Nutrients
·
2024
·Vol. 16
·期 11
·1737
·
IF 4.8
Sheng Zhao,Yuzhou Meng,Wenxun Cai,Qiwen Luo,Hongyang Gao,Qiang Shen,Dongyun Shi
Tumor cells are characterized by a delicate balance between elevated oxidative stress and enhanced antioxidant capacity. This intricate equilibrium, maintained within a threshold known as redox homeostasis, offers a unique perspective for cancer treatment by modulating reactive oxygen species (ROS) levels beyond cellular tolerability, thereby disrupting this balance. However, currently used chemotherapy drugs require larger doses to increase ROS levels beyond the redox homeostasis threshold, which may cause serious side effects. How to disrupt redox homeostasis in cancer cells more effectively remains a challenge. In this study, we found that sodium selenite and docosahexaenoic acid (DHA), a polyunsaturated fatty acid extracted from marine fish, synergistically induced cytotoxic effects in colorectal cancer (CRC) cells. Physiological doses of DHA simultaneously upregulated oxidation and antioxidant levels within the threshold range without affecting cell viability. However, it rendered the cells more susceptible to reaching the upper limit of the threshold of redox homeostasis, facilitating the elevation of ROS levels beyond the threshold by combining with low doses of sodium selenite, thereby disrupting redox homeostasis and inducing MAPK-mediated paraptosis. This study highlights the synergistic anticancer effects of sodium selenite and DHA, which induce paraptosis by disrupting redox homeostasis in tumor cells. These findings offer a novel strategy for more targeted and less toxic cancer therapies for colorectal cancer treatment.
研究领域:
肿瘤学
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细胞生物学
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药物化学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF CELL SCIENCE
·
2026
·
IF 3.9
Cui Xiang,Yang Liao,Zhang Huali,Meng Zefeng,Lang Qi,Zheng Hongda,Zhang Fang,Ni Jiayu,Wang Dengfeng,Tang Pan,Li Ru,Tang Mulan,Li Haoming,Cui Min
Paraptosis is a distinct form of programmed cell death characterized by extensive cytoplasmic vacuolation, endoplasmic reticulum (ER) dilation, and mitochondrial swelling. While previous studies have focused primarily on the ER and mitochondria, the involvement of the Golgi apparatus during paraptotic progression remains insufficiently defined. In this study, we identified previously uncharacterized high-density spherical structures, termed paraptosomes, that emerged during paraptosis in human glioblastoma U251MG cells treated with established paraptosis inducers. Further analyses revealed that paraptosome formation coincided with rapid disintegration of the Golgi apparatus, with paraptosomes closely associated with collapsing Golgi structures. Notably, Golgi fragmentation occurred early after paraptosis induction, preceding detectable ER dilation. Functional assessments indicated that Golgi disruption was accompanied by features consistent with Golgi stress responses, including increased expression of Golgi stress–associated markers and impaired secretory capacity. In addition, the ER stress transducers OASIS and ATF6, which normally undergo Golgi-dependent processing and nuclear translocation, failed to be properly processed and instead accumulated within paraptosomes. Collectively, these findings provide an initial structural and cellular-level characterization of paraptosome formation in association with Golgi disintegration and dysfunction, and expand the morphological landscape of paraptosis by identifying Golgi remodeling as an early-associated feature of this non-apoptotic cell death process.
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DOI
PubMed
高影响因子
Heliyon
·
2022
·
IF 3.776
Xiang Cui,Min Cui
Glabridin, a polyphenolic flavonoid isolated from the root of the glycyrrhiza glabra , has been demonstrated to have anti-tumor properties in human malignancies. This study found that glabridin decreased the viability of human breast cancer MDA-MB-231 and MCF7 cells in a dose-dependent manner that was not involved in the caspase-3 cascade. Glabridin promoted the formation of extensive cytoplasmic vacuolation by increasing the expression of endoplasmic reticulum (ER) stress markers BiP, XBP1s, and CHOP. The transmission electron microscopy and fluorescence with the ER chaperon KDEL suggested that the vacuoles were derived from ER. Glabridin-induced vacuolation was blocked when protein synthesis was inhibited by cycloheximide, demonstrating that protein synthesis is crucial for this process. Furthermore, we determined that glabridin causes loss of mitochondrial membrane potential as well as the production of reactive oxygen species, both of which lead to mitochondrial dysfunction. These features are consistent with a kind of programmed cell death described as paraptosis. This work reports for the first time that glabridin could induce paraptosis-like cell death, which may give new therapeutic approaches for apoptosis-resistant breast cancers.
