Sesquiterpene Lactone Deoxyelephantopin Isolated from Elephantopus scaber and Its Derivative DETD-35 Suppress BRAFV600E Mutant Melanoma Lung Metastasis in Mice

Cvetanova, Biljana; Li, Mengyi; Yang, Chung-Chih; Hsiao, Pei-Wen; Yang, Yu-Chih; Feng, Jia-Hua; Shen, Ya-Ching; Nakagawa‐Goto, Kyoko; Lee, Kuo Hsiung̀; Shyur, Lie‐Fen

doi:10.3390/ijms22063226

Cited by 13 publications

(7 citation statements)

References 53 publications

(38 reference statements)

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“…The crystal violet staining cells were quantitatively analyzed and modified according to the study of Cvetannova et al. ( 18 ). The crystal violet-stained cells were then dissolved in 250 μL 20% acetic acid.…”

Section: Methodsmentioning

confidence: 99%

Evasion of NK cell immune surveillance via the vimentin-mediated cytoskeleton remodeling

et al. 2022

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Cancer immunotherapy uses the immune system to achieve therapeutic effects; however, its effect is still limited. Therefore, in addition to immune checkpoint-based treatment, the development of other strategies that can inhibit cancer cells from resisting immune cytotoxicity is important. There are currently few studies on the mechanism of tumors using cytoskeletal proteins reorganization to participate in immune escape. In this study, we identified cancer cell lines that were sensitive or resistant to natural killer cells in urothelial and lung cancer using the natural killer cell sensitivity assay. We found that immunoresistant cancer cells avoid natural killer cell-mediated cytotoxicity by upregulation of vimentin and remodeling of actin cytoskeleton. Immunofluorescence staining showed that immune cells promoted the formation of actin filaments at the immune synapse, which was not found in immunosensitive cancer cells. Pretreatment of the actin polymerization inhibitors latrunculin B increased the cytotoxicity of natural killer cells, suggesting that cytoskeleton remodeling plays a role in resisting immune cell attack. In addition, silencing of vimentin with shRNA potentiated the cytotoxicity of natural killer cells. Interestingly, the upregulation and extension of vimentin was found in tumor islands of upper tract urothelial carcinoma infiltrated by natural killer cells. Conversely, tumors without natural killer cell invasion showed less vimentin signal. The expression level of vimentin was highly correlated with natural killer cell infiltration. In summary, we found that when immune cells attack cancer cells, the cancer cells resist immune cytotoxicity through upregulated vimentin and actin reorganization. In addition, this immune resistance mechanism was also found in patient tumors, indicating the possibility that they can be applied to evaluate the immune response in clinical diagnosis.

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Section: Methodsmentioning

confidence: 99%

Evasion of NK cell immune surveillance via the vimentin-mediated cytoskeleton remodeling

et al. 2022

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“…DET-induced anti-proliferative and pro-apoptotic activities were reversed with the supplementation of GSH (5 µM), which suppressed ROS levels and mitochondrial superoxide generation. Furthermore, DET was found to decrease the basal oxygen consumption rate of A375LM5IF4g/Luc cells by interfering with mitochondrial bioenergetics and inhibiting mitochondrial oxidative phosphorylation [ 81 ]. Similarly, in CNE1 cells, IDET induced ROS generation in a concentration- and time-dependent manner.…”

Section: Effect Of Det and Idet On Apoptosis Pathwaysmentioning

confidence: 99%

“…The mode of action of DETD-35 against cancers is same as that of DET. Several studies have shown that DETD-35 induces ROS-mediated apoptosis through multiple pathways, including Bcl-2 family protein modulation, dissipation of ΔΨm, cell cycle arrest at the G2/M phase, the inhibition of ERK phosphorylation, the induction of autophagy, and the inhibition of metastasis in various cancer cells, including melanoma and triple negative breast cancer cells [ 81 , 115 , 116 , 117 ]. Although DETD-35 has shown promising antitumor activity against melanoma, more comprehensive mechanistic research using in vivo and in vitro studies on different cancer cell models is required to evaluate the real potential of DETD-35 as an anti-cancer agent.…”

