EF24 induces ferroptosis in osteosarcoma cells through HMOX1

Lin, Haiyingjie; Rothenberg, Marc E.; Zhang, Cheng-Yong; Yang, Tingting; Deng, Zhendong; Song, Yuwei; Huang, Likun; Li, Fuxiang; Li, Qingchu; Lin, Shaoqiang; Jin, Dadi

doi:10.1016/j.biopha.2020.111202

Cited by 118 publications

(89 citation statements)

References 33 publications

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“…Researchers have proposed that this phenomenon may be an adaptive response to cellular metabolic imbalance (20). Researchers have also proposed that curcumin analogs can act as ferroptosis inducers to mediate cellular ferroptosis in a dosedependent manner in the treatment of osteosarcoma (21). This study found that curcumin significantly reduced the iron ion content in drug-resistant tumor tissues, inhibited NCOA4 and FTH1 mRNA and protein expression, and enhanced sensitivity to sunitinib.…”

Section: Discussionmentioning

confidence: 82%

Curcumin reverses the sunitinib resistance in clear cell renal cell carcinoma (ccRCC) through the induction of ferroptosis via the ADAMTS18 gene

Xu¹,

Zhu²,

Peng³

et al. 2021

Transl Cancer Res TCR

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Background:To explore the possible mechanism by which curcumin reverses the sunitinib resistance in clear cell renal cell carcinoma (ccRCC).Methods: A sunitinib-resistant ccRCC cell model was established. The MTT assay was used to determine the half maximal inhibitory concentration (IC 50 ) and drug resistance (DR) index. The effects of curcumin plus sunitinib or sunitinib alone on drug-resistant cell lines were verified by the cell counting kit-8 (CCK-8) assay, colony formation assay, and apoptosis assay. The concentration of iron ions in the cell lines was analyzed using an Abcam Iron Assay Kit. The expressions of ADAMTS18 gene and ferroptosis-related proteins (NCOA4, FTH1 and p53) after curcumin plus sunitinib treatment were analyzed by reverse transcription polymerase chain reaction (RT-PCR) and Western blotting. After transfection of curcumin plus sunitinib/sunitinib alone-treated drug-resistant cell lines with si-ADAMTS18, cell proliferation activity was assessed by the CCK-8 assay, and the protein expression levels of ADAMTS18, NCOA1, FTH1 and p53 were analyzed by Western blotting. After treatment with ferroptosis-1 (Fer-1; a ferroptosis inhibitor), the cell proliferation activity of drug-resistant cell lines treated with curcumin plus sunitinib/sunitinib alone was reassessed using the CCK-8 assay.Results: Curcumin plus sunitinib inhibited the proliferation of sunitinib-resistant ccRCC cells (P<0.05).Curcumin significantly decreased the concentration of iron ions and increased the expression of ADAMTS18 gene, while significantly inhibited ferroptosis-related protein expression (P<0.05). After silencing the ADAMTS18 gene, there was no significant difference in cell proliferation or ferroptosis-related protein expression between curcumin plus sunitinib and sunitinib-treated drug-resistant cell lines (P>0.05).Ferroptosis inhibitors reversed the inhibitory effect of curcumin on sunitinib-resistant ccRCC cell lines.Conclusions: Curcumin can reverse the sunitinib resistance in ccRCC, possibly by upregulating the expression of the ADAMTS18 gene to induce ferroptosis.

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Section: Discussionmentioning

confidence: 82%

Curcumin reverses the sunitinib resistance in clear cell renal cell carcinoma (ccRCC) through the induction of ferroptosis via the ADAMTS18 gene

Xu¹,

Zhu²,

Peng³

et al. 2021

Transl Cancer Res TCR

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“…The results suggested that EF24 induced accumulation of ROS and obvious mitochondrial fission in NSCLC cells. Compared with curcumin, EF24 induced cancer cell apoptosis and inhibit the growth of human tumor xenografts at a much lower dose [ 32 , 33 ]. In animal experiments, the dosage of EF24 that inhibit tumor growth is generally only one tenth of curcumin [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