研究领域:
肿瘤学
·
细胞生物学
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药理学
·
分子生物学
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DOI
PubMed
高影响因子
APOPTOSIS
·
2022
·Vol. 27
·期 7
·577-589
·
IF 5.561
Ma Liang,Xuan Xiaojing,Fan Minghui,Zhang Yumeng,Yuan Guozan,Huang Guozheng,Liu Zi
Chemotherapy represents one of the main conventional therapies for breast cancer. However, tumor cells develop mechanisms to evade chemotherapeutic-induced apoptosis. Thus, it is of great significance to induce non-apoptotic cell death modes, such as paraptosis, in breast cancer. Herein, a novel 8-hydroxyquinoline derivative, 5,7-dibromo-8-(methoxymethoxy)-2-methylquinoline (HQ-11), was obtained and its potential anti-breast cancer mechanisms were investigated. Our results showed that extensive cytoplasmic vacuoles derived from the endoplasmic reticulum (ER) and mitochondria were appeared in MCF7 and MDA-MB-231 breast cancer cells by HQ-11 incubation, and pretreatment of cycloheximide was able to inhibit this vacuolation and HQ-11-induced cell death, showing the characteristics of paraptosis. ER stress was involved in HQ-11-caused paraptosis evidenced by the increase of glucose-regulated protein 78, C/EBP homologous protein and polyubiquitinated proteins. Molecular docking analysis revealed a favorable binding mode of HQ-11 in the active site of the chymotrypsin-like β5 subunit of the proteasome, indicative of proteasome dysfunction under HQ-11 treatment, which might result in further aggravated ER stress. Furthermore, treatment of HQ-11 resulted in increased phosphorylation of extracellular signal-regulated kinase (ERK) and c-Jun NH 2 -terminal kinase, and inhibition of ERK with U0126 significantly attenuated HQ-11-induced ER stress and paraptosis. In addition, exposure to HQ-11 also caused apoptosis in breast cancer cells partially through activation of ERK pathway. All these results conclusively indicate that HQ-11 triggers two distinct cell death modes via inhibition of proteasome and activation of ERK pathway in breast cancer cells, providing a promising candidate in future anti-breast cancer therapy.
研究领域:
肿瘤学
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药理学
·
细胞生物学
·
分子生物学
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产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2024
·
IF 15.8
Youdong Chen,Yujie Lu,Huali Lei,Lin Liu,Xianmin Li,Yuqi Yang,Shumin Sun,Qiao Yu,Li Wang,Jie Wu,Jingrui Li,Guanghui Hou,Liang Cheng
Immunotherapy holds significant promise for cancer treatment. However, the highly immunosuppressive nature of solid tumors limits its effectiveness. Herein, we developed bioactive zinc–nickel hydroxide (ZnNi(OH)4) nanosheets (NSs) that can effectively initiate the paraptosis–pyroptosis positive feedback cycle through synergistic ionic effect, thereby mitigating the immunosuppression of solid tumors and enhancing the efficacy of immunotherapy. The acid-sensitive ZnNi(OH)4 NSs releases Ni2+ and Zn2+ in the weakly acidic tumor microenvironment. The released Ni2+ alleviated pyroptosis inhibition by inducing paraptosis and inhibiting autophagic flux. Concurrently, Ni2+ triggered release of endogenous Zn2+ within the cell through a coordination competition mechanism, further amplifying zinc overload-mediated pyroptosis. Interestingly, pyroptosis-associated oxidative stress and endoplasmic reticulum stress further promote Ni2+-mediated paraptosis, forming a positive feedback loop between pyroptosis and paraptosis. This process not only effectively kills tumor cells but also stimulates a strong inflammatory response, enhancing the antitumor immune response and immunotherapy efficacy. Overall, this study proposes an effective paraptosis–pyroptosis induction strategy based on metal ions and demonstrates the effectiveness of the positive feedback loop of paraptosis–pyroptosis in potentiating immunotherapy.
