Natural pentacyclic triterpenoid from Pristimerin sensitizes p53-deficient tumor to PARP inhibitor by ubiquitination of Chk1,Pharmacological Research

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Natural pentacyclic triterpenoid from Pristimerin sensitizes p53-deficient tumor to PARP inhibitor by ubiquitination of Chk1
Pharmacological Research ( IF 9.1 ) Pub Date : 2024-02-04 , DOI: 10.1016/j.phrs.2024.107091
Li Tao ₁ , Xiangyu Xia ₁ , Shujing Kong ₁ , Tingye Wang ₁ , Fangtian Fan ₂ , Weimin Wang ₃

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Inhibition of checkpoint kinase 1 (Chk1) has shown to overcome resistance to poly (ADP-ribose) polymerase (PARP) inhibitors and expand the clinical utility of PARP inhibitors in a broad range of human cancers. Pristimerin, a naturally occurring pentacyclic triterpenoid, has been the focus of intensive studies for its anticancer potential. However, it is not yet known whether low dose of pristimerin can be combined with PARP inhibitors by targeting Chk1 signaling pathway. In this study, we investigated the efficacy, safety and molecular mechanisms of the synergistic effect produced by the combination olaparib and pristimerin in TP53-deficient and BRCA-proficient cell models. As a result, an increased expression of Chk1 was correlated with TP53 mutation, and pristimerin preferentially sensitized p53-defective cells to olaparib. The combination of olaparib and pristimerin resulted in a more pronounced abrogation of DNA synthesis and induction of DNA double-strand breaks (DSBs). Moreover, pristimerin disrupted the constitutional levels of Chk1 and DSB repair activities. Mechanistically, pristimerin promoted K48-linked polyubiquitination and proteasomal degradation of Chk1 while not affecting its kinase domain and activity. Importantly, combinatorial therapy led to a higher rate of tumor growth inhibition without apparent hematological toxicities. In addition, pristimerin suppressed olaparib-induced upregulation of Chk1 and enhanced olaparib-induced DSB marker γΗ2ΑΧ . Taken together, inhibition of Chk1 by pristimerin has been observed to induce DNA repair deficiency, which may expand the application of olaparib in BRCA-proficient cancers harboring TP53 mutations. Thus, pristimerin can be combined for PARP inhibitor-based therapy.

中文翻译：

Pristimerin 中的天然五环三萜类化合物通过 Chk1 泛素化使 p53 缺陷型肿瘤对 PARP 抑制剂敏感

检查点激酶 1 (Chk1) 的抑制已被证明可以克服对聚 (ADP-核糖) 聚合酶 (PARP) 抑制剂的耐药性，并扩大 PARP 抑制剂在多种人类癌症中的临床应用。 Pristimerin 是一种天然存在的五环三萜类化合物，因其抗癌潜力而成为深入研究的焦点。然而，目前尚不清楚低剂量的pritimerin是否可以通过靶向Chk1信号通路与PARP抑制剂联合使用。在这项研究中，我们研究了奥拉帕尼和普里斯蒂林联合用药在TP53缺陷和BRCA丰富的细胞模型中产生的协同效应的功效、安全性和分子机制。结果，Chk1 表达增加与 TP53 突变相关，并且 pritimerin 优先使 p53 缺陷细胞对奥拉帕尼敏感。奥拉帕尼和普斯蒂莫林的组合导致更明显的 DNA 合成终止和 DNA 双链断裂 (DSB) 的诱导。此外，pritimerin 破坏了 Chk1 和 DSB 修复活性的组成水平。从机制上讲，pritimerin 促进 K48 连接的多聚泛素化和 Chk1 的蛋白酶体降解，同时不影响其激酶结构域和活性。重要的是，组合疗法可以提高肿瘤生长抑制率，且没有明显的血液学毒性。此外，pritimerin抑制奥拉帕尼诱导的Chk1上调并增强奥拉帕尼诱导的DSB标记物γH2AX。总而言之，已观察到 pritimerin 对 Chk1 的抑制会诱导 DNA 修复缺陷，这可能会扩大奥拉帕尼在具有 TP53 突变的 BRCA 相关癌症中的应用。因此，pritimerin 可以联合用于基于 PARP 抑制剂的治疗。

更新日期：2024-02-04

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