Artemisinin Derivatives Stimulate DR5-Specific TRAIL-Induced Apoptosis by Regulating Wildtype P53

Abstract

Artemisinin derivatives, widely known as commercial anti-malaria drugs, may also have huge potential in treating cancer cells. It has been reported that artemisinin derivatives can overcome resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in liver and cervical cancer cells. In our study, we demonstrated that artesunate (ATS) and dihydroartemisinin (DHA) are more efficient in killing colon cancer cells compared to artemisinin (ART). ATS/DHA induces the expression of DR5 in a P53 dependent manner in HCT116 and DLD-1 cells. Both ATS and DHA overcome the resistance to DHER-induced apoptosis in HCT116, mainly through upregulating death receptor 5 (DR5). We also demonstrate that DHA sensitizes HCT116 cells to DHER-induced apoptosis via P53 regulated DR5 expression in P53 knockdown assays. Nevertheless, a lower effect was observed in DLD-1 cells, which has a single Ser241Phe mutation in the P53 DNA binding domain. Thus, the status of P53 could be one of the determinants of TRAIL resistance in some cancer cells. Finally, the combination treatment of DHA and the TRAIL variant DHER increases cell death in 3D colon cancer spheroid models, which shows its potential as a novel therapy.

Dihydroartemisinin: A Potential Drug for the Treatment of Malignancies and Inflammatory Diseases

“…Malignant tumors threaten the life safety of people all over the world and have become the main cause of death together with cardiovascular and cerebrovascular diseases and respiratory diseases (115). It has been demonstrated that DHA exerts significant anti-tumor activity in a variety of malignant tumors, and it has no toxicity to normal cells at appropriate doses (18,20,85,94,116,117). It has been found that DHA not only is used as an adjuvant drug in combination with other chemotherapy drugs to improve drug resistance and enhance tumor killing function, but also has a significant inhibitory effect on tumors (21,29,34,39,45,46,70).…”

Dihydroartemisinin-Transferrin Adducts Enhance TRAIL-Induced Apoptosis in Triple-Negative Breast Cancer in a P53-Independent and ROS-Dependent Manner

“…Above, we proved that DHA-TF adducts significantly reduce cell viability and clonogenic capacity in TNBC cells. It has been established that artemisinins induce cell apoptosis in colon cancer cells ( 25 ). Thus, cell apoptosis of the DHA-TF treated TNBC cells was analyzed by Annexin V/PI assay and a significant increase was observed in all four cell lines compared with the untreated cells ( Figure 3A ).…”

“…DHA-TF or TRAIL loaded nanoparticles have been proved to be effective and specific to tumor cells in vivo (42-44), Which will be a promising delivery method for the combination treatment for further analysis. The P53 status is important for artemisinin induced DR5 upregulation (25). However, most of the TNBC cell lines contain mutated P53 (45), for example, MDA-MB-231 (R280K) (46), MDA-MB-436 (E204 frameshift to stop codon) (47), MDA-MB-468 (R273H) (47) and BT-549 (R249S) (48).…”

“…Cells were harvested after treated with/without DHA-TF for 24h. and western blot was carried out as previously described ( 25 ). GPX4 (R&D Systems, Minneapolis, MN) primary antibody was used.…”

“…Trimerized TRAIL binds to the extracellular domain of death receptor 4 (DR4) or death receptor 5 (DR5) to stimulate caspase cascade activation, eventually leading to cell shrinkage, DNA fragmentation, and cell apoptosis ( 24 ). TRAIL is harmless to non-transformed cells and our previous research on colon cancer cells showed that DHA enhances TRAIL efficacy, especially the DR5-specific TRAIL variant DHER-induced apoptosis ( 25 ).…”