研究领域:
癌症研究
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免疫治疗
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纳米技术
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细胞生物学
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生物化学
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产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2024
·
IF 15.8
Zhenhu Guo,Xiaohan Gao,Jingsong Lu,Ying Li,Zeping Jin,Abdul Fahad,Neema Ufurahi Pambe,Hirotaka Ejima,Xiaodan Sun,Xiumei Wang,Wensheng Xie,Guifeng Zhang,Lingyun Zhao
Regarded as one of the hallmarks of tumorigenesis and tumor progression, the evasion of apoptotic cell death would also account for treatment resistance or failure during cancer therapy. In this study, a Ca2+/Cu2+ dual-ion “nano trap” to effectively avoid cell apoptosis evasion by synchronously inducing paraptosis together with apoptosis was successfully designed and fabricated for breast cancer treatment. In brief, disulfiram (DSF)-loaded amorphous calcium carbonate nanoparticles (NPs) were fabricated via a gas diffusion method. Further on, the Cu2+-tannic acid metal phenolic network was embedded onto the NPs surface by self-assembling, followed by mDSPE-PEG/lipid capping to form the DSF-loaded Ca2+/Cu2+ dual-ions “nano trap”. The as-prepared nanotrap would undergo acid-triggered biodegradation upon being endocytosed by tumor cells within the lysosome for Ca2+, Cu2+, and DSF releasing simultaneously. The released Ca2+ could cause mitochondrial calcium overload and lead to hydrogen peroxide (H2O2) overexpression. Meanwhile, Ca2+/reactive oxygen species-associated mitochondrial dysfunction would lead to paraptosis cell death. Most importantly, cell paraptosis could be further induced and strengthened by the toxic dithiocarbamate (DTC)–copper complexes formed by the Cu2+ combined with the DTC, the metabolic products of DSF. Additionally, the released Cu2+ will be reduced by intracellular glutathione to generate Cu+, which can catalyze the H2O2 to produce a toxic hydroxyl radical by a Cu+-mediated Fenton-like reaction for inducing cell apoptosis. Both in vitro cellular assays and in vivo antitumor evaluations confirmed the cancer therapeutic efficiency by the dual ion nano trap. This study can broaden the cognition scope of dual-ion-mediated paraptosis together with apoptosis via a multifunctional nanoplatform.
研究领域:
癌症生物学
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纳米技术
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药学
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细胞生物学
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治疗学
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产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2024
·
IF 15.8
Huali Lei,Guanghui Hou,Lin Liu,Zifan Pei,Youdong Chen,Yujie Lu,Nalin Yang,Shumin Sun,Liang Cheng
Iron metabolism has emerged as a promising target for cancer therapy; however, the innate metabolic compensatory capacity of cancer cells significantly limits the effectiveness of iron metabolism therapy. Herein, bioactive gallium sulfide nanodots (GaSx), with dual functions of “reprogramming” and “interfering” iron metabolic pathways, were successfully developed for tumor iron metabolism therapy. The constructed GaSx nanodots ingeniously harness hydrogen sulfide (H2S) gas, which is released in response to the tumor microenvironment, to reprogram the inherent transferrin receptor 1 (TfR1)-ferroportin 1 (FPN1) iron metabolism axis in cancer cells. Concurrently, the gallium ions (Ga3+) derived from GaSx act as a biochemical “Trojan horse”, mimicking the role of iron and displacing it from essential biomolecular binding sites, thereby influencing the fate of cancer cells. By leveraging the dual mechanisms of Ga3+-mediated iron disruption and H2S-facilitated reprogramming of iron metabolic pathways, GaSx prompted the initiation of a paraptosis–apoptosis hybrid pathway in cancer cells, leading to marked suppression of tumor proliferation. Importantly, the dysregulation of iron metabolism induced by GaSx notably increased tumor cell susceptibility to both chemotherapy and immune checkpoint blockade (ICB) therapy. This study underscores the therapeutic promise of gas-based interventions and metal ion interference strategies for the tumor metabolism treatment.
