Kang Donghoon, Lim Yeji, Ahn Dabin, Lee Jaeseok, Park Chin-Ju
Department of Chemistry, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea.
J Med Chem. 2025 Aug 14;68(15):15683-15694. doi: 10.1021/acs.jmedchem.5c00537. Epub 2025 Jul 30.
Cellular senescence, marked by irreversible cell cycle arrest and senescence-associated secretory phenotype, contributes to aging and cancer recurrence. While chemotherapy can induce senescence in cancer cells, these therapy-induced senescent cells often resist apoptosis and promote tumor recurrence. The nuclear interaction between FOXO4 and p53 is crucial for senescent cell survival. Using NMR spectroscopy, we identified that hydrophobic interactions in the p53 transactivation domain play a key role in FOXO4 forkhead domain binding. Based on this structural information, we designed an optimized peptide inhibitor with reduced negative charges and incorporated a cationic cell-penetrating peptide for enhanced cellular delivery (CPP-CAND). CPP-CAND exhibited high selectivity for senescent cells, effectively disrupting nuclear FOXO4-p53 foci and inducing caspase-dependent apoptosis. Notably, it showed cytotoxicity against senescent cancer cells induced by different chemotherapeutic agents including doxorubicin and cisplatin. With its enhanced selectivity, l-amino acid composition, and shorter length, CPP-CAND represents a promising therapeutic candidate for targeting therapy-induced senescent cancer cells.
细胞衰老以不可逆的细胞周期停滞和衰老相关分泌表型为特征，与衰老和癌症复发有关。虽然化疗可诱导癌细胞衰老，但这些治疗诱导的衰老细胞往往抵抗凋亡并促进肿瘤复发。FOXO4与p53之间的核相互作用对衰老细胞的存活至关重要。利用核磁共振波谱，我们确定p53反式激活结构域中的疏水相互作用在FOXO4叉头结构域结合中起关键作用。基于这一结构信息，我们设计了一种优化的肽抑制剂，减少了负电荷，并引入了阳离子细胞穿透肽以增强细胞递送（CPP-CAND）。CPP-CAND对衰老细胞表现出高选择性，有效破坏核内FOXO4-p53灶并诱导半胱天冬酶依赖性凋亡。值得注意的是，它对包括阿霉素和顺铂在内的不同化疗药物诱导的衰老癌细胞具有细胞毒性。凭借其增强的选择性、L-氨基酸组成和较短的长度，CPP-CAND是靶向治疗诱导的衰老癌细胞的一种有前景的治疗候选物。
