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Prof. Lie-Fen Shyur
Agricultural Biotechnology Research Center, Academia Sinica, Taipei 115, Taiwan.

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0 anti inflammation
0 herbal and medicinal plants
0 Cancer and anticancer drug resistance
0 Enzymes from biological sources or whole cells
0 Lipidomics, metabolomics

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herbal and medicinal plants
anti inflammation

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Journal article
Published: 16 August 2021 in Cancers
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Current conventional cancer therapies for melanoma brain metastasis (MBM) remain ineffective. In this study, we demonstrated the bioefficacy of a phyto-glyceroglycolipid, 1,2-di-O-α-linolenoyl-3-O-β-galactopyranosyl-sn-glycerol (dLGG) alone, or in combination with liposomal doxorubicin (Lip-DOX) or Avastin against MBM in a syngeneic B16BM4COX−2/Luc brain-seeking melanoma mouse model. Treatment with dLGG–10, dLGG–25, dLGG–10 + Avastin–5, Lipo-DOX–2, dLGG–10 + Lipo-DOX–2 or Lipo-DOX–2 + Avastin–5 suppressed, respectively, 17.9%, 59.1%, 55.7%, 16.2%, 44.5% and 72.4% of MBM in mice relative to the untreated tumor control. Metastatic PD-L1+ melanoma cells, infiltration of M2-like macrophages and CD31+ endothelial cells, and high expression levels of 15-LOX/CYP450 4A enzymes in the brain tumor microenvironment of the tumor control mice were significantly attenuated in dLGG-treated mice; conversely, M1-like resident microglia and cytotoxic T cells were increased. A lipidomics study showed that dLGG promoted B16BM4 cells to secrete oxylipins 9,10-/12,13-EpOMEs into the culture medium. Furthermore, the conditioned medium of B16BM4 cells pretreated with dLGG or 9,10-EpOMEs + 12,13-EpOMEs drove M2-like macrophages to polarize into M1-like macrophages in vitro. An ex vivo 3D-culture assay further demonstrated that dLGG, 9,10-EpOME or 9,10-EpOME + 12,13-EpOME pretreatment attenuated B16BM4 cells invading brain tissue, and prevented microglia/macrophages infiltrating into the interface of melanoma plug and brain organ/tissue. In summary, this report provides a novel therapeutic strategy and mechanistic insights into phytogalactolipid dLGG for combating MBM.

ACS Style

Chung-Chih Yang; Meng-Ting Chang; Cheng-Kuei Chang; Lie-Fen Shyur. Phytogalactolipid dLGG Inhibits Mouse Melanoma Brain Metastasis through Regulating Oxylipin Activity and Re-Programming Macrophage Polarity in the Tumor Microenvironment. Cancers 2021, 13, 4120 .

AMA Style

Chung-Chih Yang, Meng-Ting Chang, Cheng-Kuei Chang, Lie-Fen Shyur. Phytogalactolipid dLGG Inhibits Mouse Melanoma Brain Metastasis through Regulating Oxylipin Activity and Re-Programming Macrophage Polarity in the Tumor Microenvironment. Cancers. 2021; 13 (16):4120.

Chicago/Turabian Style

Chung-Chih Yang; Meng-Ting Chang; Cheng-Kuei Chang; Lie-Fen Shyur. 2021. "Phytogalactolipid dLGG Inhibits Mouse Melanoma Brain Metastasis through Regulating Oxylipin Activity and Re-Programming Macrophage Polarity in the Tumor Microenvironment." Cancers 13, no. 16: 4120.

Journal article
Published: 22 March 2021 in International Journal of Molecular Sciences
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Melanoma is a highly metastatic disease with an increasing rate of incidence worldwide. It is treatment refractory and has poor clinical prognosis; therefore, the development of new therapeutic agents for metastatic melanoma are urgently required. In this study, we created a lung-seeking A375LM5 IF4g/Luc BRAF V600E mutant melanoma cell clone and investigated the bioefficacy of a plant sesquiterpene lactone deoxyelephantopin (DET) and its novel semi-synthetic derivative, DETD-35, in suppressing metastatic A375LM5 IF4g/Luc melanoma growth in vitro and in a xenograft mouse model. DET and DETD-35 treatment inhibited A375LM5 IF4g/Luc cell proliferation, and induced G2/M cell-cycle arrest and apoptosis. Furthermore, A375LM5 IF4g/Luc exhibited clonogenic, metastatic and invasive abilities, and several A375LM5 IF4g/Luc metastasis markers, N-cadherin, MMP2, vimentin and integrin α4 were significantly suppressed by treatment with either compound. Interestingly, DET- and DETD-35-induced Reactive Oxygen Species (ROS) generation and glutathione (GSH) depletion were found to be upstream events important for the in vitro activities, because exogenous GSH supplementation blunted DET and DETD-35 effects on A375LM5 IF4g/Luc cells. DET and DETD-35 also induced mitochondrial DNA mutation, superoxide production, mitochondrial bioenergetics dysfunction, and mitochondrial protein deregulation. Most importantly, DET and DETD-35 inhibited lung metastasis of A375LM5 IF4g/Luc in NOD/SCID mice through inhibiting pulmonary vascular permeability and melanoma cell (Mel-A+) proliferation, angiogenesis (VEGF+, CD31+) and EMT (N-cadherin) in the tumor microenvironment in the lungs. These findings indicate that DET and DETD-35 may be useful in the intervention of lung metastatic BRAFV600E mutant melanoma.

ACS Style

Biljana Cvetanova; Meng-Yi Li; Chung-Chih Yang; Pei-Wen Hsiao; Yu-Chih Yang; Jia-Hua Feng; Ya-Ching Shen; Kyoko Nakagawa-Goto; Kuo-Hsiung Lee; Lie-Fen Shyur. Sesquiterpene Lactone Deoxyelephantopin Isolated from Elephantopus scaber and Its Derivative DETD-35 Suppress BRAFV600E Mutant Melanoma Lung Metastasis in Mice. International Journal of Molecular Sciences 2021, 22, 3226 .

AMA Style

Biljana Cvetanova, Meng-Yi Li, Chung-Chih Yang, Pei-Wen Hsiao, Yu-Chih Yang, Jia-Hua Feng, Ya-Ching Shen, Kyoko Nakagawa-Goto, Kuo-Hsiung Lee, Lie-Fen Shyur. Sesquiterpene Lactone Deoxyelephantopin Isolated from Elephantopus scaber and Its Derivative DETD-35 Suppress BRAFV600E Mutant Melanoma Lung Metastasis in Mice. International Journal of Molecular Sciences. 2021; 22 (6):3226.

Chicago/Turabian Style

Biljana Cvetanova; Meng-Yi Li; Chung-Chih Yang; Pei-Wen Hsiao; Yu-Chih Yang; Jia-Hua Feng; Ya-Ching Shen; Kyoko Nakagawa-Goto; Kuo-Hsiung Lee; Lie-Fen Shyur. 2021. "Sesquiterpene Lactone Deoxyelephantopin Isolated from Elephantopus scaber and Its Derivative DETD-35 Suppress BRAFV600E Mutant Melanoma Lung Metastasis in Mice." International Journal of Molecular Sciences 22, no. 6: 3226.

