The anti-cancer activity of dihydroartemisinin is associated with induction of iron-dependent endoplasmic reticulum stress in colorectal carcinoma HCT116 cells

Abstract

Dihydroartemisinin (DHA), the main active metabolite of artemisinin derivatives, is among the artemisinin derivatives possessing potent anti-malarial and anti-cancer activities. In the present study, we found that DHA displayed significant anti-proliferative activity in human colorectal carcinoma HCT116 cells, which may be attributed to its induction of G1 phase arrest and apoptosis. To further elucidate the mechanism of action of DHA, a proteomic study employed two-dimensional gel electrophoresis (2-DE) and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) was performed. Glucose-regulated protein 78 (GRP78), which is related with endoplasmic reticulum stress (ER stress), was identified to be significantly up-regulated after DHA treatment. Further study demonstrated that DHA enhanced expression of GRP78 as well as growth arrest and DNA-damage-inducible gene 153 (GADD153, another ER stress-associated molecule) at both mRNA and protein levels. DHA treatment also led to accumulation of GADD153 in cell nucleus. Moreover, pretreatment of HCT116 cells with the iron chelator deferoxamine mesylate salt (DFO) abrogated induction of GRP78 and GADD153 upon DHA treatment, indicating iron is required for DHA-induced ER stress. This result is consistent with the fact that the anti-proliferative activity of DHA is also mediated by iron. We thus suggest the unbalance of redox may result in DHA-induced ER stress, which may contribute, at least in part, to its anti-cancer activity.

p8 attenuates the apoptosis induced by dihydroartemisinin in cancer cells through promoting autophagy

“…Since ER stress can be caused by oxidative stress, the iron-mediated endoperoxide cleavages of DHA result in the unbalance of redox to induce ER stress. 5 To response to ER stress, the translation of ATF4 mRNAs selectively increases, which induces the expression of genes involved in restoring ER homeostasis. 36 Among the ATF4 target genes, CHOP is one of the most induced, which is common considered as a mediator of apoptosis.…”

“…21 In addition, ER stress has proved to be one of the inducers of autophagy. 22 Interestingly, DHA induced-ER stress has been observed in several tumor cells, 23,24 and our previous studies have demonstrated that DHA both induce apoptosis and autophagy in various cancer cells. 25,26 The Complex relationships among ER stress, autophagy and apoptosis remain unclear, but it's perhaps noteworthy that we found p8 is involved in all of these 3 biological functions induced by DHA.…”

“…5 Recent studies have shown that the anti-cancer activity of ART derivatives including DHA is mainly executed by ironmediated cleavages of endoperoxide bridges. 5,6 Since most cancer cells have higher iron influx than normal cells, DHA exert selective toxicity toward cancer cells.…”

“…5 Recent studies have shown that the anti-cancer activity of ART derivatives including DHA is mainly executed by ironmediated cleavages of endoperoxide bridges. 5,6 Since most cancer cells have higher iron influx than normal cells, DHA exert selective toxicity toward cancer cells. 7,8 Additionally, clinical trials have shown that ART derivatives are well tolerated with insignificant side-effects in malaria therapy, indicating DHA have important potential in oncology.…”

Qinghaosu (artemisinin): Chemistry and pharmacology

“…In addition, the type of derivative was proved to target G 1 phase of the cell cycle [41] . Thus far, antitumor activity of artemisinins and the underlying mechanisms have been www.nature.com/aps Li Y Acta Pharmacologica Sinica npg widely studied [43][44][45][46][47][48][49] , however, few clinical trials were reported. Antimalarial chloroquine was used as immunosuppressive agent.…”