Publications by authors named "Jianjiang Fu"

19 Publications

  • Page 1 of 1

In vitro anti-motile effects of Rhoifolin, a flavonoid extracted from Callicarpa nudiflora on breast cancer cells via downregulating Podocalyxin-Ezrin interaction during Epithelial Mesenchymal Transition.

Phytomedicine 2021 Dec 28;93:153486. Epub 2021 Jan 28.

School of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang 330004, China. Electronic address:

Background: Callicarpa nudiflora (C. nudiflora), which is a medical herb in genus of Callicarpa, widely grows in the southern part of China. Several investigations had shown that this herb exerts anti-tumor effects. Ezrin is an important membrane-cytoskeleton-binding protein. By organizing membrane proteins and orchestrating their signal transduction, Ezrin contributes to modulation of cytoskeleton rearrangement in cell motility.

Purpose: To investigate the anti-motile properties of Rhoifolin (RFL), a flavonoid from C. nudiflora, and to determine whether its effects are related to the inhibition on Podocalyxin (PODXL)-Ezrin signal transduction.

Methods: To determine suitable concentration of RFL and exposure time on breast cancer cells, the effects of RFL on viability of breast cancer cells were evaluated by MTT assay. Then, the anti-migratory properties of RFL were determined by AP 48 chamber system and ORIS cell migration assay. F-actin in MDA-MB-231 cells was visualized by Alexa Fluor™ 488 conjugated Phalloidin. Immunoprecipitation was involved to access the effects of RFL on the interaction between Ezrin and PODXL. In addition, several EMT markers, including E-cadherin, Vimentin, Snail and Slug, were measured by Western Blotting assay and cell immunofluorescent analysis. Finally, the effects of RFL on cell migration, expression of Ezrin and EMT markers were verified by small interfering RNA (siRNA) mediated gene silencing.

Results: We showed here that treatments with 10 and 40 μM of RFL induced significant inhibitions on cell migration and alterations on the location and organization of actin cytoskeleton in breast cancer cells. Next, it was found that RFL suppressed Ezrin phosphorylation and consequent interaction with PODXL, significantly. Also, this compound showed an obvious inhibitory effect on TGF-β1-induced EMT in MDA-MB-231 cells. Furthermore, data from RNA interfering assay confirmed that the inhibitory effects of RFL on Ezrin was enhanced by the deletion of Ezrin.

Conclusion: RFL shows anti-motile properties on breast cancer cells, which is due to its potential to downregulate Podocalyxin-Ezrin interaction during Epithelial Mesenchymal Transition.
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http://dx.doi.org/10.1016/j.phymed.2021.153486DOI Listing
December 2021

HGF/c-MET pathway in cancer: from molecular characterization to clinical evidence.

Oncogene 2021 Jul 18;40(28):4625-4651. Epub 2021 Jun 18.

Department of Pathology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.

This review provides a comprehensive landscape of HGF/c-MET (hepatocyte growth factor (HGF) /mesenchymal-epithelial transition factor (c-MET)) signaling pathway in cancers. First, we generalize the compelling influence of HGF/c-MET pathway on multiple cellular processes. Then, we present the genomic characterization of HGF/c-MET pathway in carcinogenesis. Furthermore, we extensively illustrate the malignant biological behaviors of HGF/c-MET pathway in cancers, in which hyperactive HGF/c-MET signaling is considered as a hallmark. In addition, we investigate the current clinical trials of HGF/c-MET-targeted therapy in cancers. We find that although HGF/c-MET-targeted therapy has led to breakthroughs in certain cancers, monotherapy of targeting HGF/c-MET has failed to demonstrate significant clinical efficacy in most cancers. With the advantage of the combinations of HGF/c-MET-targeted therapy, the exploration of more options of combinational targeted therapy in cancers may be the major challenge in the future.
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http://dx.doi.org/10.1038/s41388-021-01863-wDOI Listing
July 2021

Role of PI3K/AKT pathway in cancer: the framework of malignant behavior.

Mol Biol Rep 2020 Jun 24;47(6):4587-4629. Epub 2020 Apr 24.

Department of Pathology, The Third Affiliated Hospital of Guangzhou Medical University, 63 Duobao Road, Guangzhou, 510150, China.