Journal article
Published: 16 October 2020 in Journal of Experimental Botany
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Polyacetylene compounds from Bidens pilosa are known to have several pharmacological activities. In this study, we identified major genes encoding enzymes involved in the biosynthesis of polyacetylene in B. pilosa. Seven polyacetylene metabolites present in B. pilosa leaves were induced by methyl jasmonate (MeJA) treatment and physical wounding. Transcriptome analysis via high-throughput sequencing revealed 39 202 annotated gene fragment sequences. A DNA microarray established by the 39 202 annotated genes was used to profile gene expression in B. pilosa leaf and root tissues. As no polyacetylene compounds were found in roots, the gene expression pattern in root tissue was used as a negative control. By subtracting MeJA-induced genes in roots, we obtained 1216 genes in leaves showing an approximate three-fold increase in expression post-MeJA treatment. Nine genes encoding enzymes with desaturation function were selected for confirmation of expression by qRT–PCR. Among them, two genes, BPTC030748 and BPTC012564, were predicted to encode Δ12-oleate desaturase (OD) and Δ12-fatty acid acetylenase (FAA), respectively. In B. pilosa leaves, RNAi knock-down concomitantly decreased, while virus-mediated transient overexpression of either gene elevated polyacetylene content. In summary, we demonstrate that two important enzymes, Δ12-oleate desaturase and Δ12-fatty acid acetylenase, involved in desaturation of linear fatty acid precursors play a role in polyacetylene biosynthesis in an important medicinal plant, Bidens pilosa.

ACS Style

Hisao-Hang Chung; Hieng-Ming Ting; Wei-Hsi Wang; Ya-Ting Chao; Cheng-Han Hsieh; Maria Karmella Apaya; Yi-Chang Sung; Shih-Shun Lin; Fang-Yu Hwu; Lie-Fen Shyur. Elucidation of enzymes involved in the biosynthetic pathway of bioactive polyacetylenes in Bidens pilosa using integrated omics approaches. Journal of Experimental Botany 2020, 72, 525 -541.

AMA Style

Hisao-Hang Chung, Hieng-Ming Ting, Wei-Hsi Wang, Ya-Ting Chao, Cheng-Han Hsieh, Maria Karmella Apaya, Yi-Chang Sung, Shih-Shun Lin, Fang-Yu Hwu, Lie-Fen Shyur. Elucidation of enzymes involved in the biosynthetic pathway of bioactive polyacetylenes in Bidens pilosa using integrated omics approaches. Journal of Experimental Botany. 2020; 72 (2):525-541.

Chicago/Turabian Style

Hisao-Hang Chung; Hieng-Ming Ting; Wei-Hsi Wang; Ya-Ting Chao; Cheng-Han Hsieh; Maria Karmella Apaya; Yi-Chang Sung; Shih-Shun Lin; Fang-Yu Hwu; Lie-Fen Shyur. 2020. "Elucidation of enzymes involved in the biosynthetic pathway of bioactive polyacetylenes in Bidens pilosa using integrated omics approaches." Journal of Experimental Botany 72, no. 2: 525-541.

Journal article
Published: 15 May 2020 in Scientific Reports
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Polyunsaturated fatty acids (PUFAs) have been suggested for cardiovascular health. This study was conducted to investigate the prognostic impacts of the PUFA metabolites, oxylipins, on clinical outcomes in coronary artery disease (CAD). A total of 2,239 patients with stable CAD were prospectively enrolled and followed up regularly. Among them, twenty-five consecutive patients with new onset of acute myocardial infarction (AMI) within 2-year follow-up were studied. Another 50 gender- and age-matched patients without clinical cardiovascular events for more than 2 years were studied for control. Baseline levels of specific arachidonic acid metabolites were significantly higher in patients with subsequent AMI than in the controls. In Kaplan-Meier analysis, the incidence of future AMI was more frequently seen in patients with higher baseline levels of 8-hydroxyeicosatetraenoic acid (HETE), 9-HETE, 11-HETE, 12-HETE, 15-HETE, 19-HETE, 20-HETE, 5,6-epoxyeicosatrienoic acid (EET), 8,9-EET, 11,12-EET, or 14-15-EET when compared to their counterparts (all the P < 0.01). Further, serum levels of these specific HETEs, except for 11,12-EET, were positively correlated to the levels of some inflammatory and cardiac biomarker such as tumor necrosis factor-α and N-terminal pro B-type natriuretic peptide. Accordingly, serum specific oxylipins levels are increased and associated with the consequent onset of AMI, suggesting their potential role for secondary prevention in clinically stable CAD.

ACS Style

Chin-Chou Huang; Meng-Ting Chang; Hsin-Bang Leu; Wei-Hsian Yin; Wei-Kung Tseng; Yen-Wen Wu; Tsung-Hsien Lin; Hung-I Yeh; Kuan-Cheng Chang; Ji-Hung Wang; Chau-Chung Wu; Lie-Fen Shyur; Jaw-Wen Chen. Association of Arachidonic Acid-derived Lipid Mediators with Subsequent Onset of Acute Myocardial Infarction in Patients with Coronary Artery Disease. Scientific Reports 2020, 10, 8105 .

AMA Style

Chin-Chou Huang, Meng-Ting Chang, Hsin-Bang Leu, Wei-Hsian Yin, Wei-Kung Tseng, Yen-Wen Wu, Tsung-Hsien Lin, Hung-I Yeh, Kuan-Cheng Chang, Ji-Hung Wang, Chau-Chung Wu, Lie-Fen Shyur, Jaw-Wen Chen. Association of Arachidonic Acid-derived Lipid Mediators with Subsequent Onset of Acute Myocardial Infarction in Patients with Coronary Artery Disease. Scientific Reports. 2020; 10 (1):8105.

Chicago/Turabian Style

Chin-Chou Huang; Meng-Ting Chang; Hsin-Bang Leu; Wei-Hsian Yin; Wei-Kung Tseng; Yen-Wen Wu; Tsung-Hsien Lin; Hung-I Yeh; Kuan-Cheng Chang; Ji-Hung Wang; Chau-Chung Wu; Lie-Fen Shyur; Jaw-Wen Chen. 2020. "Association of Arachidonic Acid-derived Lipid Mediators with Subsequent Onset of Acute Myocardial Infarction in Patients with Coronary Artery Disease." Scientific Reports 10, no. 1: 8105.

Journal article
Published: 13 January 2020 in Cancers
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Recurrence and metastasis are the main causes of triple-negative breast cancer (TNBC) mortality. On the basis of our clinical cohorts and integrative omics analyses, we hypothesized that understanding the interplay between fatty acid binding protein (FABP) and epoxy-eicosatrienoic acid (EET) driven metastatic progression can uncover a new opportunity for TNBC intervention. In this study, the biological relevance of increased protein expression of CYP2C19, FABP4, and FABP5 in TNBC tumors and in the TNBC cell line (MDA-MB-231), as well as its highly metastatic lung seeking variant (LM6) were delineated from publicly available datasets, shRNA-mediated knockdown, EET supplementation, cancer and stromal cell co-cultures, and an orthotopic and resection xenograft tumor mouse model. We found that the high expression levels of CYP2C19 and FABP4 and FABP5 are critical in TNBC metastatic transformation and stromal cell interactions. Furthermore, EET-associated nuclear translocation of FABP4 and FABP5 and nuclear accumulation of SREBP-2 or PPAR-γ influence TNBC cell proliferation, migratory transformation, and distal metastasis priming. Most notably, we uncovered novel bioefficacy and modes of action of the anticancer drug doxorubicin and a phytogalactolipid, 1,2-di-O-α-linolenoyl-3-O-β-galactopyranosyl-sn-glycerol (dLGG), which effectively attenuated TNBC recurrence and lung metastasis through deregulating the FABP/EET dynamics and levels. This study, therefore, introduces a novel approach to combating TNBC by targeting the FABP/EET/CYP-associated metastatic signaling network.

