TY  - JOUR
A1  - Zhivkova, Veselina
A1  - Kiecker, Felix
A1  - Langer, Peter
A1  - Eberle, Jürgen
T1  - Crucial role of reactive oxygen species (ROS) for the proapoptotic effects of indirubin derivative DKP-073 in melanoma cells
JF  - Molecular carcinogenesis
N2  - Melanoma represents a prime example demonstrating the success of targeted therapy in cancer. Nevertheless, it remained a deadly disease until now, and the identification of new, independent strategies as well as the understanding of their molecular mechanisms may help to finally overcome the high mortality. Both indirubins and TNF-related apoptosis-inducing ligand (TRAIL) represent promising candidates. Here, the indirubin derivative DKP-073 is shown to trigger apoptosis in melanoma cells, which is enhanced by the combination with TRAIL and is accompanied by complete loss of cell viability. Addressing the signaling cascade, characteristic molecular steps were identified as caspase-3 activation, downregulation of XIAP, upregulation of p53 and TRAIL receptor 2, loss of mitochondrial membrane potential, and STAT-3 dephosphorylation. The decisive step, however, turned out to be the early production of ROS already at 1 h. This was proven by antioxidant pretreatment, which completely abolished apoptosis induction and loss of cell viability as well as abrogated all signaling effects listed above. Thus, ROS appeared as upstream of all proapoptotic signaling. The data indicate a dominant role of ROS in apoptosis regulation, and the new pathway may expose a possible Achilles heel of melanoma.
KW  - apoptosis
KW  - kinase pathway
KW  - melanoma
KW  - stat 3
Y1  - 2018
U6  - https://doi.org/10.1002/mc.22924
SN  - 0899-1987
SN  - 1098-2744
VL  - 58
IS  - 2
SP  - 258
EP  - 269
PB  - Wiley
CY  - Hoboken
ER  -