Given that the PI3K/AKT pathway has manifested its compelling influence on multiple cellular process, we further review the roles of hyperactivation of PI3K/AKT pathway in various human cancers. We state the abnormalities of PI3K/AKT pathway in different cancers, which are closely related with tumorigenesis, proliferation, growth, apoptosis, invasion, metastasis, epithelial-mesenchymal transition, stem-like phenotype, immune microenvironment and drug resistance of cancer cells. In addition, we investigated the current clinical trials of inhibitors against PI3K/AKT pathway in cancers and found that the clinical efficacy of these inhibitors as monotherapy has so far been limited despite of the promising preclinical activity, which means combinations of targeted therapy may achieve better efficacies in cancers. In short, we hope to feature PI3K/AKT pathway in cancers to the clinic and bring the new promising to patients for targeted therapies.
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http://dx.doi.org/10.1007/s11033-020-05435-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295848PMC
June 2020

Co-Delivery of Gemcitabine and Paclitaxel in cRGD-Modified Long Circulating Nanoparticles with Asymmetric Lipid Layers for Breast Cancer Treatment.

Molecules 2018 Nov 7;23(11). Epub 2018 Nov 7.

National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine, Jiangxi University of Traditional Chinese Medicine, Nanchang 330006, China.

Combination chemotherapy is a common clinical practice in cancer treatment. Here, cyclic RGD (arginylglycylaspartic acid) peptide was introduced to the surface of lipid/calcium/phosphate (LCP) asymmetric lipid layer nanoparticles for the co-delivery of paclitaxel (PTX) and gemcitabine monophosphate (GMP) (P/G-NPs). The sphere-like morphology of P/G-NPs displays a well-distributed particle size, and high entrapment efficiency and drug loading for both PTX and GMP, with a positive zeta potential. P/G-NPs were stable for up to 15 days. The cellular uptake of these cyclic RGD-modified nanoparticles was significantly higher than that of unmodified nanoparticles over 2 h incubation. Compared with the combination of free PTX and GMP (P/G-Free), P/G-NPs exhibited a longer circulation lifetime and improved absorption for PTX and GMP. Polyethylene glycol was responsible for a higher plasma concentration and a decreased apparent volume of distribution (V). Nanoparticles enhanced the drug accumulation in tumors compared with other major organs after 24 h. P/G-NPs nearly halted tumor growth, with little evidence of general toxicity, whereas P/G-Free had only a modest inhibitory effect at 16 mg/kg of GMP and 2.0 mg/kg of PTX. Increased levels of apoptosis within tumors were detected in P/G-NPs group by approximately 43.6% (TUNEL assay). When compared with GMP NPs, PTX NPs, and P/G-Free, P/G-NPs decreased expression of B-cell lymphoma-2 and B-cell lymphoma-extra large proteins, and increased expression of cleaved poly-ADP-ribose polymerase-1. Calreticulin expression in tumors also increased upon the co-delivery of PTX and GMP. The antitumor effect of P/G-NPs is more powerful than P/G-Free, GMP NP, or PTX NP alone, without obvious toxicity.
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http://dx.doi.org/10.3390/molecules23112906DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6278289PMC
November 2018

Curcolonol suppresses the motility of breast cancer cells by inhibiting LIM kinase 1 to downregulate cofilin 1 phosphorylation.

Int J Oncol 2018 Dec 10;53(6):2695-2704. Epub 2018 Oct 10.

Department of Pharmacology, School of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang, Jiangxi 330004, P.R. China.

Curcolonol (CCL) is a furan type sesquiterpene isolated from several medical herbs. Based on previous results of anti-migratory activity screening, in this study, we investigated the effects of CCL on cancer cell motility. By in vitro migration assay, we found that CCL significantly inhibited the vertical and horizontal migration of breast cancer cells induced by transforming growth factor (TGF)-β1. In addition, CCL also exerted inhibitory effects on F-actin polymerization in breast cancer cells when the cells were dyed with phalloidin. Given the close association between F-actin and ADF/cofilin, the effects of CCL on the expression and phosphorylation of cofilin 1 were explored. It was observed that there were minimal changes in the expression of cofilin 1; however, the phosphorylation of cofilin 1 was significantly inhibited by CCL in a dose-dependent manner. Furthermore, CCL significantly inhibited the activity of LIM kinase 1 (LIMK1), although almost no effects were observed on LIMK1 expression and phosphorylation. However, the inhibitory effects of CCL on LIMK1 activity were antagonized and enhanced by the overexpression and knockdown of LIMK1, respectively. Based on the current data, it is thus suggested that the suppressive effects of CCL on breast cancer cell motility are due to its potential to reduce the phosphorylation of cofilin 1, which may be associated with the inhibition of the catalytic activity of LIMK1.
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http://dx.doi.org/10.3892/ijo.2018.4592DOI Listing
December 2018

In vitro inhibitory properties of sesquiterpenes from Chloranthus serratus on cell motility via down-regulation of LIMK1 activation in human breast cancer.