ACS Style

Maria Karmella Apaya; Pei-Wen Hsiao; Yu-Chih Yang; Lie-Fen Shyur. Deregulating the CYP2C19/Epoxy-Eicosatrienoic Acid-Associated FABP4/FABP5 Signaling Network as a Therapeutic Approach for Metastatic Triple-Negative Breast Cancer. Cancers 2020, 12, 199 .

AMA Style

Maria Karmella Apaya, Pei-Wen Hsiao, Yu-Chih Yang, Lie-Fen Shyur. Deregulating the CYP2C19/Epoxy-Eicosatrienoic Acid-Associated FABP4/FABP5 Signaling Network as a Therapeutic Approach for Metastatic Triple-Negative Breast Cancer. Cancers. 2020; 12 (1):199.

Chicago/Turabian Style

Maria Karmella Apaya; Pei-Wen Hsiao; Yu-Chih Yang; Lie-Fen Shyur. 2020. "Deregulating the CYP2C19/Epoxy-Eicosatrienoic Acid-Associated FABP4/FABP5 Signaling Network as a Therapeutic Approach for Metastatic Triple-Negative Breast Cancer." Cancers 12, no. 1: 199.

Journal article
Published: 25 June 2019 in Molecules
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The v-raf murine sarcoma viral homolog B1 (BRAF) inhibitor drug vemurafenib (PLX4032) is used to treat melanoma; however, epidemiological evidence reveals that it could cause cutaneous keratoacanthomas and squamous cell carcinoma in cancer patients with the most prevalent HRASQ61L mutation. In a two-stage skin carcinogenesis mouse model, the skin papillomas induced by 7,12-dimethylbenz[a]anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA) (DT) resemble the lesions in BRAF inhibitor-treated patients. In this study, we investigated the bioactivity of Mentha aquatica var. Kenting Water Mint essential oil (KWM-EO) against PDV cells, mouse keratinocytes bearing HRASQ61L mutation, and its effect on inhibiting papilloma formation in a two-stage skin carcinogenesis mouse model with or without PLX4032 co-treatment. Our results revealed that KWM-EO effectively attenuated cell viability, colony formation, and the invasive and migratory abilities of PDV cells. Induction of G2/M cell-cycle arrest and apoptosis in PDV cells was also observed. KWM-EO treatment significantly decreased the formation of cutaneous papilloma further induced by PLX4032 in DT mice (DTP). Immunohistochemistry analyses showed overexpression of keratin14 and COX-2 in DT and DTP skin were profoundly suppressed by KWM-EO treatment. This study demonstrates that KWM-EO has chemopreventive effects against PLX4032-induced cutaneous side-effects in a DMBA/TPA-induced two-stage carcinogenesis model and will be worth further exploration for possible application in melanoma patients.

ACS Style

Chih-Ting Chang; Wen-Ni Soo; Yu-Hsin Chen; Lie-Fen Shyur. Essential Oil of Mentha aquatica var. Kenting Water Mint Suppresses Two-Stage Skin Carcinogenesis Accelerated by BRAF Inhibitor Vemurafenib. Molecules 2019, 24, 2344 .

AMA Style

Chih-Ting Chang, Wen-Ni Soo, Yu-Hsin Chen, Lie-Fen Shyur. Essential Oil of Mentha aquatica var. Kenting Water Mint Suppresses Two-Stage Skin Carcinogenesis Accelerated by BRAF Inhibitor Vemurafenib. Molecules. 2019; 24 (12):2344.

Chicago/Turabian Style

Chih-Ting Chang; Wen-Ni Soo; Yu-Hsin Chen; Lie-Fen Shyur. 2019. "Essential Oil of Mentha aquatica var. Kenting Water Mint Suppresses Two-Stage Skin Carcinogenesis Accelerated by BRAF Inhibitor Vemurafenib." Molecules 24, no. 12: 2344.

Journal article
Published: 09 May 2019 in Journal of Experimental & Clinical Cancer Research
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Current prognostic tools and targeted therapeutic approaches have limited value for metastatic triple negative breast cancer (TNBC). Building upon current knowledge, we hypothesized that epoxyeicosatrienoic acids (EETs) and related CYP450 epoxygenases may have differential roles in breast cancer signaling, and better understanding of which may uncover potential directions for molecular stratification and personalized therapy for TNBC patients. We analyzed the oxylipin metabolome of paired tumors and adjacent normal mammary tissues from patients with pathologically confirmed breast cancer (N = 62). We used multivariate statistical analysis to identify important metabolite contributors and to determine the predictive power of tumor tissue metabolite clustering. In vitro functional assays using a panel of breast cancer cell lines were carried out to further confirm the crucial roles of endogenous and exogenous EETs in the metastasis transformation of TNBC cells. Deregulation of associated downstream signaling networks associated with EETs/CYPs was established using transcriptomics datasets from The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC). Comparative TNBC proteomics using the same tissue specimens subjected to oxylipin metabolomics analysis was used as validation set. Metabolite-by-metabolite comparison, tumor immunoreactivity, and gene expression analyses showed that CYP epoxygenases and arachidonic acid-epoxygenation products, EET metabolites, are strongly associated with TNBC metastasis. Notably, all the 4 EET isomers (5,6-, 8,9-, 11,12-, and 14,15-EET) was observed to profoundly drive the metastasis transformation of mesenchymal-like TNBC cells among the TNBC (basal- and mesenchymal-like), HER2-overexpressing and luminal breast cancer cell lines examined. Our pathway analysis revealed that, in hormone-positive breast cancer subtype, CYP epoxygenase overexpression is more related to immune cell-associated signaling, while EET-mediated Myc, Ras, MAPK, EGFR, HIF-1α, and NOD1/2 signaling are the molecular vulnerabilities of metastatic CYP epoxygenase-overexpressing TNBC tumors. This study suggests that categorizing breast tumors according to their EET metabolite ratio classifiers and CYP epoxygenase profiles may be useful for prognostic and therapeutic assessment. Modulation of CYP epoxygenase and EET-mediated signaling networks may offer an effective approach for personalized treatment of breast cancer, and may be an effective intervention option for metastatic TNBC patients.

ACS Style

Maria Karmella Apaya; Jeng-Yuan Shiau; Guo-Shiou Liao; Yu-Jen Liang; Chia-Wei Chen; Hsin-Chou Yang; Chi-Hong Chu; Jyh-Cherng Yu; Lie-Fen Shyur. Integrated omics-based pathway analyses uncover CYP epoxygenase-associated networks as theranostic targets for metastatic triple negative breast cancer. Journal of Experimental & Clinical Cancer Research 2019, 38, 187 .

AMA Style

Maria Karmella Apaya, Jeng-Yuan Shiau, Guo-Shiou Liao, Yu-Jen Liang, Chia-Wei Chen, Hsin-Chou Yang, Chi-Hong Chu, Jyh-Cherng Yu, Lie-Fen Shyur. Integrated omics-based pathway analyses uncover CYP epoxygenase-associated networks as theranostic targets for metastatic triple negative breast cancer. Journal of Experimental & Clinical Cancer Research. 2019; 38 (1):187.

