Prospective Mechanism of Action of the Tubulysin Synthetic Derivative (TAM 1344) in HCT116 Colon Cancer Cell Line

مقال فى مجلة

2023

تم النشر فى: https://www.sciencedirect.com/journal/journal-of-king-saud-university-science/v…

Abstract: Tubulin is still a highly valued target in cancer chemotherapy. Agents that target tubulin
and microtubule dynamic are considered to be of high therapeutic potential. We conducted a study to
assess the effects of TAM1344, a synthetic cytolysin that is derived from the natural tubulysins on the
proliferation of cancer cell lines. Tubulysins are a group of naturally occurring cytotoxic compounds
that are produced by Myxobacteria. Our results show that TAM1344 exhibit strong antiproliferative
activity against different cancer cell lines at low nanomolar concentration. The measured IC50 values
in HCT116, A549 and MCF7 cancer cell lines were 0.14nM, 0.24nM & 0.09nM, respectively. In a
direct comparison, the three cell lines were more sensitive to the drugs than the myxobacterial natural
products tubulysin-A and –B. Additionally, in HCT116 cells, TAM1344 induces destabilization and
depletion of the interphase microtubules as indicated by Immunofluorescence staining. Furthermore,
the spindle pools of dividing cells show unusual, condensed phenotyping, a characteristic phenotype
of many anti-tubulin agents. The nuclei of treated cells look fragmented in comparison to control cells,
as detected with DAPI or PI staining. Furthermore, at low concentrations, TAM1344 induces an
accumulation of the cells in the G2/M phase of the cell cycle, and therefore apoptotic induction, as
indicated with flow cytometry analysis. In addition, it provoked an apoptotic process, marked by
elevated caspase-3 activity. To conclude, the results indicate that TAM1344 is a novel, highly effective
microtubule-targeting agent

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