Phytomedicine 2018 Oct 13;49:23-31. Epub 2018 Jun 13.

Network and Educational Technology Center, Jiangxi University of Traditional Chinese Medicine, 818 Meiling Rd, Nanchang 330004, China. Electronic address:

Background: LIM kinase 1 plays an important role in tumor cell invasion and metastasis by regulating architecture of actin cytoskeleton, and inhibiting activity of this kinase may be a promising strategy to prevent cancer cells from distant spread. In our previous studies, we found several extracts from the medical herbs in genus Chloranthus to exhibit anti-metastatic effects.

Purpose: The aim of this study is to find LIMK1 inhibitors from Chloranthus serratus, a medical herb from genus Chloranthus and to evaluate their effects on cell motility.

Methods: Three sesquiterpenes, chloranthalactone E (compound 1), serralactone A (compound 2, SERA is used in the further testing), and 8β, 9α-dihydroxylindan-4(5), 7(11)-dien-8α, 12-olide (compound 3) were isolated from Chloranthus serratus, and the anti-LIMK1 activities of these compounds were investigated by kinase-Glo luminescent kinase assay. Then, the anti-LIMK1 properties of SERA were verified by kinase-Glo luminescent kinase assay and western blot assay. The effects of SERA on F-actin polymerization and cell migration were investigated by Phalloidin dying, AP 48 chamber system and ORIS™ cell migration assay. Furthermore, the inhibitory effects of SERA on LIMK1 were confirmed by overexpression of LIMK1 and small interfering RNA (siRNA) mediated gene silencing.

Results: we reported here that among the three sesquiterpenes, SERA showed significantly inhibition on LIMK1 activity, and the IC values on MDA-MB-231 and MDA-MB-468 cells were 3.14 μM and 4.64 μM, respectively. Furthermore, it was also found that SERA significantly suppressed LIMK1 and cofilin1 phosphorylation, F-actin polymerization and also cell migration. Data from LIMK1 overexpression and RNA interfering assay confirmed that the inhibitory effects of SERA on LIMK1 was antagonized and enhanced by the overexpression and knockdown of LIMK1.

Conclusion: collectively, it was concluded that SERA exhibited significant inhibitory effects on breast cancer cells migration, and these effects of this sesquiterpene are due to its properties reducing the activation of LIM kinase 1.
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http://dx.doi.org/10.1016/j.phymed.2018.06.009DOI Listing
October 2018

Inhibitory effects of luteolin‑4'‑O‑β‑D‑glucopyranoside on P2Y12 and thromboxane A2 receptor‑mediated amplification of platelet activation in vitro.

Int J Mol Med 2018 Jul 19;42(1):615-624. Epub 2018 Apr 19.

Department of Pharmacology, School of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang, Jiangxi 330004, P.R. China.

Platelet activation and subsequent accumulation at sites of vascular injury are central to thrombus formation, which is considered to be a trigger of several cardiovascular diseases. Callicarpa nudiflora (C. nudiflora) Hook is a traditional Chinese medicinal herb for promoting blood circulation by removing blood stasis. In our previous study, several compounds extracted from this herb, including luteolin‑4'‑O‑β‑D‑glucopyranoside (LGP), were revealed to exert inhibitory effects on adenosine diphosphate (ADP)‑induced platelet aggregation. The aim of present study was to confirm these antiplatelet effects and elucidate the potential mechanisms. Using a platelet‑aggregation assay, it was revealed that LGP significantly inhibited platelet aggregation induced by ADP, U46619 and arachidonic acid. It was also found that LGP exhibited marked inhibitory effects on the activation of αIIbβ3 integrin, the secretion of serotonin from granules, and the synthesis of thromboxane A2. In addition, the results showed that LGP suppressed Ras homolog family member A and phosphoinositide 3‑kinase/Akt/glycogen synthase kinase 3β signal transduction. Data from a radiolabeled ligand‑binding assay indicated that LGP exhibited apparent competing effects on thromboxane receptor (TP) and P2Y12 receptors. In conclusion, the data presented here demonstrated that LGP, a natural compound from C. nudiflora Hook, inhibited the development of platelet aggregation and amplification of platelet activation. These inhibitory effects may be associated with its dual‑receptor inhibition on P2Y12 and TP receptors.
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http://dx.doi.org/10.3892/ijmm.2018.3634DOI Listing
July 2018