Chicago/Turabian Style

Maria Karmella Apaya; Jeng-Yuan Shiau; Guo-Shiou Liao; Yu-Jen Liang; Chia-Wei Chen; Hsin-Chou Yang; Chi-Hong Chu; Jyh-Cherng Yu; Lie-Fen Shyur. 2019. "Integrated omics-based pathway analyses uncover CYP epoxygenase-associated networks as theranostic targets for metastatic triple negative breast cancer." Journal of Experimental & Clinical Cancer Research 38, no. 1: 187.

Original research article
Published: 28 January 2019 in Frontiers in Pharmacology
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Mutated proto-oncogene BRAF is a bona fide therapeutic target for melanomas. Regrettably, melanoma acquires resistance to BRAF inhibitors, e.g., vemurafenib (PLX4032) casting doubt on this promising melanoma targeted therapy. In this study, we explored the bioactivity of triterpenoid saponin cumingianoside A (CUMA), isolated from leaves and twigs of Dysoxylum cumingianum against PLX4032-resistant BRAFV 600E mutant melanoma A375-R in vitro and in vivo. Our data show that CUMA treatment inhibited A375-R melanoma cell proliferation in a time- and dose-dependent manner. CUMA also suppressed the activity of CDK1/cyclin B1 complex and led to G2/M-phase arrest of A375-R cells. Furthermore, CUMA treatment resulted in induction of apoptosis as shown by the increased activation of caspase 3 and caspase 7, and the proteolytic cleavage of poly(ADP-ribose) polymerase (PARP). We also observed that CUMA induced autophagy-like activity in A375-R cells, as shown by the increased expression of autophagy-related genes and increased formation of autophagosomes. Moreover, we found that CUMA treatment induced ER stress response and co-treatment with an ER stress inhibitor (4-PBA) could attenuate apoptosis induced by CUMA. Importantly, orally administered CUMA as a single agent or in combination with PLX4032 exhibited strong tumor growth inhibition in a PLX4032-resistant A375-R xenograft mouse model, and with little toxicity. This is the first report to explore the anti-tumor activity of CUMA in vitro and in vivo mechanistically, and our results imply that this triterpenoid saponin may be suitable for development into an anti-melanoma agent.

ACS Style

Biljana Cvetanova; Ya-Ching Shen; Lie-Fen Shyur. Cumingianoside A, a Phyto-Triterpenoid Saponin Inhibits Acquired BRAF Inhibitor Resistant Melanoma Growth via Programmed Cell Death. Frontiers in Pharmacology 2019, 10, 1 .

AMA Style

Biljana Cvetanova, Ya-Ching Shen, Lie-Fen Shyur. Cumingianoside A, a Phyto-Triterpenoid Saponin Inhibits Acquired BRAF Inhibitor Resistant Melanoma Growth via Programmed Cell Death. Frontiers in Pharmacology. 2019; 10 ():1.

Chicago/Turabian Style

Biljana Cvetanova; Ya-Ching Shen; Lie-Fen Shyur. 2019. "Cumingianoside A, a Phyto-Triterpenoid Saponin Inhibits Acquired BRAF Inhibitor Resistant Melanoma Growth via Programmed Cell Death." Frontiers in Pharmacology 10, no. : 1.

Journal article
Published: 06 November 2018 in Phytomedicine
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Cisplatin (CP) is a chemotherapeutic drug for treating melanoma that also causes adverse side effects in cancer patients. This study investigated the bioefficacy of a phytoagent deoxyelephantopin (DET) in inhibiting B16 melanoma cell activity, its synergism with CP against metastatic melanoma, and its capability to attenuate CP side effects in animals. DET and CP bioactivities were assessed by MTT assay, isobologram analysis, time-lapse microscopy, migration and invasion assays, flow cytometry and western blotting. In vivo bioluminescence imaging was used to detect lung metastasis of B16 cells carrying COX-2 reporter gene in syngeneic mice. H&E staining and immunohistochemistry were used to evaluate the compound/drug efficacy and CP side effects. Nephrotoxicity caused by CP treatment in mice was evaluated by UPLC/ESI-QTOF MS−based metabolomics and haematometry. DET, alone or in combination with cisplatin, inhibited B16 cell proliferation, migration, and invasion, and induced cell-cycle arrested at the G2/M phase and de-regulated cell-cycle mediators in cancer cells. In a murine B16COX-Luc metastatic allograft model, CP2 (2 mg/kg) treatment inhibited B16 lung metastasis accompanied by severe body weight loss, renal damage and inflammation, and haematological toxicity. DET10 and CP cotreatment (DET10+CP1) or sequential treatment (CP2→DET10) significantly inhibited formation of pulmonary melanoma foci and reduced renal damage. DET pretreatment (Pre-DET10) or CP2→DET10 treatment had the longest survival (52 vs. 37 days for tumor control mice). CP treatment caused abnormally accumulated urea cycle metabolites and serotonin metabolite hippuric acid in renal tissues that were not seen with DET alone or in combination with CP. The CP and DET combination may be an effective intervention for melanoma with reduced side effects.

ACS Style

Wen-Wan Chao; Ya-Wen Cheng; Yet-Ran Chen; Shu-Hua Lee; Ching-Yi Chiou; Lie-Fen Shyur. Phyto-sesquiterpene lactone deoxyelephantopin and cisplatin synergistically suppress lung metastasis of B16 melanoma in mice with reduced nephrotoxicity. Phytomedicine 2018, 56, 194 -206.

AMA Style

Wen-Wan Chao, Ya-Wen Cheng, Yet-Ran Chen, Shu-Hua Lee, Ching-Yi Chiou, Lie-Fen Shyur. Phyto-sesquiterpene lactone deoxyelephantopin and cisplatin synergistically suppress lung metastasis of B16 melanoma in mice with reduced nephrotoxicity. Phytomedicine. 2018; 56 ():194-206.

Chicago/Turabian Style

Wen-Wan Chao; Ya-Wen Cheng; Yet-Ran Chen; Shu-Hua Lee; Ching-Yi Chiou; Lie-Fen Shyur. 2018. "Phyto-sesquiterpene lactone deoxyelephantopin and cisplatin synergistically suppress lung metastasis of B16 melanoma in mice with reduced nephrotoxicity." Phytomedicine 56, no. : 194-206.

