Luo Yunlin, Nie Mingcheng, Chen Yuekang, Huang Xinyu, Cui Xuehai, Lin Wan, Xu Liyan, Li Enmin, Cheng Yinwei
Cancer Research Center, Shantou University Medical College, Shantou 515041, Guangdong, PR China.
The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou 515041, Guangdong, PR China.
Curr Cancer Drug Targets. 2025 Jan 6. doi: 10.2174/0115680096327635241021115944.
Among the Poly(ADP-ribose) Polymerase (PARP) family in mammals, PARP1 is the first identified and well-studied member that plays a critical role in DNA damage repair and has been proven to be an effective target for cancer therapy. Here, we have reviewed not only the role of PARP1 in different DNA damage repair pathways, but also the working mechanisms of several PARP inhibitors (PARPi), inhibiting Poly-ADP-ribosylation (PARylation) processing and PAR chains production to trap PARP1 on impaired DNA and inducing Transcription- replication Conflicts (TRCs) by inhibiting the PARP1 activity. This review has systematically summarized the latest clinical application of six authorized PARPi, including olaparib, rucaparib, niraparib, talazoparib, fuzuloparib and pamiparib, in monotherapy and combination therapies with chemotherapy, radiotherapy, and immunotherapy, in different kinds of cancer. Furthermore, probable challenges in PARPi application and drug resistance mechanisms have also been discussed. Despite these challenges, further development of new PARP1 inhibitors appears promising as a valuable approach to cancer treatment.
在哺乳动物的聚（ADP - 核糖）聚合酶（PARP）家族中，PARP1是首个被鉴定且深入研究的成员，它在DNA损伤修复中起关键作用，并且已被证明是癌症治疗的有效靶点。在此，我们不仅综述了PARP1在不同DNA损伤修复途径中的作用，还阐述了几种PARP抑制剂（PARPi）的作用机制，这些抑制剂通过抑制聚ADP - 核糖基化（PARylation）过程和PAR链生成，将PARP1捕获在受损DNA上，并通过抑制PARP1活性诱导转录 - 复制冲突（TRCs）。本综述系统总结了六种获批的PARPi，包括奥拉帕利、卢卡帕利、尼拉帕利、他拉唑帕利、氟唑帕利和帕米帕利，在不同类型癌症的单药治疗以及与化疗、放疗和免疫疗法联合治疗中的最新临床应用。此外，还讨论了PARPi应用中可能面临的挑战以及耐药机制。尽管存在这些挑战，但新型PARP1抑制剂作为一种有价值的癌症治疗方法，其进一步发展前景广阔。