1, 6-di-O-caffeoyl-β-D-glucopyranoside, a natural compound from Callicarpa nudiflora Hook impairs P2Y and thromboxane A receptor-mediated amplification of platelet activation and aggregation.

Phytomedicine 2017 Dec 16;36:273-282. Epub 2017 Oct 16.

Jiangxi Provincial Institute for Drug Control, Nanchang, 330029, China. Electronic address:

Background: Platelet activation and subsequent accumulation at sites of vascular injury perform a central role in thrombus formation, which is believed to be the trigger of several cardiovascular diseases, such as atherosclerosis, myocardial infarction and strokes. In this sense, the search for agents that are capable of blocking platelets aggregation has important implications for these diseases. Callicarpa nudiflora (C. nudiflora) Hook is a traditional Chinese medicine herb for eliminating stasis to subdue swelling and hemostasis. Our previous study found several compounds extracted from this herb, including 1, 6-di-O-caffeoyl-β-D-glucopyranoside (CGP), showed inhibitory effects on adenosine diphosphate (ADP) induced platelet aggregation.

Purpose: The aim of current study is confirmation of the anti-platelet effects and elucidation of the probable mechanisms.

Methods: The experiments were performed on platelet rich plasma freshly isolated from SD rat. ADP, U46619 or arachidonic acid (AA) induced platelet aggregation assay were performed to evaluate the anti-platelet properties of CGP. Activated αβ integrin abundance, serotonin (5-HT) secretion, thromboxane A (TXA) synthesis was determined to assess the effects of CGP on platelet activation. Furthermore, RhoA and PI3K/Akt/GSK3β signal transduction were analyzed by Western Blotting assay. In addition, radiolabelled ligand binding assay was involved to evaluate the ability of CGP binding to thromboxane prostanoid (TP) and P2Y receptors.

Results: CGP inhibited platelet aggregation induced by ADP, U46619 and arachidonic acid (AA), significantly. Furthermore, it is also found that LGP exhibited obvious inhibitory effects on αβ integrin activation, serotonin (5-HT) secretion from granule and thromboxane A (TXA) synthesis. Next, we found that CGP suppressed RhoA and PI3K/Akt/GSK3β signal transduction. Data from radiolabelled ligand binding assay showed that CGP displayed apparent competing effects on TP and P2Y receptors.

Conclusion: Collectively, the data presented here demonstrated that CGP, a natural compound from Callicarpa nudiflora Hook, inhibited the development of platelet aggregation and amplification of platelet activation. These inhibitory effects may be associated with its dual-receptor inhibition on P2Y and TP receptors.
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http://dx.doi.org/10.1016/j.phymed.2017.10.012DOI Listing
December 2017

The natural compound codonolactone attenuates TGF-β1-mediated epithelial-to-mesenchymal transition and motility of breast cancer cells.

Oncol Rep 2016 Jan 4;35(1):117-26. Epub 2015 Nov 4.

Network and Educational Technology Center, Jiangxi University of Traditional Chinese Medicine, Nanchang, Jiangxi 330004, P.R. China.

