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Mitotic catastrophe and p53-dependent senescence induction in T-cell malignancies exposed to nonlethal dosage of GL-V9

  • Hui Li
  • Po Hu
  • Zhanyu Wang
  • Hongzheng Wang
  • Xiaoxuan Yu
  • Xiangyuan Wang
  • Yingjie Qing
  • Mengyuan Zhu
  • Jingyan Xu
  • Zhiyu Li
  • Qinglong GuoEmail author
  • Hui HuiEmail author
Genotoxicity and Carcinogenicity

Abstract

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.

Keywords

Mitotic catastrophe Cellular senescence p53 ND GL-V9 T-cell malignancies 

Abbreviations

T-ALL

T-cell acute lymphoblastic leukemia

T-NHL

T cell non-Hodgkin lymphomas

ND GL-V9

Nonlethal dosage of GL-V9

CHK1

Checkpoint kinase 1

CHK2

Checkpoint kinase 2

CDK1

Cyclin B1-dependent kinase

Mad2

Mitotic arrest deficient 2

Plks

Polo-like kinases

SA-β-Gal

Senescence-associated β-galactosidase

PARP

Poly (ADP-ribose) polymerase

CFSE

Carboxyfluorescein diacetate succinimidyl ester

MRD

Minimal residual disease

Notes

Acknowledgements

This work was supported by the Drug Innovation Major Project (Nos. 2017ZX09301014, 2018ZX09711001-003-007, 2017ZX09101003-005-023), the National Science and Technology Major Project (No. 2018ZX09711001-005-023), the Project Program of State Key Laboratory of Natural Medicines, China Pharmaceutical University (No. SKLNMZZCX201823), the Nation Natural Science Foundation of China (Nos. 81903647, 81503096, 81673461, 81873046, 81830105), Project funded by China Postdoctoral Science Foundation (No. 2018M642373), Natural Science Foundation of Jiangsu province (Nos. BK20190560 and BE2018711), Program for Changjiang Scholars and Innovative Research Team in University (PCSIRT-IRT1193), Nanjing Medical Science and Technology Development Project (YKK17074), the Open Project of State Key Laboratory Cultivation Base for TCM Quality and Efficacy, Nanjing University of Chinese Medicine (Nos. TCMQ and E201704), and “Double First-Class” University project (CPU 2018GF11, CPU2018GF05).

Author contributions

HL designed and performed research and analyzed data and wrote the manuscript; PH and ZW performed research. HW and XY analyzed data; YQ collected data; XW and MZ performed statistical analysis; JX edited the manuscript; ZL analyzed the compound; QG and HH conceptualized the project, directed experiment design and data analysis.

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.

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© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.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 OptimizationChina Pharmaceutical UniversityNanjingPeople’s Republic of China
  2. 2.Department of HematologyThe Affiliated DrumTower Hospital of Nanjing University Medical SchoolNanjingPeople’s Republic of China

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