Mitotic catastrophe and p53-dependent senescence induction in T-cell malignancies exposed to nonlethal dosage of GL-V9
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.
KeywordsMitotic catastrophe Cellular senescence p53 ND GL-V9 T-cell malignancies
T-cell acute lymphoblastic leukemia
T cell non-Hodgkin lymphomas
- ND GL-V9
Nonlethal dosage of GL-V9
Checkpoint kinase 1
Checkpoint kinase 2
Cyclin B1-dependent kinase
Mitotic arrest deficient 2
Poly (ADP-ribose) polymerase
Carboxyfluorescein diacetate succinimidyl ester
Minimal residual disease
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).
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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