Research article
Published: 27 September 2018 in International Journal of Cancer
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This study demonstrates the bioefficacy and gives mechanistic insights into a plant galactolipid 1,2‐di‐O‐linolenoyl‐3‐O‐β‐galactopyranosyl‐sn‐glycerol (dLGG) against metastatic melanoma using a syngeneic mouse model implanted with B16COX‐2/Luc melanoma. dLGG–20 (p.o. dLGG 20 mg/kg) and anti‐cancer drug CP–2 (i.p. cisplatin 2 mg/kg) treatment significantly inhibited lung metastasis of melanoma in mice 91% and 57%, respectively, as determined by bioluminescence intensity. Moreover, dLGG–20 and CP–2 treatment prolonged mouse mean survival time. dLGG‐20 treatment significantly inhibited the expression levels of several molecular markers, i.e., PCNA, MMP2, COX‐2, VEGF, vimentin, snail, TGF‐β, β‐catenin, TNF‐α, PD‐1 and PD‐L1 in mouse lung tissues compared to tumor control mice. Significant inhibition of macrophage and neutrophil infiltration and promotion of CD8+Tc cell recruitment in the lung microenvironment was observed in dLGG‐20‐treated mice. A LC/MS–based comparative oxylipin metabolomics study showed that dLGG‐20 treatment significantly induced (5.0‐ to 12.8‐fold) the 12/15‐LOX catalyzed oxylipin products in mouse serum including 17‐HDHA from DHA, 15‐HEPE from EPA, 8‐ and 12‐HETEs from AA, and CYP450‐derived 20‐HETE from AA. CP‐2 treatment increased 12/15‐LOX derived 8‐, 11‐ and 12‐HETEs from AA, and CYP450 derived 11(12)‐EET from AA and 9,10‐DHOME from LA by 5.3‐ to 8.1‐fold. Of note, dLGG and 17‐HDHA were more effective than CP in preventing B16 melanoma cell‐induced pulmonary vascular permeability in mice through inhibition of TNF‐α production, up‐regulation of tight junction proteins claudin1 and ZO‐2, and deregulation of Src activation. In conclusion, this study shows the novel therapeutic effect of phytoagent dLGG and suggests its potential as a therapeutic agent for metastatic melanoma. This article is protected by copyright. All rights reserved.

ACS Style

Chung-Chih Yang; Cheng-Kuei Chang; Meng-Ting Chang; Lie-Fen Shyur. Plant galactolipid dLGG suppresses lung metastasis of melanoma through deregulating TNF-α-mediated pulmonary vascular permeability and circulating oxylipin dynamics in mice. International Journal of Cancer 2018, 143, 3248 -3261.

AMA Style

Chung-Chih Yang, Cheng-Kuei Chang, Meng-Ting Chang, Lie-Fen Shyur. Plant galactolipid dLGG suppresses lung metastasis of melanoma through deregulating TNF-α-mediated pulmonary vascular permeability and circulating oxylipin dynamics in mice. International Journal of Cancer. 2018; 143 (12):3248-3261.

Chicago/Turabian Style

Chung-Chih Yang; Cheng-Kuei Chang; Meng-Ting Chang; Lie-Fen Shyur. 2018. "Plant galactolipid dLGG suppresses lung metastasis of melanoma through deregulating TNF-α-mediated pulmonary vascular permeability and circulating oxylipin dynamics in mice." International Journal of Cancer 143, no. 12: 3248-3261.

Journal article
Published: 24 March 2018 in The FEBS Journal
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Tumor necrosis factor (TNF)-α activates a diverse array of signaling pathways in vascular endothelial cells (ECs), leading to the inflammatory phenotype that contributes to the vascular dysfunction and neutrophil emigration in patients with sepsis. To date, it is not well understood what key regulator might coordinate signaling pathways to achieve inflammatory response in TNF-α-stimulated ECs. This study investigated the role of dual specificity phosphatase-6 (DUSP6) in the regulation of endothelial inflammation. Using knockout mice, we found that DUSP6 is important for TNF-α-induced endothelial intercellular adhesion molecule-1 (ICAM-1) expression in aorta and in vein. Moreover, genetic deletion of Dusp6 in pulmonary circulation significantly alleviated the susceptibility of mice to lung injury caused by neutrophil recruitment during experimental sepsis induced by TNF-α or lipopolysaccharide (LPS). The role of DUSP6 was further investigated in primary human umbilical vein endothelial cells (HUVECs). Employing RNAi approach in which endogenous DUSP6 was ablated, we showed a critical function of DUSP6 to facilitate TNF-α-induced ICAM-1 expression and endothelial leukocyte interaction. Interestingly, DUSP6-promoted endothelial inflammation is independent of extracellular signaling-regulated kinase (ERK) signaling. On the other hand, inducible DUSP6 leads to activation of canonical nuclear factor (NF)-κB-mediated transcription of ICAM-1 gene in TNF-α-stimulated human ECs. These results are the first to demonstrate a positive role of DUSP6 in endothelial inflammation-mediated pathological process and the underlying mechanism through which DUSP6 promotes NF-κB signaling in the inflamed ECs. Our findings suggest that manipulation of DUSP6 holds great potential for the treatment of acute inflammatory diseases. This article is protected by copyright. All rights reserved.

ACS Style

Shu-Fang Hsu; Yu-Bin Lee; Ying-Chu Lee; Ai-Ling Chung; Maria Karmella Apaya; Lie-Fen Shyur; Ching-Feng Cheng; Feng-Ming Ho; Tzu-Ching Meng. Dual specificity phosphatase DUSP 6 promotes endothelial inflammation through inducible expression of ICAM ‐1. The FEBS Journal 2018, 285, 1593 -1610.

AMA Style

Shu-Fang Hsu, Yu-Bin Lee, Ying-Chu Lee, Ai-Ling Chung, Maria Karmella Apaya, Lie-Fen Shyur, Ching-Feng Cheng, Feng-Ming Ho, Tzu-Ching Meng. Dual specificity phosphatase DUSP 6 promotes endothelial inflammation through inducible expression of ICAM ‐1. The FEBS Journal. 2018; 285 (9):1593-1610.

Chicago/Turabian Style

Shu-Fang Hsu; Yu-Bin Lee; Ying-Chu Lee; Ai-Ling Chung; Maria Karmella Apaya; Lie-Fen Shyur; Ching-Feng Cheng; Feng-Ming Ho; Tzu-Ching Meng. 2018. "Dual specificity phosphatase DUSP 6 promotes endothelial inflammation through inducible expression of ICAM ‐1." The FEBS Journal 285, no. 9: 1593-1610.

Original research article
Published: 29 June 2017 in Frontiers in Pharmacology
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A novel plant sesquiterpene lactone derivative, DETD-35, originating from parental deoxyelephantopin (DET) was previously observed to effectively suppress human triple negative breast cancer (TNBC) MDA-MB-231 cell activity and tumor growth in mice. In this study, the mechanisms underlying the activity of DETD-35 were elucidated. DET and DETD-35 induced reactive oxygen species (ROS) which caused structural damage and dysfunction of mitochondria and increased cytosolic calcium level, subsequently evoking exosome release from the cancer cells. Intriguingly, exosomes induced by both compounds had an atypical function. Cancer cell-derived exosomes commonly show metastatic potential, but upon DET/DETD-35 treatment exosomes showed anti-proliferative activity against MDA-MB-231 cells. Quantitative proteome analysis of TNBC cell-secreted exosomes showed that DET and DETD-35 attenuated the expression of proteins related to cell migration, cell adhesion, and angiogenesis. Furthermore, several exosomal proteins participating in biological mechanisms such as oxidative stress and decrease of transmembrane potential of mitochondria were found deregulated by treatment with either compound. Pretreatment with ROS scavenger, N-acetylcysteine, blockaded DET- or DETD-35-induced oxidative stress and calcium dependent exosome release mechanisms, and also reverted DET- or DETD-35-induced reprogramming exosomal protein expression profiles resulting in attenuation of exosomal toxicity against TNBC cell proliferation. In summary, this study shows that a plant-derived sesquiterpene lactone DET and its analog DETD-35 inhibitory TNBC cell activities through oxidative stress-induced cancer cell releasing exosomes in tandem with alteration of exosomal protein composition and functions. The findings of this study suggest that DETD-35 may be suitable for further development into an anti-TNBC drug.