Section: Det-derivatives (Detds)mentioning

confidence: 99%

Deoxyelephantopin and Its Isomer Isodeoxyelephantopin: Anti-Cancer Natural Products with Multiple Modes of Action

Mehmood

Muanprasat

2022

Molecules

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Cancer is a leading cause of morbidity and mortality worldwide. The development of cancer involves aberrations in multiple pathways, representing promising targets for anti-cancer drug discovery. Natural products are regarded as a rich source for developing anti-cancer therapies due to their unique structures and favorable pharmacology and toxicology profiles. Deoxyelephantopin and isodeoxyelephantopin, sesquiterpene lactone compounds, are major components of Elephantopus scaber and Elephantopus carolinianus, which have long been used as traditional medicines to treat multiple ailments, including liver diseases, diabetes, bronchitis, fever, diarrhea, dysentery, cancer, renal disorders, and inflammation-associated diseases. Recently, deoxyelephantopin and isodeoxyelephantopin have been extensively explored for their anti-cancer activities. This review summarizes and discusses the anti-cancer activities of deoxyelephantopin and isodeoxyelephantopin, with an emphasis on their modes of action and molecular targets. Both compounds disrupt several processes involved in cancer progression by targeting multiple signaling pathways deregulated in cancers, including cell cycle and proliferation, cell survival, autophagy, and invasion pathways. Future directions of research on these two compounds towards anti-cancer drug development are discussed.

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“…Moreover, to establish a metastatic model, human cell lines (e.g., A375 and A2058) can be injected through the i.v. route, usually in the tail vein, and frequently metastasize to the lungs [240][241][242]. Although this procedure allows for rapid spreading of melanoma cells, it does not recapitulate the metastization process that occurs in human disease since, in this case, metastatic cells derive from a primary tumor [90].…”

Section: Xenograft Modelmentioning

confidence: 99%

The Challenging Melanoma Landscape: From Early Drug Discovery to Clinical Approval

Matias

Pinho

Penetra

et al. 2021

Cells

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Melanoma is recognized as the most dangerous type of skin cancer, with high mortality and resistance to currently used treatments. To overcome the limitations of the available therapeutic options, the discovery and development of new, more effective, and safer therapies is required. In this review, the different research steps involved in the process of antimelanoma drug evaluation and selection are explored, including information regarding in silico, in vitro, and in vivo experiments, as well as clinical trial phases. Details are given about the most used cell lines and assays to perform both two- and three-dimensional in vitro screening of drug candidates towards melanoma. For in vivo studies, murine models are, undoubtedly, the most widely used for assessing the therapeutic potential of new compounds and to study the underlying mechanisms of action. Here, the main melanoma murine models are described as well as other animal species. A section is dedicated to ongoing clinical studies, demonstrating the wide interest and successful efforts devoted to melanoma therapy, in particular at advanced stages of the disease, and a final section includes some considerations regarding approval for marketing by regulatory agencies. Overall, considerable commitment is being directed to the continuous development of optimized experimental models, important for the understanding of melanoma biology and for the evaluation and validation of novel therapeutic strategies.

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Sesquiterpene Lactone Deoxyelephantopin Isolated from Elephantopus scaber and Its Derivative DETD-35 Suppress BRAFV600E Mutant Melanoma Lung Metastasis in Mice

Cited by 13 publications

References 53 publications

Evasion of NK cell immune surveillance via the vimentin-mediated cytoskeleton remodeling

Evasion of NK cell immune surveillance via the vimentin-mediated cytoskeleton remodeling

Deoxyelephantopin and Its Isomer Isodeoxyelephantopin: Anti-Cancer Natural Products with Multiple Modes of Action

The Challenging Melanoma Landscape: From Early Drug Discovery to Clinical Approval

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