Novel Compound, ND-17, Regulates the JAK/STAT, PI3K/AKT, and MAPK Pathways and Restrains Human T-lymphoid Leukemia Development.

Abstract

BACKGROUND:

T cell acute lymphoblastic leukemia (T-ALL) is an invasive hematological malignant disorder of T cell progenitors. The Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway plays an important role in the development of T-ALL and in the inhibition of the key molecule, JAK2, and could suppress T-ALL cell proliferation.

OBJECTIVE:

The objective of this study was to investigate the in vitro anti-tumor effects of a novel nilotinib derivative, ND-17, on cancer cell lines via its interactions with JAK2.

METHODS:

The effects of ND-17 on cell proliferation and on cell cycle and apoptosis were evaluated using the tetrazolium assay and flow cytometry, respectively. In addition, the ND-17/JAK2 binding interactions were evaluated using surface plasmon resonance and western blot analyses.

RESULTS:

ND-17 exerted the greatest inhibitory effects on T-ALL cells amongst all hematological cancer cell lines tested. Flow cytometric analysis indicated that ND-17 blocked the cell cycle at the S phase in T-ALL cells. Nilotinib did not significantly inhibit T-ALL cell growth or regulate the cell cycle. Preliminary investigations revealed that the regulation of cyclin-dependent kinases/cyclins was attributed to ND-17-induced cell cycle arrest. Furthermore, ND-17 could bind to JAK2 with strong affinity, and more importantly, ND-17 bound to the ATP pocket of JAK2 in a manner similar to the potent inhibitor. Thus, ND-17 treatment exhibited a prominent effect in inhibiting the phosphorylation of JAK2 in T-ALL cells. An increase in the phosphorylation of JAK2 was observed in interleukin-6- stimulated Jurkat cells, which was reversed by ND-17 treatment. Meanwhile, the combination of TG- 101348 and ND-17 led to further improvement in inhibiting the phosphorylation of JAK2. Moreover, the transfection and knockdown of JAK2 altered the inhibitory effect of ND-17 on Jurkat cell viability. In addition, ND-17 treatment suppressed the JAK/STAT, phosphatidylinositol-3-kinase/protein kinase B/mechanistic target of rapamycin, and mitogen-activated protein kinase/extracellular signal-regulated protein kinases 1 and 2 signaling pathways.

CONCLUSION:

These findings suggest that ND-17 could be a promising JAK2 inhibitor for the treatment of T-ALL.

• Authors: Weina Ma, Yanhong Liu, Panpan Lei, Man Zhu, Xiaoyan Pan
• Journal: Current cancer drug targets (Curr Cancer Drug Targets) Vol. 22 Issue 5 Pg. 404-413 ( 2022) ISSN: 1873-5576 [Electronic] Netherlands
• PMID: 35249489 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright© Bentham Science Publishers; For any queries, please email at [email protected].

Chemical References

• STAT3 Transcription Factor
• Janus Kinase 2
• Proto-Oncogene Proteins c-akt

Topics

• Apoptosis
• Humans
• Janus Kinase 2 (metabolism, pharmacology)
• Phosphatidylinositol 3-Kinases (metabolism)
• Precursor T-Cell Lymphoblastic Leukemia-Lymphoma (drug therapy)
• Proto-Oncogene Proteins c-akt (metabolism)
• STAT3 Transcription Factor (metabolism)
• Signal Transduction