ACS Style

Jeng-Yuan Shiau; Yong-Qun Chang; Kyoko Nakagawa-Goto; Kuo-Hsiung Lee; Lie-Fen Shyur. Phytoagent Deoxyelephantopin and Its Derivative Inhibit Triple Negative Breast Cancer Cell Activity through ROS-Mediated Exosomal Activity and Protein Functions. Frontiers in Pharmacology 2017, 8, 398 .

AMA Style

Jeng-Yuan Shiau, Yong-Qun Chang, Kyoko Nakagawa-Goto, Kuo-Hsiung Lee, Lie-Fen Shyur. Phytoagent Deoxyelephantopin and Its Derivative Inhibit Triple Negative Breast Cancer Cell Activity through ROS-Mediated Exosomal Activity and Protein Functions. Frontiers in Pharmacology. 2017; 8 ():398.

Chicago/Turabian Style

Jeng-Yuan Shiau; Yong-Qun Chang; Kyoko Nakagawa-Goto; Kuo-Hsiung Lee; Lie-Fen Shyur. 2017. "Phytoagent Deoxyelephantopin and Its Derivative Inhibit Triple Negative Breast Cancer Cell Activity through ROS-Mediated Exosomal Activity and Protein Functions." Frontiers in Pharmacology 8, no. : 398.

Journal article
Published: 25 May 2017 in Oncotarget
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// Jeng-Yuan Shiau 1, 4 , Kyoko Nakagawa-Goto 2 , Kuo-Hsiung Lee 3 and Lie-Fen Shyur 1, 4, 5 1 Institute of Biotechnology, National Taiwan University, Taipei, Taiwan 2 College of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan 3 Natural Products Research Laboratories, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, USA 4 Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan 5 PhD Program in Translational Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan Correspondence to: Lie-Fen Shyur, email: [email protected] Keywords: breast cancer, sesquiterpene lactone, oxidative stress, paraptosis Received: March 10, 2017 Accepted: April 18, 2017 Published: May 25, 2017 ABSTRACT Triple negative breast cancer (TNBC) is a highly metastatic cancer among the breast cancer subgroups. A thorny issue for clinical therapy of TNBC is lack of an efficient targeted therapeutic strategy. We previously created a novel sesquiterpene lactone analog (named DETD-35) derived from plant deoxyelephantopin (DET) which exhibits potent effects against human TNBC MDA-MB-231 tumor growth in a xenograft mouse model. Here we studied the mechanisms of both DET and DETD-35 against MDA-MB-231 cells. DETD-35 (3-fold decreased in IC 50 ) exhibited better anti-TNBC cell activity than DET as observed through induction of reactive oxygen species production (within 2 h treatment) and damage to the ER structures, resulting in ER-derived cytoplasmic vacuolation and ubiquitinated protein accumulation in the treated cells. Intriguingly, the effects of both compounds were blockaded by pretreatment with ROS scavengers, N -acetylcysteine and reduced glutathione, and protein synthesis inhibitor, cycloheximide. Further, knockdown of MEK upstream regulator RAF1 and autophagosomal marker LC3, and co-treatment with JNK or ERK1/2 inhibitor resulted in the most significant attenuation of DETD-35-induced morphological and molecular or biochemical changes in cancer cells, while the inhibitory effect of DET was not influenced by MAPK inhibitor treatment. Therefore, DETD-35 exerted both ER stress-mediated paraptosis and apoptosis, which may explain its superior activity to DET against TNBC cells. Although the chemotherapeutic drug paclitaxel induced vacuole-like structures in MDA-MB-231 cells, no paraptotic cell death features were detected. This study provides a strategy for combating TNBC through sesquiterpene lactone analogs by induction of oxidative and ER stresses that cause paraptosis-like cell death. Jeng-Yuan Shiau1,4, Kyoko Nakagawa-Goto2, Kuo-Hsiung Lee3 and Lie-Fen Shyur1,4,5 1Institute of Biotechnology, National Taiwan University, Taipei, Taiwan 2College of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan 3Natural Products Research Laboratories, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, USA 4Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan 5PhD Program in Translational Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan Correspondence to: Lie-Fen Shyur, email: [email protected] Keywords: breast cancer, sesquiterpene lactone, oxidative stress, paraptosis Received: March 10, 2017 Accepted: April 18, 2017 Published: May 25, 2017 ABSTRACT Triple negative breast cancer (TNBC) is a highly metastatic cancer among the breast cancer subgroups. A thorny issue for clinical therapy of TNBC is lack of an efficient targeted therapeutic strategy. We previously created a novel sesquiterpene lactone analog (named DETD-35) derived from plant deoxyelephantopin (DET) which exhibits potent effects against human TNBC MDA-MB-231 tumor growth in a xenograft mouse model. Here we studied the mechanisms of both DET and DETD-35 against MDA-MB-231 cells. DETD-35 (3-fold decreased in IC50) exhibited better anti-TNBC cell activity than DET as observed through induction of reactive oxygen species production (within 2 h treatment) and damage to the ER structures, resulting in ER-derived cytoplasmic vacuolation and ubiquitinated protein accumulation in the treated cells. Intriguingly, the effects of both compounds were blockaded by pretreatment with ROS scavengers, N-acetylcysteine and reduced glutathione, and protein synthesis inhibitor, cycloheximide. Further, knockdown of MEK upstream regulator RAF1 and autophagosomal marker LC3, and co-treatment with JNK or ERK1/2 inhibitor resulted in the most significant attenuation of DETD-35-induced morphological and molecular or biochemical changes in cancer cells, while the inhibitory effect of DET was not influenced by MAPK inhibitor treatment. Therefore, DETD-35 exerted both ER stress-mediated paraptosis and apoptosis, which may explain its superior activity to DET against TNBC cells. Although the chemotherapeutic drug paclitaxel induced vacuole-like structures in MDA-MB-231 cells, no paraptotic cell death features were detected. This study provides a strategy for combating TNBC through sesquiterpene lactone analogs by induction of oxidative and ER stresses that cause paraptosis-like cell death.

ACS Style

Jeng-Yuan Shiau; Kyoko Nakagawa-Goto; Kuo-Hsiung Lee; Lie-Fen Shyur. Phytoagent deoxyelephantopin derivative inhibits triple negative breast cancer cell activity by inducing oxidative stress-mediated paraptosis-like cell death. Oncotarget 2017, 8, 56942 -56958.

AMA Style

Jeng-Yuan Shiau, Kyoko Nakagawa-Goto, Kuo-Hsiung Lee, Lie-Fen Shyur. Phytoagent deoxyelephantopin derivative inhibits triple negative breast cancer cell activity by inducing oxidative stress-mediated paraptosis-like cell death. Oncotarget. 2017; 8 (34):56942-56958.

Chicago/Turabian Style

Jeng-Yuan Shiau; Kyoko Nakagawa-Goto; Kuo-Hsiung Lee; Lie-Fen Shyur. 2017. "Phytoagent deoxyelephantopin derivative inhibits triple negative breast cancer cell activity by inducing oxidative stress-mediated paraptosis-like cell death." Oncotarget 8, no. 34: 56942-56958.

Journal article
Published: 01 January 2017 in Phytomedicine
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This study suggests that AC-3E extracts can be employed as a double-barreled approach to treat human ER+ breast cancer by attacking both cancer cells and tumor-associated blood vessel cells.

