Free docosahexaenoic acid promotes ferroptotic cell death via lipoxygenase dependent and independent pathways in cancer cells

Shan, Kai; Feng, Na; Zhu, Dongxiao; Qu, Huamin; Fu, Guoling; Li, Jiaqi; Cui, Jing; Chen, Heyan; Wang, Rong; Qi, Yumin; Chen, Yong Q.

doi:10.1007/s00394-022-02940-w

Cited by 23 publications

(20 citation statements)

References 63 publications

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“…Ferroptosis is a regulated form of cell death characterized by the accumulation of iron-dependent lipid peroxides in the cell membrane, leading to oxidative damage and cell death. Studies have demonstrated that DHA can induce ferroptosis in cancer cells by elevating lipid peroxide levels [ 78 , 79 ]. DHA-induced ferroptosis is dependent on the iron-dependent lipoxygenase (LOX) pathway, which is involved in lipid peroxide production.…”

Section: Discussionmentioning

confidence: 99%

Docosahexaenoic Acid, a Key Compound for Enhancing Sensitization to Drug in Doxorubicin-Resistant MCF-7 Cell Line

et al. 2023

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Drug resistance is a well-known and significant obstacle in the battle against cancer, rendering chemotherapy treatments often ineffective. To improve the effectiveness of chemotherapy, researchers are exploring the use of natural molecules that can enhance its ability to kill cancer cells and limit their spread. Docosahexaenoic acid (DHA), a lipid found in marine fish, has been shown to enhance the cytotoxicity of various anti-cancer drugs in vitro and in vivo. While the combined use of chemotherapeutic drugs with DHA demonstrated promising preliminary results in clinical trials, there is still a significant amount of information to be discovered regarding the precise mechanism of action of DHA. As the biological pathways involved in the chemosensitization of already chemoresistant MCF-7 cells are still not entirely unraveled, in this study, we aimed to investigate whether DHA co-treatment could enhance the ability of the chemotherapy drug doxorubicin to inhibit the growth and invasion of MCF-7 breast cancer cells (MCF-7/Dox) that had become resistant to the drug. Upon treating MCF-7/Dox cells with DHA or DHA–doxorubicin, it was observed that the DHA–doxorubicin combination effectively enhanced cancer cell death by impeding in vitro propagation and invasive ability. In addition, it led to an increase in doxorubicin accumulation and triggered apoptosis by arresting the cell cycle at the G2/M phase. Other observed effects included a decrease in the multi-drug resistance (MDR) carrier P-glycoprotein (P-gp) and TG2, a tumor survival factor. Augmented quantities of molecules promoting apoptosis such as Bak1 and caspase-3 and enhanced lipid peroxidation were also detected. Our findings in the cell model suggest that DHA can be further investigated as a natural compound to be used alongside doxorubicin in the treatment of breast cancer that is unresponsive to chemotherapy.

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Section: Discussionmentioning

confidence: 99%

Docosahexaenoic Acid, a Key Compound for Enhancing Sensitization to Drug in Doxorubicin-Resistant MCF-7 Cell Line

et al. 2023

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“…The increased DHA effectively activates ferroptosis-mediated tumor killing by promoting ROS accumulation, lipid peroxidation, and protein oxidation. 43 Inhibition of System Xc- has been reported to decrease the levels of CoA, which is synthesized from cysteine via the pantothenate pathway and plays a role in many metabolic pathways, particularly lipid metabolism, and can affect the sensitivity to ferroptosis. 44 This finding indicates that GP90 improves the CP treatment sensitivity by activating transferrin and reducing Gpx4- and SLC7A11-induced ferroptosis.…”

Section: Discussionmentioning

confidence: 99%

Structural characterization of a sulfated polysaccharide from Gracilariopsis lemaneiformis and its potentiation of cisplatin antitumor activity in Colon-26 carcinoma tumor-bearing mice by inducing ferroptosis

Cai

Luo²,

Chen

et al. 2023

Food Funct.

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“…Ferroptosis can be affected by externally adding ferroptosis-related metabolic substrates. The addition of iron and docosahexaenoic acid (DHA) can induce ferroptosis in PCa cells by affecting the balance of cellular iron metabolism and lipid metabolism, respectively [ 153 , 154 ]. More importantly, the addition of iron potentiated the efficacy of antiandrogenic drugs, and in PCa xenografts, the combination of bicalutamide and iron exacerbated the oxidative damage of cells and inhibited the growth of tumors, which was not the case when the two were used alone.…”

Section: Ferroptosis As a Promising Treatment In Pcamentioning

confidence: 99%

Ferroptosis landscape in prostate cancer from molecular and metabolic perspective

et al. 2023

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Prostate cancer is a major disease that threatens men’s health. Its rapid progression, easy metastasis, and late castration resistance have brought obstacles to treatment. It is necessary to find new effective anticancer methods. Ferroptosis is a novel iron-dependent programmed cell death that plays a role in various cancers. Understanding how ferroptosis is regulated in prostate cancer will help us to use it as a new way to kill cancer cells. In this review, we summarize the regulation and role of ferroptosis in prostate cancer and the relationship with AR from the perspective of metabolism and molecular pathways. We also discuss the feasibility of ferroptosis in prostate cancer treatment and describe current limitations and prospects, providing a reference for future research and clinical application of ferroptosis.

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Free docosahexaenoic acid promotes ferroptotic cell death via lipoxygenase dependent and independent pathways in cancer cells

Cited by 23 publications

References 63 publications

Docosahexaenoic Acid, a Key Compound for Enhancing Sensitization to Drug in Doxorubicin-Resistant MCF-7 Cell Line

Docosahexaenoic Acid, a Key Compound for Enhancing Sensitization to Drug in Doxorubicin-Resistant MCF-7 Cell Line

Structural characterization of a sulfated polysaccharide from Gracilariopsis lemaneiformis and its potentiation of cisplatin antitumor activity in Colon-26 carcinoma tumor-bearing mice by inducing ferroptosis

Ferroptosis landscape in prostate cancer from molecular and metabolic perspective

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