EF24 exerts cytotoxicity against NSCLC via inducing ROS accumulation

et al. 2021

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Background The role of Diphenyldifluoroketone (EF24), a synthetic analogue of curcumin with noteworthy antitumor potential, remains unclear in non-small cell lung cancer (NSCLC). Herein, the inhibitory effect of EF24 on NSCLC and its mechanism were studied. Methods Cytotoxicity was measured by MTT assay, colony formation assay and xenograft model. Cell apoptosis and reactive oxygen species (ROS) level were quantified by flow cytometer. Protein level was detected by western blot assay. Mitochondria and autophagosomes were observed using transmission electron microscope and confocal microscopy. Results In-vitro, EF24 significantly induced proliferation inhibition, apoptosis, mitochondrial fission and autophagy of NSCLC cell lines. These cytotoxic effects were significantly attenuated by two reactive oxygen species (ROS) scavengers, indicating its anti-cancer effects largely depend on ROS accumulation. In-vivo, EF24 inhibited tumor growth in a dose-dependent manner. Moreover, no pathological changes of heart, lung, spleen, kidney and liver of mice were observed. Collectively, EF24 induced ROS accumulation, in turn activates cell apoptosis, and then exerts its cytotoxicity on NSCLC cells. Conclusions The results showed that EF24 exerted cytotoxicity against NSCLC via ROS accumulation. Thus, EF24 might serve as a potential anti-cancer agent for the treatment of NSCLC.

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“…The upregulation of HMOX1 is evident in many different human malignancies, wherein it plays an important role in regulating the stability of the tumor microenvironment in a manner that promotes tumor cell proliferation, angiogenesis, and metastasis [21]. However, HMOX1 can also promote ferroptosis in cancer cells in therapeutic contexts [22]. There is also prior evidence that HMOX1 primarily plays a bene cial role in IR injury [23].…”

Section: Discussionmentioning

confidence: 99%

miR-3587 Targets HMOX1 to Attenuate Ferroptotic Renal Injury Following Ischemia-Reperfusion

Liu

Zhang

et al. 2021

Preprint

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Renal ischemia-reperfusion (IR) is frequently observed in patients who are critically ill, yet there are no reliable or effective approaches to treating this condition. This study aimed to investigate the miRNA-mRNA regulatory networks that are involved in IR-related ferroptotic renal injury. Bioinformatics method was used to screen critical hub gene and its upstream miRNA from Renal IR-related data sets in Gene Expression Omnibus, and further experiments were conducted to verify the regulatory effect of miRNA on critical hub gene. Heme oxygenase-1 (HMOX1) was identified as a critical hub gene that was found to be significantly upregulated during the early stages of renal IR injury. miR-3587 was identified as a putative regulator of HMOX1. When a miR-3587 inhibitor was applied in a hypoxia-reoxygenation model system using renal tubular epithelial cells, HMOX1 expression was significantly increased relative to that observed in the control hypoxia-reoxygenation group, with concomitant increases in glutathione peroxidase 4 (GPX4) protein levels, enhanced cell viability, a reduction in malondialdehyde content, and the restoration of normal mitochondrial membrane potential. Preliminary evidence suggests that utilizing miR-3587 inhibitors can further promote HMOX1 upregulation, thereby protecting renal tissues from IR-induced ferroptosis.

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EF24 induces ferroptosis in osteosarcoma cells through HMOX1

Cited by 118 publications

References 33 publications

Curcumin reverses the sunitinib resistance in clear cell renal cell carcinoma (ccRCC) through the induction of ferroptosis via the ADAMTS18 gene

Curcumin reverses the sunitinib resistance in clear cell renal cell carcinoma (ccRCC) through the induction of ferroptosis via the ADAMTS18 gene

EF24 exerts cytotoxicity against NSCLC via inducing ROS accumulation

miR-3587 Targets HMOX1 to Attenuate Ferroptotic Renal Injury Following Ischemia-Reperfusion

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