School of Life Science and Technology, China Pharmaceutical University, 24 Tongjiaxiang, 210009, Nanjing, P.R. China.
Apoptosis. 2024 Jun;29(5-6):865-881. doi: 10.1007/s10495-023-01926-1. Epub 2023 Dec 25.
The restoration of the function of p53 in tumors is a therapeutic strategy for the highly frequent mutation of the TP53 tumor suppressor gene. P460 is a wild-type peptide derived from the p53 C-terminus and has been proven to be capable of restoring the tumor suppressor function of p53. The poor accumulation of drugs in tumors is a serious hindrance to tumor treatment. For enhancing the activity of P460, the tumor-targeting sequence Arg-Gly-Asp-Arg (RGDR, C-end rule peptide) was introduced into the C-terminus of P460 to generate the new peptide P462. P462 presented better activity than P460 in inhibiting the proliferation of cancer cells and increasing the number of tumor cells undergoing apoptosis. Cell adhesion analysis and tumor imaging results revealed that P462 showed more specific and extensive binding with tumor cells and greater accumulation in tumors than the wild-type peptide. Importantly, treatment with P462 was more efficacious than that with P460 in vivo and was associated with considerably improved tumor-homing activity. This study highlights the importance of the roles of the tumor-homing sequence RGDR in the enhancement in cell attachment and tumor accumulation. The results of this work indicate that P462 could be a novel drug candidate for tumor treatment.
恢复肿瘤中 p53 的功能是治疗 TP53 肿瘤抑制基因高频突变的一种治疗策略。P460 是源自 p53 C 末端的野生型肽，已被证明能够恢复 p53 的肿瘤抑制功能。药物在肿瘤中的蓄积不良是肿瘤治疗的严重障碍。为了增强 P460 的活性，将肿瘤靶向序列 Arg-Gly-Asp-Arg（RGDR，C 末端规则肽）引入到 P460 的 C 末端，生成新的肽 P462。与 P460 相比，P462 在抑制癌细胞增殖和增加细胞凋亡数量方面表现出更好的活性。细胞黏附分析和肿瘤成像结果表明，与野生型肽相比，P462 与肿瘤细胞具有更特异和广泛的结合，并且在肿瘤中的蓄积更多。重要的是，与 P460 相比，P462 在体内的治疗效果更好，并且与肿瘤归巢活性的显著改善相关。本研究强调了肿瘤归巢序列 RGDR 在增强细胞黏附和肿瘤蓄积中的重要作用。该工作的结果表明，P462 可能是一种新型的肿瘤治疗药物候选物。
