Jolkinolide B targets thioredoxin and glutathione systems to induce ROS-mediated paraptosis and apoptosis in bladder cancer cells

Sang, Jun; Li, Wei; Diao, Hongjuan; Fan, Run-Zhu; Huang, Jia-Luo; Gan, Liu; Zou, Ming-Feng; Tang, Gui‐Hua; Yin, Sheng

doi:10.1016/j.canlet.2021.03.030

Cited by 46 publications

(20 citation statements)

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“…Such a feature is especially prominent in anticancer research, with approximately 70% of FDA-approved anticancer drugs being either natural products or their derivatives . Recently, our group has revealed that Euphorbiaceae diterpenoids are a rich source of privileged structures in anticancer drug development. − Herein, we conducted a phenotypic screening of a Euphorbiaceae diterpenoid library consisting of 255 structurally diverse compounds and identified a series of daphnane diterpenoids (DDs) that are highly potent in killing CRPC cells. The lead, DD1 , could selectively inhibit the proliferation of CRPC cells and completely block the tumor growth in different mouse models at extremely low dosages.…”

Section: Introductionmentioning

confidence: 99%

Discovery of Highly Potent Daphnane Diterpenoids Uncovers Importin-β1 as a Druggable Vulnerability in Castration-Resistant Prostate Cancer

Huang

Yan

et al. 2022

J. Am. Chem. Soc.

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Importins are overexpressed in many cancers and mediate the abnormal nuclear transport of oncogenic factors. The druggable potential of importins still remains unclear, largely because of the lack of potent inhibitors. Herein, the anti-castration-resistant prostate cancer (CRPC) screening of a Euphorbiaceae diterpenoid library followed by target fishing led to the identification of a highly potent importin-β1 inhibitor, daphnane diterpenoid DD1. DD1 selectively inhibited the growth and survival of CRPC cells at subnanomolar concentrations and completely blocked tumor growth in preclinical models at an extremely low dosage. Mechanistic studies revealed that targeting of importin-β1 by DD1 significantly reduced the nuclear accumulation of key CRPC drivers, shutting down their downstream oncogenic signaling. Disruption of the predicted binding sites of DD1 on importin-β1 abolished this anti-CRPC effect. These findings suggest that importin-β1 is an effective therapeutic target in CRPC and that DD1 as the most potent importin-β1 inhibitor to date can be developed as therapeutics for treatment of this disease.

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Section: Introductionmentioning

confidence: 99%

Discovery of Highly Potent Daphnane Diterpenoids Uncovers Importin-β1 as a Druggable Vulnerability in Castration-Resistant Prostate Cancer

Huang

Yan

et al. 2022

J. Am. Chem. Soc.

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“…The metabolites changes may relate to the cell apoptosis. It has been illustrated that the decrease of glutathione is a potential early activation signal to apoptosis, and the subsequent generation of reactive oxygen species (ROS) promotes cell apoptosis 54,55 .With the increasing amount of NK cells, the relative intensity of glutathione decreases (figure 3c). The statistically significant difference not only exists between the groups with and without co-culturing with NK cells, but also exists between the groups co-cultured with different amount of NK cells.…”

Section: Resultsmentioning

confidence: 99%

“…It has been illustrated that the decrease of glutathione is a potential early activation signal to apoptosis, and the subsequent generation of reactive oxygen species (ROS) promotes cell apoptosis. 54,55 With the increasing amount of NK cells, the relative intensity of glutathione decreases (Fig. 3c).…”

Section: The Changes Of Specic Metabolites In Hepg2 Cells Induced By Nk Cellsmentioning

confidence: 90%

Dynamic metabolic change of cancer cells induced by natural killer cells at the single-cell level studied by label-free mass cytometry

et al. 2022

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“…It is well established that the escalated ROS production contributes to mitochondrial dysfunction and/or ER stress, which is a prerequisite for the formation of paraptotic vacuoles [ 6 , 7 ]. However, excess ROS are often quenched by increased antioxidant enzymatic and nonenzymatic pathways in cancer cells, eventually leading tumor development and drug resistance [ 10 , 37 , 49 ]. We found that ROS levels were concentration-dependently elevated in both MDA-MB-231 and MCF-7 cells challenged with YRL1091 ( Figure 8 A), which were subsequently inhibited by NAC ( Figure 8 B).…”

Section: Discussionmentioning

confidence: 99%

Induction of Paraptotic Cell Death in Breast Cancer Cells by a Novel Pyrazolo[3,4-h]quinoline Derivative through ROS Production and Endoplasmic Reticulum Stress

Nguyen

Lee

et al. 2022

Antioxidants

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Chemotherapy has been a standard intervention for a variety of cancers to impede tumor growth, mainly by inducing apoptosis. However, development of resistance to this regimen has led to a growing interest and demand for drugs targeting alternative cell death modes, such as paraptosis. Here, we designed and synthesized a novel derivative of a pyrazolo[3,4-h]quinoline scaffold (YRL1091), evaluated its cytotoxic effect, and elucidated the underlying molecular mechanisms of cell death in MDA-MB-231 and MCF-7 breast cancer (BC) cells. We found that YRL1091 induced cytotoxicity in these cells with numerous cytoplasmic vacuoles, one of the distinct characteristics of paraptosis. YRL1091-treated BC cells displayed several other distinguishing features of paraptosis, excluding autophagy or apoptosis. Briefly, YRL1091-induced cell death was associated with upregulation of microtubule-associated protein 1 light chain 3B, downregulation of multifunctional adapter protein Alix, and activation of extracellular signal-regulated kinase 1/2 and c-Jun N-terminal kinase. Furthermore, the production of reactive oxygen species (ROS) and newly synthesized proteins were also observed, subsequently causing ubiquitinated protein accumulation and endoplasmic reticulum (ER) stress. Collectively, these results indicate that YRL1091 induces paraptosis in BC cells through ROS generation and ER stress. Therefore, YRL1091 can serve as a potential candidate for the development of a novel anticancer drug triggering paraptosis, which may provide benefit for the treatment of cancers resistant to conventional chemotherapy.

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Jolkinolide B targets thioredoxin and glutathione systems to induce ROS-mediated paraptosis and apoptosis in bladder cancer cells

Cited by 46 publications

References 46 publications

Discovery of Highly Potent Daphnane Diterpenoids Uncovers Importin-β1 as a Druggable Vulnerability in Castration-Resistant Prostate Cancer

Discovery of Highly Potent Daphnane Diterpenoids Uncovers Importin-β1 as a Druggable Vulnerability in Castration-Resistant Prostate Cancer

Dynamic metabolic change of cancer cells induced by natural killer cells at the single-cell level studied by label-free mass cytometry

Induction of Paraptotic Cell Death in Breast Cancer Cells by a Novel Pyrazolo[3,4-h]quinoline Derivative through ROS Production and Endoplasmic Reticulum Stress

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