RT Journal Article
SR Electronic
T1 Synthetic Tubulysin Derivative, Tubugi-1, Against Invasive Melanoma Cells: The Cell Death Triangle
JF Anticancer Research
JO Anticancer Res
FD International Institute of Anticancer Research
SP 5403
OP 5415
DO 10.21873/anticanres.13734
VO 39
IS 10
A1 DIJANA DRAČA
A1 SANJA MIJATOVIĆ
A1 TAMARA KRAJNOVIĆ
A1 GORAN N. KALUĐEROVIĆ
A1 LUDGER A. WESSJOHANN
A1 DANIJELA MAKSIMOVIĆ-IVANIĆ
YR 2019
UL http://ar.iiarjournals.org/content/39/10/5403.abstract
AB Background/Aim: Tubugi-1 is a more stable and accessible synthetic counterpart of natural tubulysins. This study aimed to evaluate its cytotoxic potential against anaplastic human melanoma cells. Materials and Methods: The viability of A-375 cells was determined by 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and crystal violet assay. The type of cell death and proliferative rate were investigated using flow cytometry and fluorescent microscopy, while the molecular background was evaluated by western blot. Results: Tubugi-1 reduced the viability of A-375 cells, inducing massive micronucleation, followed by augmented expression of inhibitor of nuclear factor-κB and caspase-2, typical of a mitotic catastrophe. Disturbed proliferation and G2M block with prominent caspase activity, weakened the expression of B-cell lymphoma 2 and B-cell lymphoma 2-associated X transient up-regulation, coexisted with intensive autophagy. Specific inhibition of autophagy by chloroquine resulted in conversion from mitotic catastrophe to rapid apoptosis. Conclusion: Multilevel anticancer action of tubugi-1 is extended by co-application of an autophagy inhibitor, giving a new dimension in further preclinical advancement of this potential agent.