Codonolactone (CLT), a natural product, is the major bioactive component of Atractylodes lancea, and also found in a range of other medical herbs, such as Codonopsis pilosula, Chloranthus henryi Hemsl and Atractylodes macrocephala Koidz. This sesquiterpene lactone has been demonstrated to exhibit a range of activities, including anti-allergic activity, anti-inflammatory, anticancer, gastroprotective and neuroprotective activity. Previously, we found that CLT showed significant anti-metastatic properties in vitro and in vivo. In order to determine whether EMT-involved mechanisms contribute to the anti-metastatic effects of CLT, we checked the anti-EMT properties of CLT and its potential mechanisms. Here it was demonstrated that CLT inhibited TGF-β1-induced epithelial-mesenchymal transition (EMT) in vitro and in vivo. Furthermore, downregulation of TGF-β signaling was associated with the anti-EMT properties of CLT. Data from western blotting showed that, in breast cancer cells, TGF-β1 stimulated the activation of Runx2, and CLT blocked the activation of Runx2. Finally, to verify whether CLT-induced EMT inhibition leads to suppression of metastatic potential, the effects of CLT on cell invasion and migration were determined. It was found that TGF-β1-induced migration and invasion was significantly blocked by CLT in both MDA-MB-231 and MDA-MB-468 cells. Collectively, our findings demonstrated that CLT inhibited programming of EMT in vitro and in vivo, resulting in inhibition of motility of metastatic breast cancer cells. The inhibitory effect of CLT was due to its ability to inhibit TGF-β signaling and Runx2 phosphorylation.
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http://dx.doi.org/10.3892/or.2015.4394DOI Listing
January 2016

The natural compound codonolactone impairs tumor induced angiogenesis by downregulating BMP signaling in endothelial cells.

Phytomedicine 2015 Oct 19;22(11):1017-26. Epub 2015 Aug 19.

Department of Pharmacology, School of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang 330004, China. Electronic address:

Background: Angiogenesis, the recruitment of new blood vessels, was demonstrated that is an essential component of the growth of a tumor beyond a certain size and the metastatic pathway. The potential use of angiogenesis-based agents, such as those involving natural and synthetic inhibitors as anticancer drugs is currently under intense investigation. In this study, the anti-angiogenic properties of codonolactone (CLT), a sesquiterpene lactone from Atractylodes lancea, were examined in endothelial cells.

Purpose: Our published study reported that CLT shows significant anti-metastatic properties in vitro and in vivo. In order to determine whether angiogenic-involved mechanisms contribute to the anti-metastatic effects of CLT, we checked the anti-angiogenic properties of CLT and its potential mechanisms.

Study Design/methods: Human umbilical vein endothelial cells (HUVECs) and EA.hy 926 cells were involved in this study. Immunofluorescence assay for cells and immunohistochemistry assay for tissues were used to check the expression of angiogenic markers. In vitro migration and invasion of endothelial cells treated with and without CLT were analyzed. Protein expressions were measured by Western blot analysis. For MMPs activity assay, fluorescence resonance energy transfer-based MMPs activity assay and gelatin zymography assay were involved in this study.

Results: Here we demonstrated that CLT exhibited inhibition on cancer cell induced angiogenesis in vivo, and direct inhibited migration and invasion of endothelial cells in vitro. Moreover, we observed that the down-regulation of MMPs and VEGF-VEGFR2 was involved in the anti-angiogenic effects of CLT. Data from Western blotting showed that, in endothelial cells, CLT reduced Runx2 activation and BMP signaling.

Conclusion: Our findings demonstrated that CLT impaired the development of angiogenesis both in vitro and in vivo by direct inhibition on endothelial cells. These inhibitory effects were depended on its ability to interference with BMP signaling in endothelial cells, which may cause inhibition of MMPs expression and VEGF secretion by down-regulating Runx2 activation.
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http://dx.doi.org/10.1016/j.phymed.2015.07.009DOI Listing
October 2015

The anthraquinone derivative Emodin inhibits angiogenesis and metastasis through downregulating Runx2 activity in breast cancer.

Int J Oncol 2015 Apr 10;46(4):1619-28. Epub 2015 Feb 10.

Department of Pharmacology, College of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang 330004, P.R. China.

Emodin (EMD) is an anthraquinone derivative extracted from the root and rhizome of Rheum palmatum L. which exhibits a range of activities, including anti-bacterial, antitumor, diuretic and vasorelaxant effects. The ability to inhibit metastasis and angiogenesis was shown in previous pharmacological studies, but clear information to address EMD affecting angiogenesis and metastasis in human breast cancer is still lacking. In the present study, we evaluated a possible role for EMD in angiogenesis and metastasis induced by breast cancer cells. It was revealed here that EMD attenuated tumor cell-induced metastasis and angiogenesis both in vitro and in vivo. Furthermore, it was found that these inhibitory effects were caused by MMPs and VEGFR-2 inhibition in metastatic breast cancer cells and endothelial cells, respectively. Western blot analysis showed reduction of Runx2 activation in the EMD-treated cells. ELISA based Runx2 transcription factor assay showed that the interaction between Runx2 and target sequences was inhibited by EMD. Our findings suggested that the inhibitory effects of EMD on tumor-induced metastasis and angiogenesis were caused by MMPs and VEGFR-2 inhibition, which may be associated with the downregulation of Runx2 transcriptional activity.
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http://dx.doi.org/10.3892/ijo.2015.2888DOI Listing
April 2015

In vitro inhibitory effects of terpenoids from Chloranthus multistachys on epithelial-mesenchymal transition via down-regulation of Runx2 activation in human breast cancer.