研究领域:
癌症生物学
·
纳米技术
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药理学
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治疗学
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产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
·
2020
·
IF 3.263
Hui-feng Pang,Xin-xiao Li,Yu-hua Zhao,Jian-kang Kang,Jun-ying Li,Wei Tian,Chun-miao Wang,Hua-xin Hou,Dan-rong Li
Ovarian cancer is the leading cause of death among gynecologic cancer patients. Although platinum-based chemotherapy as a frontline treatment for ovarian cancer has been widely used in clinical settings, its clinical efficacy is not satisfactory due to the resistance of ovarian cancer cells to apoptosis . Therefore, it is of great significance to induce non-apoptotic programed cell death patterns, such as paraptosis , in ovarian cancer. In this study, we aimed to explore the potential anticancer mechanisms of novel rhein derivative 4a, which was modified with rhein as a lead compound. The results showed that a wide range of vacuoles from the endoplasmic reticulum and mitochondria appeared in ovarian SKOV3, SKOV3-PM4, and A2780 cells treated with derivative 4a, and the cell death caused by derivative 4a is a type of non-apoptotic and non-autophagic death, which is caused by expansion and damage of the endoplasmic reticulum or mitochondria, showing the characteristics of para-apoptotic death. Furthermore, derivative 4a stimulated the unfolded protein reaction of ovarian cancer cells by upregulating the expression of Bip78 and activating the PERK-eIF2α-ATF4 pathways. Notably, rhein derivative 4a-induced cell death was positively correlated with activation of p38, ERK, and JNK, and negatively correlated with Alix, a known protein that inhibits paraptosis. In addition, derivative 4a treatment also induced G2/M phase arrest in ovarian cancer cells. Taken together, our study reveals that derivative 4a induces paraptosis, and this finding can serve as a basis in developing a new strategy for the treatment of antiapoptotic ovarian cancer.
研究领域:
肿瘤学
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细胞生物学
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药理学
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DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2023
·
IF 5.8
Lin Zhao,Bingling Zhong,Yanyan Zhu,Haoyi Zheng,Xumei Wang,Ying Hou,Jin-Jian Lu,Nana Ai,Xiuli Guo,Wei Ge,Yan-Yan Ma,Xiuping Chen
Glioblastoma multiforme (GBM) is one of the most lethal malignant tumors in the human brain, with only a few chemotherapeutic drugs available after surgery. Nitrovin (difurazone) is widely used as an antibacterial growth promoter in livestock. Here, we reported that nitrovin might be a potential anticancer lead. Nitrovin showed significant cytotoxicity to a panel of cancer cell lines. Nitrovin induced cytoplasmic vacuolation, reactive oxygen species (ROS) generation, MAPK activation, and Alix inhibition but had no effect on caspase-3 cleavage and activity, suggesting paraptosis activation. Nitrovin-induced cell death of GBM cells was significantly reversed by cycloheximide (CHX), N-acetyl-l-cysteine (NAC), glutathione (GSH), and thioredoxin reductase 1 (TrxR1) overexpression. Vitamins C and E, inhibitors of pan-caspase, MAPKs, and endoplasmic reticulum (ER) stress failed to do so. Nitrovin-triggered cytoplasmic vacuolation was reversed by CHX, NAC, GSH, and TrxR1 overexpression but not by Alix overexpression. Furthermore, nitrovin interacted with TrxR1 and significantly inhibited its activity. In addition, nitrovin showed a significant anticancer effect in a zebrafish xenograft model, which was reversed by NAC. In conclusion, our results showed that nitrovin induced non-apoptotic and paraptosis-like cell death mediated by ROS through targeting TrxR1. Nitrovin might be a promising anticancer lead for further development.
研究领域:
肿瘤学
·
药理学
·
细胞生物学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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