ACS Style

Kuang-Ming Shang; Tzu-Hsuan Su; Wai-Leng Lee; Wen-Wei Hsiao; Ching-Yi Chiou; Bing-Ying Ho; Sheng-Yang Wang; Lie-Fen Shyur. Novel effect and the mechanistic insights of fruiting body extract of medicinal fungus Antrodia cinnamomea against T47D breast cancer. Phytomedicine 2017, 24, 39 -48.

AMA Style

Kuang-Ming Shang, Tzu-Hsuan Su, Wai-Leng Lee, Wen-Wei Hsiao, Ching-Yi Chiou, Bing-Ying Ho, Sheng-Yang Wang, Lie-Fen Shyur. Novel effect and the mechanistic insights of fruiting body extract of medicinal fungus Antrodia cinnamomea against T47D breast cancer. Phytomedicine. 2017; 24 ():39-48.

Chicago/Turabian Style

Kuang-Ming Shang; Tzu-Hsuan Su; Wai-Leng Lee; Wen-Wei Hsiao; Ching-Yi Chiou; Bing-Ying Ho; Sheng-Yang Wang; Lie-Fen Shyur. 2017. "Novel effect and the mechanistic insights of fruiting body extract of medicinal fungus Antrodia cinnamomea against T47D breast cancer." Phytomedicine 24, no. : 39-48.

Journal article
Published: 01 November 2016 in Phytomedicine
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Supplement of copper significantly enhanced the inhibitory effect of curcumin treatment on migration and viability of oral cancer cells. Together, these findings provide molecular insight into the role of copper in overcoming insensitivity of oral cancer cells to curcumin treatment, suggesting a new strategy for cancer therapy.

ACS Style

Hui-Mei Lee; Vyomesh Patel; Lie-Fen Shyur; Wai-Leng Lee. Copper supplementation amplifies the anti-tumor effect of curcumin in oral cancer cells. Phytomedicine 2016, 23, 1535 -1544.

AMA Style

Hui-Mei Lee, Vyomesh Patel, Lie-Fen Shyur, Wai-Leng Lee. Copper supplementation amplifies the anti-tumor effect of curcumin in oral cancer cells. Phytomedicine. 2016; 23 (12):1535-1544.

Chicago/Turabian Style

Hui-Mei Lee; Vyomesh Patel; Lie-Fen Shyur; Wai-Leng Lee. 2016. "Copper supplementation amplifies the anti-tumor effect of curcumin in oral cancer cells." Phytomedicine 23, no. 12: 1535-1544.

Review article
Published: 26 October 2016 in Pharmacological Research
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In spite of the current advances and achievements in systems biology and translational medicinal research, the current strategies for cancer therapy, such as radiotherapy, targeted therapy, immunotherapy and chemotherapy remain palliative or unsatisfactory due to tumor metastasis or recurrence after surgery/therapy, drug resistance, adverse side effects, and so on. Oxidative stress (OS) plays a critical role in chronic/acute inflammation, carcinogenesis, tumor progression, and tumor invasion/metastasis which is also attributed to the dynamic and complex properties and activities in the tumor microenvironment (TME). Re-educating or reprogramming tumor-associated stromal or immune cells in the TME provides an approach for restoring immune surveillance impaired by disease in cancer patients to increase overall survival and reduce drug resistance. Herbal medicines or plant-derived natural products have historically been a major source of anti-cancer drugs. Delving into the lore of herbal medicine may uncover new leads for anti-cancer drugs. Phytomedicines have been widely documented to directly or indirectly target multiple signaling pathways and networks in cancer cells. A combination of anti-cancer drugs and polypharmacological plant-derived extracts or compounds may offer a significant advantage in sensitizing the efficacy of monotherapy and overcoming drug-induced resistance in cancer patients. This review introduces several phytochemicals and phytoextracts derived from medicinal plants or dietary vegetables that have been studied for their efficacy in preclinical cancer models. We address the underlying modes of action of induction of OS and deregulation of TME-associated stromal cells, mediators and signaling pathways, and reference the related clinical investigations that look at the single or combination use of phytochemicals and phytoextracts to sensitize anti-cancer drug effects and/or overcome drug resistance.

ACS Style

Yu-Ting Cheng; Chun-Chih Yang; Lie-Fen Shyur. Phytomedicine—Modulating oxidative stress and the tumor microenvironment for cancer therapy. Pharmacological Research 2016, 114, 128 -143.

AMA Style

Yu-Ting Cheng, Chun-Chih Yang, Lie-Fen Shyur. Phytomedicine—Modulating oxidative stress and the tumor microenvironment for cancer therapy. Pharmacological Research. 2016; 114 ():128-143.

Chicago/Turabian Style

Yu-Ting Cheng; Chun-Chih Yang; Lie-Fen Shyur. 2016. "Phytomedicine—Modulating oxidative stress and the tumor microenvironment for cancer therapy." Pharmacological Research 114, no. : 128-143.

Book chapter
Published: 25 October 2016 in Medicinal Plants - Recent Advances in Research and Development
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“Plant bioactive compounds” are secondary metabolites mainly composed of terpenoids, alkaloids, and phenolics that are observed to have varied pharmacological effects in preventing or intervening in human disorders. Due to the great potential of plant secondary metabolites for use in the nutraceutical and pharmaceutical industries, genetic engineering techniques and bioreactor approaches may be efficient ways to mass produce bioactive compounds for industrial use. However, before mass production strategies can be implemented to fulfill industrial needs, a full understanding of the biosynthetic pathways and underlying regulation mechanisms must be gained. The conventional “one enzyme, one gene” study approach is insufficient for elucidating the biosynthetic pathways of most bioactive compounds, especially those of non-model medicinal plants due to lack of available whole genome information. It is foreseen that the emerging “omics” technologies will be useful platforms to provide more global genomics, transcriptomics, proteomics, and metabolomics information to help uncover the biosynthesis pathways of secondary metabolites, especially in medicinal plants. The aim of this review is to summarize the current research progress and knowledge in deciphering the biosynthesis pathways of plant bioactive secondary metabolites selected from the three major compound types using omics approaches.

ACS Style

Hsiao-Hang Chung; Yi-Chang Sung; Lie-Fen Shyur. Deciphering the Biosynthetic Pathways of Bioactive Compounds In Planta Using Omics Approaches. Medicinal Plants - Recent Advances in Research and Development 2016, 129 -165.

AMA Style

Hsiao-Hang Chung, Yi-Chang Sung, Lie-Fen Shyur. Deciphering the Biosynthetic Pathways of Bioactive Compounds In Planta Using Omics Approaches. Medicinal Plants - Recent Advances in Research and Development. 2016; ():129-165.

Chicago/Turabian Style

Hsiao-Hang Chung; Yi-Chang Sung; Lie-Fen Shyur. 2016. "Deciphering the Biosynthetic Pathways of Bioactive Compounds In Planta Using Omics Approaches." Medicinal Plants - Recent Advances in Research and Development , no. : 129-165.

