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

Huang, Jia-Luo; Yan, Xue-Long; Li, Wei; Fan, Run-Zhu; Shen, Li; Chen, Jianghe; Zhang, Zhenhua; Sang, Jun; Gan, Liu; Chen, Hongwu; Wang, Junjian; Yin, Sheng

doi:10.1021/jacs.2c06449

Cited by 17 publications

(6 citation statements)

References 44 publications

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“…As 5-FU, the first-line drug for CRC treatment, performs its efficacy via inhibiting DNA biosynthesis [ 9 ], the mechanism of which is different from that of 2 , we further explored whether the combination of 5-FU and 2 could improve the therapeutic activity. As shown in Figure 5 I, 2 dose-dependently increased the cytotoxic activity of 5-FU in HCT-116 cells, with 7 times improvement under the administration of 4 μM of 2 .…”

Section: Resultsmentioning

confidence: 99%

“…These compounds have the potential to exert anti-CRC effects by interfering with the pathways of metastasis, invasion, apoptosis, and angiogenesis. In the past few years, our group has endeavored to discover anticancer agents from Euphorbiaceae plants, and has proven that terpenoids from Euphorbiaceae are a rich source of privileged structures in anticancer drug development [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

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Glochodpurnoid B from Glochidion puberum Induces Endoplasmic Reticulum Stress-Mediated Apoptosis in Colorectal Cancer Cells

et al. 2023

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Glochidpurnoids A and B (1 and 2), two new coumaroyl or feruloyl oleananes, along with 17 known triterpenoids (3-19) were obtained from the stems and twigs of Glochidion puberum. Their structures were elucidated by extensive spectroscopic data analyses, chemical methods, and single crystal X-ray diffraction. All compounds were screened for cytotoxicity against the colorectal cancer cell line HCT-116, and 2, 3, 5, 6, 11, and 17 showed remarkable inhibitory activities (IC50: 0.80-2.99 μM), being more active than the positive control 5-fluorouracil (5-FU). The mechanistic study of 2, the most potent compound, showed that it could induce endoplasmic reticulum (ER) stress-mediated apoptosis and improve the sensitivity of HCT-116 cells to 5-FU.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Glochodpurnoid B from Glochidion puberum Induces Endoplasmic Reticulum Stress-Mediated Apoptosis in Colorectal Cancer Cells

et al. 2023

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“…Cellular Thermal Shift Assay. 32 For the cellular thermal shift experiment, HEL cells were harvested, eluted with PBS, and subsequently lysed with PBS buffer with 1 mM protease inhibitor cocktail (Roche Applied Science). To lyse the cells, three freeze−thaw and thaw cycles in liquid nitrogen were performed.…”

Section: Compound 21 Triggers Apoptosis In Hel Cellsmentioning

confidence: 99%

Design and Synthesis of Cytotoxic Water-Soluble Rocaglaol Derivatives against HEL Cells by Inhibiting Fli-1

Ge,

Ming,

et al. 2024

J. Nat. Prod.

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Rocaglaol, embedding a cyclopenta[b]benzofuran scaffold, was isolated mainly from the plants of Aglaia and exhibited nanomolar level antitumor activity. However, the drug-like properties of these compounds are poor. To improve the physicochemical properties of rocaglaol, 36 nitrogen-containing phenyl-substituted rocaglaol derivatives were designed and synthesized. These derivatives were tested for the inhibitory effects on three tumor cell lines, HEL, MDA-231, and SW480, using the MTT assay. Among them, 22 derivatives exhibited good cytotoxic activities with IC 50 values between 0.11 ± 0.07 and 0.88 ± 0.02 μM. Fourteen derivatives exhibited stronger cytotoxicity than the positive control, adriamycin. In particular, a water-soluble derivative revealed selective cytotoxic effects on HEL cells (IC 50 = 0.19 ± 0.01 μM). This compound could induce G1 cell cycle arrest and apoptosis in HEL cells. Western blot assays suggested that the water-soluble derivative could downregulate the expression of the marker proteins of apoptosis, PARP, caspase-3, and caspase-9, thus inducing apoptosis. Further CETSA and Western blot studies implied that this water-soluble derivative might be an inhibitor of friend leukemia integration 1 (Fli-1). This water-soluble derivative may serve as a potential antileukemia agent by suppressing the expression of Fli-1.L eukemia, a malignant blood system disorder, is one of the main reasons for deaths worldwide, and its incidence is growing annually. 1 In American, it is reported that the number of leukemia cases could rise to 59 610, and approximately 23 710 people will die from leukemia in 2023. 1 Chemotherapy is a vital method for curing this disease. A variety of drugs, including arabinoside, hydroxyurea, cyclophosphamide, and vincristine,

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“…Another example of a diterpene with cytotoxic activity is a daphnane diterpene. A comprehensive study of its effects on castration-resistant prostate cancer (CRPC), including the use of daphnane−BODIPY conjugate 21, was reported by Huang et al 48 in 2022. They showed selective growth inhibition of CRPC cells and complete blockage of tumor growth in preclinical models after treatment with a daphnane derivative containing benzoyl and phenyl groups and identified importin-β1 as its direct target.…”

Section: ■ Diterpenes and Diterpenoidsmentioning

confidence: 99%

Terpenes and Terpenoids Conjugated with BODIPYs: An Overview of Biological and Chemical Properties

Stanková,

Jurášek,

Hajdúch

et al. 2024

J. Nat. Prod.

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Advancements in small-molecule research have created the need for sensitive techniques to accurately study biological processes in living systems. Fluorescent-labeled probes have become indispensable tools, particularly those that use boron−dipyrromethene (BODIPY) dyes. Terpenes and terpenoids are organic compounds found in nature that offer diverse biological activities, and BODIPY-based probes play a crucial role in studying these compounds. Monoterpene−BODIPY conjugates have exhibited potential for staining bacterial and fungal cells. Sesquiterpene−BODIPY derivatives have been used to study sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA), indicating their potential for drug development. Owing to their unique properties, diterpenes have been investigated using BODIPY conjugates to evaluate their mechanisms of action. Triterpene−BODIPY conjugates have been synthesized for biological studies, with different spacers affecting their cytotoxicity. Fluorescent probes, inspired by terpenoid-containing vitamins, have also been developed. Derivatives of tocopherol, coenzyme Q10, and vitamin K1 can provide insights into their oxidation−reduction abilities. All these probes have diverse applications, including the study of cell membranes to investigate immune responses and antioxidant properties. Further research in this field can help better understand and use terpenes and terpenoids in various biological contexts.

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

Cited by 17 publications

References 44 publications

Glochodpurnoid B from Glochidion puberum Induces Endoplasmic Reticulum Stress-Mediated Apoptosis in Colorectal Cancer Cells

Glochodpurnoid B from Glochidion puberum Induces Endoplasmic Reticulum Stress-Mediated Apoptosis in Colorectal Cancer Cells

Design and Synthesis of Cytotoxic Water-Soluble Rocaglaol Derivatives against HEL Cells by Inhibiting Fli-1

Terpenes and Terpenoids Conjugated with BODIPYs: An Overview of Biological and Chemical Properties

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