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p53激活剂和潜在的环疗方法，也可能减轻化疗药物在治疗大肠癌中的副作用。我们研究了一组具有野生型或突变型p53的结直肠癌（CRC）细胞系以及Nutlin-3a治疗（10μM）后的非致瘤性胎儿肠细胞系中的细胞增殖。然后，我们在单独或在使用Nutlin-3a（10μM）预处理后，在给予活性伊立替康代谢产物SN-38（0.001μM-1μM）后24和48小时评估了细胞凋亡。

Nutlin-3a处理（10μM）在72和96 h显着降低了野生型p53表达细胞系（FHS 74和HCT116 ^{+ / +}）的增殖，但对p53突变或缺失的细胞系无效（Caco-2 ，SW480和HCT 116 ^-/-）。SN-38处理在48小时后诱导了所有细胞系的显着凋亡。Nutlin-3a意外地增加了p53野生型CRC细胞HCT116中的细胞死亡^{+ / +}，而Nutlin-3a预处理可在p53野生型正常细胞系FHs 74中提供SN-38的保护。这些结果证明Nutlin-3a在p53野生型非恶性肠细胞系中具有选择性的抑制生长的功效，使化疗药物选择性靶向恶性细胞。这些研究突显了Nutlin-3a在化学疗法后最大程度地减少肠道粘膜损伤的潜力。