Journal article
Published: 05 April 2016 in Molecular Cancer Therapeutics
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Acquired resistance to vemurafenib develops through reactivation of RAF/MEK/ERK signaling or bypass mechanisms. Recent combination therapies such as a MEK inhibitor combined with vemurafenib show improvement in major clinical end points, but the percentage of patients with adverse toxic events is higher than with vemurafenib monotherapy and most patients ultimately relapse. Therefore, there is an urgent need to develop new antimelanoma drugs and/or adjuvant agents for vemurafenib therapy. In this study, we created a novel semiorganically modified derivative, DETD-35, from deoxyelephantopin (DET), a plant sesquiterpene lactone demonstrated as an anti-inflammatory and anti–mammary tumor agent. Our results show that DETD-35 inhibited proliferation of a panel of melanoma cell lines, including acquired vemurafenib resistance A375 cells (A375-R) established in this study, with superior activities to DET and no cytotoxicity to normal melanocytes. DETD-35 suppressed tumor growth and reduced tumor mass as effectively as vemurafenib in A375 xenograft study. Furthermore, DETD-35 also reduced tumor growth in both acquired (A375-R) and intrinsic (A2058) vemurafenib resistance xenograft models, where vemurafenib showed no antitumor activity. Notably, the combination of DETD-35 and vemurafenib exhibited the most significant effects in both in vitro and in vivo xenograft studies due to synergism of the compound and the drug. Mechanistic studies suggested that DETD-35 overcame acquired vemurafenib resistance at least in part through deregulating MEK-ERK, Akt, and STAT3 signaling pathways and promoting apoptosis of cancer cells. Overall, our results suggest that DETD-35 may be useful as a therapeutic or adjuvant agent against BRAFV600E mutant and acquired vemurafenib resistance melanoma. Mol Cancer Ther; 15(6); 1163–76. ©2016 AACR.

ACS Style

Jia-Hua Feng; Kyoko Nakagawa-Goto; Kuo-Hsiung Lee; Lie-Fen Shyur. A Novel Plant Sesquiterpene Lactone Derivative, DETD-35, Suppresses BRAFV600E Mutant Melanoma Growth and Overcomes Acquired Vemurafenib Resistance in Mice. Molecular Cancer Therapeutics 2016, 15, 1163 -1176.

AMA Style

Jia-Hua Feng, Kyoko Nakagawa-Goto, Kuo-Hsiung Lee, Lie-Fen Shyur. A Novel Plant Sesquiterpene Lactone Derivative, DETD-35, Suppresses BRAFV600E Mutant Melanoma Growth and Overcomes Acquired Vemurafenib Resistance in Mice. Molecular Cancer Therapeutics. 2016; 15 (6):1163-1176.

Chicago/Turabian Style

Jia-Hua Feng; Kyoko Nakagawa-Goto; Kuo-Hsiung Lee; Lie-Fen Shyur. 2016. "A Novel Plant Sesquiterpene Lactone Derivative, DETD-35, Suppresses BRAFV600E Mutant Melanoma Growth and Overcomes Acquired Vemurafenib Resistance in Mice." Molecular Cancer Therapeutics 15, no. 6: 1163-1176.

Journal article
Published: 25 March 2016 in Molecular Oncology
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Triple‐negative breast cancer (TNBC) is associated with high grade, metastatic phenotype, younger patient age, and poor prognosis. The discovery of an effective anti‐TNBC agent has been a challenge in oncology. In this study, fifty‐eight ester derivatives (DETDs) with a novel sesquiterpene dilactone skeleton were organically synthesized from a bioactive natural product deoxyelephantopin (DET). Among them, DETD‐35 showed potent antiproliferative activities against a panel of breast cancer cell lines including TNBC cell line MDA‐MB‐231, without inhibiting normal mammary cells M10. DETD‐35 exhibited a better effect than parental DET on inhibiting migration, invasion, and motility of MDA‐MB‐231 cells in a concentration‐dependent manner. Comparative study of DETD‐35, DET and chemotherapeutic drug paclitaxel (PTX) showed that PTX mainly caused a typical time‐dependent G2/M cell‐cycle arrest, while DETD‐35 or DET treatment induced cell apoptosis. In vivo efficacy of DETD‐35 was evaluated using a lung metastatic MDA‐MB‐231 xenograft mouse model. DETD‐35 significantly suppressed metastatic pulmonary foci information along with the expression level of VEGF and COX‐2 in SCID mice. DETD‐35 also showed a synergistic antitumor effect with PTX in vitro and in vivo. This study suggests that the novel compound DETD‐35 may have a potential to be further developed into a therapeutic or adjuvant agent for chemotherapy against metastatic TNBC.

ACS Style

Kyoko Nakagawa-Goto; Jo-Yu Chen; Yu-Ting Cheng; Wai-Leng Lee; Munehisa Takeya; Yohei Saito; Kuo-Hsiung Lee; Lie-Fen Shyur. Novel sesquiterpene lactone analogues as potent anti-breast cancer agents. Molecular Oncology 2016, 10, 921 -937.

AMA Style

Kyoko Nakagawa-Goto, Jo-Yu Chen, Yu-Ting Cheng, Wai-Leng Lee, Munehisa Takeya, Yohei Saito, Kuo-Hsiung Lee, Lie-Fen Shyur. Novel sesquiterpene lactone analogues as potent anti-breast cancer agents. Molecular Oncology. 2016; 10 (6):921-937.

Chicago/Turabian Style

Kyoko Nakagawa-Goto; Jo-Yu Chen; Yu-Ting Cheng; Wai-Leng Lee; Munehisa Takeya; Yohei Saito; Kuo-Hsiung Lee; Lie-Fen Shyur. 2016. "Novel sesquiterpene lactone analogues as potent anti-breast cancer agents." Molecular Oncology 10, no. 6: 921-937.

Review article
Published: 09 March 2016 in Pharmacology & Therapeutics
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Integrative approaches in cancer therapy have recently been extended beyond the induction of cytotoxicity to controlling the tumor microenvironment and modulating inflammatory cascades and pathways such as lipid mediator biosynthesis and their dynamics. Profiling of important lipid messengers, such as oxylipins, produced as part of the physiological response to pharmacological stimuli, provides a unique opportunity to explore drug pharmacology and the possibilities for molecular management of cancer physiopathology. Whereas single targeted chemotherapeutic drugs commonly lack efficacy and invoke drug resistance and/or adverse effects in cancer patients, traditional herbal medicines are seen as bright prospects for treating complex diseases, such as cancers, in a systematic and holistic manner. Understanding the molecular mechanisms of traditional medicine and its bioactive chemical constituents may aid the modernization of herbal remedies and the discovery of novel phytoagents for cancer management. In this review, systems-based polypharmacology and studies to develop multi-target drugs or leads from phytomedicines and their derived natural products that may overcome the problems of current anti-cancer drugs, are proposed and summarized.

ACS Style

Maria Karmella Apaya; Meng-Ting Chang; Lie-Fen Shyur. Phytomedicine polypharmacology: Cancer therapy through modulating the tumor microenvironment and oxylipin dynamics. Pharmacology & Therapeutics 2016, 162, 58 -68.

AMA Style

Maria Karmella Apaya, Meng-Ting Chang, Lie-Fen Shyur. Phytomedicine polypharmacology: Cancer therapy through modulating the tumor microenvironment and oxylipin dynamics. Pharmacology & Therapeutics. 2016; 162 ():58-68.

Chicago/Turabian Style

Maria Karmella Apaya; Meng-Ting Chang; Lie-Fen Shyur. 2016. "Phytomedicine polypharmacology: Cancer therapy through modulating the tumor microenvironment and oxylipin dynamics." Pharmacology & Therapeutics 162, no. : 58-68.