Phytomedicine 2015 Jan 27;22(1):165-72. Epub 2014 Nov 27.

Department of Chemistry of Chinese materia medica, School of Pharmacy, Jiangxi University of Traditional Chinese Medicine, 18 Yunwan Rd, Nanchang 330004, China. Electronic address:

From Chloranthus multistachys, three terpenoids - lupeol (1), henrilabdane B (2), and istanbulin A (3) were isolated. Structures of compounds were established by NMR and MS. We reported here that ISTA (3) suppressed cell invasion, but lupeol (1) and henrilabdane B (2) did not. Furthermore, ISTA significantly inhibited the ability of adhesion and migration in vitro. Next, mechanisms of ISTA-induced inhibitory effects on in vitro metastasis were investigated. Sequential treatment data revealed that ISTA dramatically inhibited EGF-induced EMT. Western blot indicated that ISTA also significantly suppressed expression of E-cadherin, vimentin, and slug. In addition, ISTA inhibited Runx2 activation and phosph-Runx2 expression. Collectively, ISTA exhibited significant inhibitory effects on in vitro metastatic potential via inducing EMT inhibition, which may be associated with inhibition of transcriptional activity of Runx2.
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http://dx.doi.org/10.1016/j.phymed.2014.11.010DOI Listing
January 2015

Codonolactone, a sesquiterpene lactone isolated from Chloranthus henryi Hemsl, inhibits breast cancer cell invasion, migration and metastasis by downregulating the transcriptional activity of Runx2.

Int J Oncol 2014 Nov 4;45(5):1891-900. Epub 2014 Sep 4.

Department of Pharmacology, School of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang 330004, P.R. China.

Metastasis is the most insidious aspect of breast cancer, but effective strategies to control this malignant process are still lacking. In previous studies, we screened over 200 extracts from plants of genus Chloranthaceae by bioactivity-guided fractionation, and found that Codonolactone (CLT) exhibited potential antimetastatic properties in breast cancer cells. This sesquiterpene lactone was isolated from Chloranthus henryi Hemsl, and is also found in other medical herbs, such as Codonopsis pilosula, Atractylodes macrocephala Koidz and others. Here, we report that CLT inhibited the ability of invasion and migration in metastatic breast cancer cells. Furthermore, CLT exhibited significant suppression on formation of lung metastatic foci of breast cancer in vivo. We next investigated the mechanism of CLT-induced metastasis inhibitory effects in breast cancer cells. A significant inhibition on activity and expression of MMP-9 and MMP-13 was observed. Moreover, data from western blotting, Runx2 transcription factor assay and chromatin immunoprecipitation assay showed that binding ability of Runx2 to sequences of the mmp-13 promoter was inhibited by CLT. Collectively, these findings suggested that the antimetastatic properties of CLT in breast cancer were due to the inhibition of MMPs, which might be associated with a downregulation of Runx2 transcriptional activity.
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http://dx.doi.org/10.3892/ijo.2014.2643DOI Listing
November 2014

The dineolignan from Saururus chinensis, manassantin B, inhibits tumor-induced angiogenesis via downregulation of matrix metalloproteinases 9 in human endothelial cells.

Oncol Rep 2014 Aug 11;32(2):659-67. Epub 2014 Jun 11.

Department of Pharmacology, College of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang, Jiangxi 330004, P.R. China.

