Mecheliolide elicits ROS-mediated ERS driven immunogenic cell death in hepatocellular carcinoma

Xu, Zhongren; Xu, Jianqiang; Sun, Shibo; Lin, Wei; Li, Yongming; Lu, Qiuyue; Li, Fuwei; Ye, Zhibin; Lu, Yunlong; Liu, Wukun

doi:10.1016/j.redox.2022.102351

Cited by 57 publications

(32 citation statements)

References 65 publications

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“…Therefore, the synergistic effect of NDs and UTMD for promoting ICD was furter evaluated. Typical molecules used for validating ICD were CRT exposure on cell surface, HMGB-1 and ATP release, which facilitated anti-tumor immunity [ 39 , 40 ].…”

Section: Resultsmentioning

confidence: 99%

Ultrasound targeted microbubble destruction-triggered nitric oxide release via nanoscale ultrasound contrast agent for sensitizing chemoimmunotherapy

et al. 2023

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Immunotherapy had demonstrated inspiring effects in tumor treatment, but only a minority of people could benefit owing to the hypoxic and immune-suppressed tumor microenvironment (TME). Therefore, there was an urgent need for a strategy that could relieve hypoxia and increase infiltration of tumor lymphocytes simultaneously. In this study, a novel acidity-responsive nanoscale ultrasound contrast agent (L-Arg@PTX nanodroplets) was constructed to co-deliver paclitaxel (PTX) and L-arginine (L-Arg) using the homogenization/emulsification method. The L-Arg@PTX nanodroplets with uniform size of about 300 nm and high drug loading efficiency displayed good ultrasound diagnostic imaging capability, improved tumor aggregation and achieved ultrasound-triggered drug release, which could prevent the premature leakage of drugs and thus improve biosafety. More critically, L-Arg@PTX nanodroplets in combination with ultrasound targeted microbubble destruction (UTMD) could increase cellular reactive oxygen species (ROS), which exerted an oxidizing effect that converted L-Arg into nitric oxide (NO), thus alleviating hypoxia, sensitizing chemotherapy and increasing the CD8 + cytotoxic T lymphocytes (CTLs) infiltration. Combined with the chemotherapeutic drug PTX-induced immunogenic cell death (ICD), this promising strategy could enhance immunotherapy synergistically and realize powerful tumor treatment effect. Taken together, L-Arg@PTX nanodroplets was a very hopeful vehicle that integrated drug delivery, diagnostic imaging, and chemoimmunotherapy. Graphical Abstract

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Section: Resultsmentioning

confidence: 99%

Ultrasound targeted microbubble destruction-triggered nitric oxide release via nanoscale ultrasound contrast agent for sensitizing chemoimmunotherapy

et al. 2023

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“…Specifically, while the suppression of apoptosis was prevalent in AXL high MM2 and MM2‐R cells, necroptosis was inhibited mainly in MITF high MM3 cells, particularly in MM3‐R cells (Figures 5A and S6). Notably, a strong induction of the production of mitochondrial reactive oxygen species (ROS), which can be correlated immunogenic cell death (ICD) was found, 36 sharply reduced by Z‐VAD in MM2/MM2‐R cells and by necrostatin‐1 in MM3/MM3‐R cells (Figure 5B). The higher propensity of MITF high MM3 and MM3‐R cells to undergo necroptosis following romidepsin‐IFN treatment was also confirmed by the induction of pMLKL and RIP1 necroptotic markers as compared to AXL high MM2 and MMR‐2 (Figure 5C).…”

Section: Resultsmentioning

confidence: 99%

Reversing vemurafenib‐resistance in primary melanoma cells by combined romidepsin and type I IFN treatment through blocking of tumorigenic signals and induction of immunogenic effects

Fragale,

Stellacci,

Romagnoli

et al. 2023

Intl Journal of Cancer

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BRAF V600 mutations are the most common oncogenic alterations in melanoma cells, supporting proliferation, invasion, metastasis and immune evasion. In patients, these aberrantly activated cellular pathways are inhibited by BRAFi whose potent antitumor effect and therapeutic potential are dampened by the development of resistance.Here, by using primary melanoma cell lines, generated from lymph node lesions of metastatic patients, we show that the combination of two FDA-approved drugs, the histone deacetylate inhibitor (HDCAi) romidepsin and the immunomodulatory agent IFN-α2b, reduces melanoma proliferation, long-term survival and invasiveness and overcomes acquired resistance to the BRAFi vemurafenib (VEM). Targeted resequencing revealed that each VEM-resistant melanoma cell line and the parental counterpart are characterized by a distinctive and similar genetic fingerprint, shaping the differential and specific antitumor modulation of MAPK/AKT pathways by combined

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“…Natural compounds play a significant role in the exploitation of novel cancer drugs, and various natural products have been used in pre-clinical evaluation and clinical treatment. Our group and others have already identified many natural products killing cancer cells via inhibition of TrxR. − Herein, we isolated two compounds DAP and AP from Alternaria sp. MG1 and investigated the antitumor effect of these two natural compounds.…”

Section: Resultsmentioning

confidence: 99%

Alterperylenol as a Novel Thioredoxin Reductase Inhibitor Induces Liver Cancer Cell Apoptosis and Ferroptosis

Tian

et al. 2022

J. Agric. Food Chem.

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Natural products are a rich resource for discovering innovational drugs. Herein, we isolated and characterized two compounds dihydroalterperylenol (DAP) and alterperylenol (AP) from Alternaria sp. MG1, an endophytic fungus isolated from Vitis quinquangularis, and investigated the underlying antitumor mechanism of AP. Mechanistically, AP inhibits the growth of HepG2 cells by targeting the selenoprotein thioredoxin reductase (TrxR) and ultimately induces cell apoptosis and ferroptosis. Compared to DAP, the α,β-unsaturated carbonyl structure of AP is an indispensable moiety for its antitumor activity and TrxR inhibition. Specifically, inhibition of TrxR causes the extensive reactive oxygen species and consequently results in DNA damage, G2/M cell cycle arrest, and mitochondrial fission. Furthermore, ferroptosis is driven via excess toxic lipid peroxidation and elevation of intracellular iron levels via regulating iron-related proteins. In vivo validation also shows that AP owns anticancer activity in xenograft mice. Collectively, our results disclose a novel natural TrxR inhibitor AP exerting the antitumor effect via inducing cell apoptosis and ferroptosis and evidence that AP is a promising candidate agent for liver carcinoma therapy. The link of TrxR inhibition to ferroptosis further highlights the physiological importance of TrxR in regulating ferroptosis.

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Mecheliolide elicits ROS-mediated ERS driven immunogenic cell death in hepatocellular carcinoma

Cited by 57 publications

References 65 publications

Ultrasound targeted microbubble destruction-triggered nitric oxide release via nanoscale ultrasound contrast agent for sensitizing chemoimmunotherapy

Ultrasound targeted microbubble destruction-triggered nitric oxide release via nanoscale ultrasound contrast agent for sensitizing chemoimmunotherapy

Reversing vemurafenib‐resistance in primary melanoma cells by combined romidepsin and type I IFN treatment through blocking of tumorigenic signals and induction of immunogenic effects

Alterperylenol as a Novel Thioredoxin Reductase Inhibitor Induces Liver Cancer Cell Apoptosis and Ferroptosis

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