State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, People's Republic of China.
Department of Hematology, The Affiliated DrumTower Hospital of Nanjing University Medical School, Nanjing, 210008, People's Republic of China.
Arch Toxicol. 2020 Jan;94(1):305-323. doi: 10.1007/s00204-019-02623-2. Epub 2019 Nov 23.
Mitotic catastrophe of cancer cells induced by drugs is characterized by low dosage and low toxicity, representing a significant advantage in the cancer treatment. Effective therapeutic options are limited for T-cell malignancies patients who are still treated by high-dose multiagent chemotherapy, potentially followed by hematopoietic stem cell transplantation, highlighting the urgency for identification of more effective anti-T-cell malignancies drugs. The use of antineoplastic drugs which induced tumor cell mitotic catastrophe would be a new strategy for cancer therapy. Nevertheless, there is still no effective mitotic catastrophe agent in T-cell malignancies. Our study showed that nonlethal dosage (ND) of GL-V9 (5-hydroxy-8-methoxy-2-phenyl-7-(4-(pyrrolidin-1-yl) butoxy) 4 H-chromen-4-one) (2 µM), a potential anticancer drug, not only attenuated cell growth and survival, but also arrested the cell cycle in G2/M phase and induced multipolar spindles, nuclear alterations (micronucleation and multinucleation), which are the most prominent morphological characteristics of mitotic catastrophe, in T-cell malignancies cell lines including Jurkat, HuT-102, and HuT-78. Moreover, ND GL-V9 could trigger DNA damage, and significantly influence several mitosis-associated proteins. Besides, results showed that ND GL-V9 increased the activity of senescence-associated β-galactosidase (SA-β-Gal) following the induction of mitotic catastrophe in Jurkat and HuT-102 cells with intact p53, while causing apoptosis in p53-deficient HuT-78 cells. We concluded that the anti-T-cell malignancies effects of ND GL-V9 and clarified the precise regulation in the process of mitosis under the action of GL-V9 in T-cell malignancies. Our data provided new evidence for the study of T-cell malignancies treatment associated with mitotic catastrophe and cellular senescence induction.
药物诱导的癌细胞有丝分裂灾难的特点是低剂量和低毒性，这在癌症治疗中是一个显著的优势。对于 T 细胞恶性肿瘤患者，有效的治疗选择有限，他们仍然接受高剂量多药化疗，可能随后进行造血干细胞移植，这凸显了识别更有效的抗 T 细胞恶性肿瘤药物的紧迫性。使用诱导肿瘤细胞有丝分裂灾难的抗肿瘤药物将是癌症治疗的新策略。然而，在 T 细胞恶性肿瘤中仍然没有有效的有丝分裂灾难药物。我们的研究表明，非致死剂量（ND）的 GL-V9（5-羟基-8-甲氧基-2-苯基-7-（4-（吡咯烷-1-基）丁氧基）4H-色烯-4-酮）（2µM），一种潜在的抗癌药物，不仅减弱了细胞生长和存活，而且还将细胞周期阻滞在 G2/M 期，并诱导多极纺锤体、核改变（微核形成和多核形成），这些是有丝分裂灾难的最显著形态特征，在 T 细胞恶性肿瘤细胞系中包括 Jurkat、HuT-102 和 HuT-78。此外，ND GL-V9 可以触发 DNA 损伤，并显著影响几种有丝分裂相关蛋白。此外，结果表明，ND GL-V9 在 Jurkat 和 HuT-102 细胞中诱导有丝分裂灾难后，在 p53 完整的情况下增加衰老相关β-半乳糖苷酶（SA-β-Gal）的活性，而在 p53 缺陷的 HuT-78 细胞中引起细胞凋亡。我们得出结论，ND GL-V9 具有抗 T 细胞恶性肿瘤作用，并阐明了 GL-V9 在 T 细胞恶性肿瘤中作用下有丝分裂过程中的精确调控。我们的数据为研究与有丝分裂灾难和细胞衰老诱导相关的 T 细胞恶性肿瘤治疗提供了新的证据。
