DHA exhibits synergistic therapeutic efficacy with cisplatin to induce ferroptosis in pancreatic ductal adenocarcinoma via modulation of iron metabolism

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is an extremely lethal cancer with limited treatment options. Cisplatin (DDP) is used as a mainstay of chemotherapeutic agents in combination with other drugs or radiotherapy for PDAC therapy. However, DDP exhibits severe side-effects that can lead to discontinuation of therapy, and the acquired drug resistance of tumor cells presents serious clinical obstacles. Therefore, it is imperative to develop a more effective and less toxic therapeutic strategy. We and others have previously discovered that dihydroartemisinin (DHA) represents a safe and promising therapeutic agent to preferentially induce cancer cell ferroptosis. In the present study, we find that DHA could intensively strengthen the cytotoxicity of DDP and significantly reduce its effective concentrations both in vitro and in vivo. Combination of DHA and DDP synergistically inhibits the proliferation and induces DNA damage of PDAC cells. Mechanically, the combinative treatment impairs mitochondrial homeostasis, characterized by destroyed mitochondrial morphology, decreased respiratory capacity, reduced ATP production, and accumulated mitochondria-derived ROS. Further studies show that ferroptosis contributes to the cytotoxic effects in PDAC cells under the challenge of DHA and DDP, together with catastrophic accumulation of free iron and unrestricted lipid peroxidation. Moreover, pharmacologic depleting of the free iron reservoir or reconstituted expression of FTH contributes to the tolerance of DHA/DDP-induced ferroptosis, while iron addition accelerates the ferroptotic cell death. In summary, these results provide experimental evidence that DHA acts synergistically with DDP and renders PDAC cells vulnerable to ferroptosis, which may act as a promising therapeutic strategy.

Overcoming the compensatory elevation of NRF2 renders hepatocellular carcinoma cells more vulnerable to disulfiram/copper-induced ferroptosis

“…Small molecule erastin was first discovered for specifically inducing ferroptosis in RAS mutant tumor cells, while sparing litter cytotoxicity to the non-malignant normal cells. Subsequently, RSL3, sorafenib, artemisinin and other molecules were identified for the ability to induce ferroptosis [ 29 , 36 , 37 ]. In the present work, we found that DSF/Cu, a FDA-approved clinical anti-alcoholism drug, selectively attenuates the abilities of proliferation, migration, invasion and angiogenesis in HCC cells at a low concentration.…”

TEOA Promotes Autophagic Cell Death via ROS-Mediated Inhibition of mTOR/p70S6k Signaling Pathway in Pancreatic Cancer Cells

“…However, acquired drug resistance and high toxicity lead to the discontinuation of therapy. Our recent study demonstrated that dihydroartemisinin could effectively optimize the antitumor activity of cisplatin, and significantly reduced its effective concentrations (Du et al, 2021). Therefore, it's interesting to explore whether TEOA could be a promising adjuvant to improve the chemotherapy or overcome the chemoresistance of pancreatic cancer in the future.…”

Integrated analysis identifies TfR1 as a prognostic biomarker which correlates with immune infiltration in breast cancer

“…Artesunate exhibited cytotoxic effects, and its internalization in retinoblastoma cells was dependent on the expression of TfR1 at the membrane [ 47 ]. Increasing evidence suggests that dihydroartemisinin (DHA), a clinically used antimalarial agent, exhibits anticancer activity in numerous cancer cells [ 48 , 49 ]. DHA treatment resulted in iron deficiency by decreasing the expression of cell-surface TfR1 through an endocytic pathway [ 48 , 49 ].…”

“…Increasing evidence suggests that dihydroartemisinin (DHA), a clinically used antimalarial agent, exhibits anticancer activity in numerous cancer cells [ 48 , 49 ]. DHA treatment resulted in iron deficiency by decreasing the expression of cell-surface TfR1 through an endocytic pathway [ 48 , 49 ]. Sulfasalazine, an anti-inflammatory drug, is extensively used in chronic, long-term therapy of inflammatory bowel disease (ulcerative colitis) and rheumatoid arthritis.…”