Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China.
Department of Infectious Diseases and Hepatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China.
BMC Med. 2023 Jul 13;21(1):253. doi: 10.1186/s12916-023-02904-9.
PARP inhibitor (PARPi), as a kind of DNA damage repair inhibitor, has been shown to be effective in various solid tumors and hematologic malignancies. Natural killer/T cell lymphoma (NKTCL) is a highly aggressive malignancy, the treatment of which has long been a major challenge in the clinic. Here, we investigated the efficacy and mechanism of PARPi, and the therapeutic value of PARPi combined with cisplatin in NKTCL.
The cell proliferation, cell apoptosis, and cell cycle of NKTCL cells were detected respectively by CCK-8 and flow cytometry. The changes of mRNA expression and protein level were measured respectively by mRNA-sequencing, quantitative real-time PCR, western blotting, and immunofluorescence. LMO2 expression was detected by immunohistochemistry and western blotting. Targeted knockdown of LMO2 was conducted by short hairpin RNA. The tumor xenograft models were established to evaluate the efficacy of drugs in vivo.
PARPi inhibited cell proliferation, promoted cell apoptosis, and induced S-phase cell cycle arrest in NKTCL cells. PARPi led to the accumulation of DNA damage by blocking DNA repair and DNA replication. Additionally, LMO2 deficiency reduced the sensitivity of NKTCL cells to PARPi. Finally, the combination of PARPi and cisplatin exhibited significant synergistic effects both in vitro and in vivo.
In summary, we found that PARPi exerted an anti-tumor effect via LMO2 and synergized with cisplatin in NKTCL, which provides the theoretical basis for the clinical application of PARPi.
聚腺苷二磷酸核糖聚合酶（PARP）抑制剂作为一种 DNA 损伤修复抑制剂，已在多种实体瘤和血液恶性肿瘤中显示出疗效。自然杀伤/T 细胞淋巴瘤（NKTCL）是一种侵袭性很强的恶性肿瘤，其治疗一直是临床上的一大挑战。在这里，我们研究了 PARP 抑制剂的疗效和机制，以及 PARP 抑制剂联合顺铂治疗 NKTCL 的治疗价值。
分别通过 CCK-8 和流式细胞术检测 NKTCL 细胞的增殖、细胞凋亡和细胞周期。通过 mRNA 测序、实时定量 PCR、Western blot 和免疫荧光分别检测 mRNA 表达和蛋白水平的变化。通过免疫组化和 Western blot 检测 LMO2 表达。通过短发夹 RNA 进行 LMO2 的靶向敲低。建立肿瘤异种移植模型以评估体内药物的疗效。
PARPi 抑制了 NKTCL 细胞的增殖，促进了细胞凋亡，并诱导了 S 期细胞周期停滞。PARPi 通过阻断 DNA 修复和 DNA 复制导致 DNA 损伤的积累。此外，LMO2 缺失降低了 NKTCL 细胞对 PARPi 的敏感性。最后，PARPi 和顺铂联合在体外和体内均表现出显著的协同作用。
总之，我们发现 PARPi 通过 LMO2 发挥抗肿瘤作用，并与 NKTCL 中的顺铂协同作用，为 PARPi 的临床应用提供了理论依据。
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