Dihydroartemisinin induces endothelial cell anoikis through the activation of the JNK signaling pathway

Abstract

Angiogenesis is required for the growth and metastasis of solid tumors. The anti-malarial agent dihydroartemisinin (DHA) demonstrates potent anti-angiogenic activity, but the underlying molecular mechanisms are not yet fully understood. During the process of angiogenesis, endothelial cells migrating from existing capillaries may undergo programmed cell death after detaching from the extracellular matrix, a process that is defined as anchorage-dependent apoptosis or anoikis. In the present study, DHA-induced cell death was compared in human umbilical vein endothelial cells (HUVECs) cultured in suspension and attached to culture plates. In suspended HUVECs, the cell viability was decreased and apoptosis was increased with the treatment of 50 µM DHA for 5 h, while the same treatment did not affect the attached HUVECs. In addition, 50 µM DHA increased the phosphorylation of c-Jun N-terminal kinase (JNK) in suspended HUVECs, but not in attached HUVECs, for up to 5 h of treatment. The JNK inhibitor, SP600125, reversed DHA-induced cell death in suspended HUVECs, suggesting that the JNK pathway may mediate DHA-induced endothelial cell anoikis. The data from the present study indicates a novel mechanism for understanding the anti-angiogenic effects of DHA, which may be used as a component for chemotherapy.

Dose dependent effects of cadmium on tumor angiogenesis

“…Bax-facilitated release of cytochrome c and FasL-engaged Fas mediate apoptosis via the intrinsic mitochondrial pathway [ 84 – 86 ]. In the presence of NF-κB inhibitor, low-dose Cd increased JNK phosphorylation, which resulted in a substantial decrease in viable cell count [ 67 , 87 ]. On the other hand, activated NF-κB reduced the level of phosphorylated JNK and maintained the number of viable ECs [ 67 ].…”

Dihydroartemisinin enhances VEGFR1 expression through up-regulation of ETS-1 transcription factor

“…On cellular level, DHA exerted a significant inhibitory effect on apoptosis, migration and tube-like formation of ECs 37 . Several signaling cascades including NF-κB, PKC, ERK, JNK, and p38 MAPK pathway have been reported to mediate the effects of DHA 38 - 42 . For example, DHA activates JNK signaling pathway and then increases the expression of cyclooxygenase-2 and matrix metalloproteinase-13 (MMP-13) 43 .…”

Development of nanoscale drug delivery systems of dihydroartemisinin for cancer therapy: A review

“…In addition, direct inhibition of endothelial cells (ECs) also strongly halts the progression of angiogenesis, as ECs are major components of vessels. Specifically, DHA inhibits the proliferation, induces the apoptosis or anoikis and promotes the autophagy of ECs by suppressing the extracellular signal regulated kinase (ERK) signaling pathway, activating the c-Jun N-terminal kinase (JNK) signaling pathway and downregulating the Akt/mTOR pathway, respectively [70] , [71] , [72] . Furthermore, DHA can also prevent ECs from forming a vascular plexus by inhibiting the phosphorylation of STAT3 and the subsequent expression of fatty acid synthase (FASN) [73] .…”