p53 expressing cell lines (FHS 74 and HCT116) at 72 and 96 h, but was without effect in cell lines with mutated or deleted p53 (Caco-2, SW480, and HCT 116). SN-38 treatment induced significant apoptosis in all cell lines after 48 h. Nutlin-3a unexpectedly increased cell death in the p53 wild-type CRC cell line, HCT116, while Nutlin-3a pre-treatment provided protection from SN-38 in the p53 wild-type normal cell line, FHs 74. These results demonstrate Nutlin-3a's selective growth-arresting efficacy in p53 wild-type non-malignant intestinal cell lines, enabling the selective targeting of malignant cells with chemotherapy drugs. These studies highlight the potential of Nutlin-3a to minimise intestinal mucosal damage following chemotherapy.
Nutlin-3a 是一种 p53 激活剂，也是一种潜在的周期治疗方法，它可能减轻化疗药物在治疗结直肠癌中的副作用。我们研究了野生型或突变型 p53 的结直肠癌细胞系（CRC）以及非肿瘤性胎儿肠细胞系在 Nutlin-3a 处理（10 μM）后的细胞增殖情况。然后，我们评估了活性伊立替康代谢物 SN-38（0.001 μM-1 μM）单独给药或用 Nutlin-3a（10 μM）预处理后 24 和 48 小时的细胞凋亡情况。Nutlin-3a 处理（10 μM）在 72 和 96 小时显着降低了野生型 p53 表达细胞系（FHS 74 和 HCT116）的增殖，但对突变型或缺失型 p53 的细胞系（Caco-2、SW480 和 HCT 116）没有影响。SN-38 处理在 48 小时后诱导所有细胞系的显着凋亡。Nutlin-3a 出人意料地增加了 p53 野生型 CRC 细胞系 HCT116 的细胞死亡，而 Nutlin-3a 预处理为 p53 野生型正常细胞系 FHs 74 提供了对 SN-38 的保护。这些结果表明，Nutlin-3a 在 p53 野生型非恶性肠细胞系中具有选择性的生长抑制作用，能够使化疗药物选择性地靶向恶性细胞。这些研究强调了 Nutlin-3a 减少化疗后肠粘膜损伤的潜力。