Manassantin B (MB) is a neolignan isolated from Saururus chinensis that exhibits a range of activities, including anti-inflammatory, antiseptic and antitumor activity. MB was recently found to affect cell adhesion and expression of several adhesion molecules. Based on the important roles of these adhesion molecules in angiogenesis, we evaluated a possible role for MB in tumor-induced angiogenesis in endothelial cells (ECs). In the present study, we found that MB blocked tumor-induced tube formation of ECs and significantly inhibited the invasion of ECs through the reconstituted basement membrane. MB suppressed the activity of matrix metalloproteinases (MMPs) and downregulated the expression of matrix metalloproteinases 9. Western blotting showed reduction of RUNX2 activation by MB. RUNX2 transcription factor assay and chromatin immunoprecipitation assay showed that the interaction between RUNX2 and target sequences in the matrix metalloproteinases 9 promoters was inhibited by MB. Our findings suggested that the inhibitory effects of MB on tumor-induced angiogenesis were caused by matrix metalloproteinases 9 inhibition, which was associated with the downregulation of RUNX2 transcriptional activity.
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http://dx.doi.org/10.3892/or.2014.3244DOI Listing
August 2014

In vitro anti-angiogenic properties of LGD1069, a selective retinoid X-receptor agonist through down-regulating Runx2 expression on Human endothelial cells.

BMC Cancer 2011 Jun 7;11:227. Epub 2011 Jun 7.

Department of Pharmacology, College of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang, 330004 China.

Background: LGD1069 (Targretin®) is a selective retinoid X receptor (RXR) ligand, which is used in patients for cutaneous T-cell lymphoma. Our published study reported that LGD1069 inhibited tumor-induced angiogenesis in non-small cell lung cancer. In present study, we found that LGD1069 suppressed the proliferation, adhesion, invasion and migration of endothelial cells directly, and affected the expression of vegf and some matrix genes.

Methods: Human umbilical vein endothelial cells (HUVECs) were used for in vitro study. MTT assay and Sulforhodamine B assay were used for cell viability assay; the tube formation assay was used to investigate the effect of LGD1069 on angiogenesis in vitro. In vitro adhesion, migration and invasion of HUVEC cells were analyzed by Matrigel adhesion, migration and invasion assay. Gene expressions were measured by RT-PCR and Western blot analysis.

Results: Our data showed here that LGD1069 inhibited the activation of TGF-β/Smad pathway significantly. Furthermore, it was demonstrated that expression of Runx2 was suppressed pronouncedly during incubation with LGD1069. Runx2 is a DNA-binding transcription factor which plays a master role in tumor-induced angiogenesis and cancer cells metastasis by interaction with the TGF-β/Smad pathway of transcriptional modulators.

Conclusions: Our results suggested that LGD1069 may impair angiogenic and metastatic potential induced by tumor cells through suppressing expression of Runx2 directly on human endothelial cells, which may point out new pathway through which LGD1069 display anti-angiogenic properties, and provide new molecular evidence to support LGD1069 as a potent anti-metastatic agent in cancer therapy.
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http://dx.doi.org/10.1186/1471-2407-11-227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3120806PMC
June 2011

(-)Gossypol and its combination with imatinib induce apoptosis in human chronic myeloid leukemic cells.

Leuk Lymphoma 2007 Nov;48(11):2204-12

Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.

Chronic myeloid leukemia (CML) is characterized by the presence of chimeric protein BCR-ABL associated with high tyrosine kinase (TK) activity, which leads to cell tumorogenicity, resistance to apoptosis, and differentiation. Gossypol is a natural polyphenolic compound isolated from cottonseed and has antiproliferative activity in a variety of cancer cell lines. (-)Gossypol is proved the potent component. Here we examined the growth inhibitory effect of (-)gossypol and its combination with imatinib in K562 cells. (-)Gossypol inhibited cell growth, promoted apoptosis, induced DeltaPsim loss, and cytochrome C release. Furthermore, (-)gossypol had a synergistic inhibitory effect on growth in K562 cells when combined with imatinib. Enhanced apoptosis, cytochrome C release, and caspase 3 cleavage as well as noticeable decrease of Mcl-1 and Bcl-XL were observed in K562 cells treated with both (-)gossypol and imatinib. These results suggest that (-)gossypol induced apoptosis in K562 cells through a mitochondria pathway and that the combination of imatinib and (-)gossypol might be an effective treatment for CML.
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http://dx.doi.org/10.1080/10428190701583991DOI Listing
November 2007

Transcriptomic signatures in breast cancer.

Mol Biosyst 2007 Jul 5;3(7):466-72. Epub 2007 Jun 5.

Stanford University Medical Center, Stanford, CA 94305-5494, USA.

High throughput DNA microarray technology has been broadly applied to the study of breast cancer to classify molecular subtypes, to predict outcome, survival, response to treatment, and for the identification of novel therapeutic targets. Although results are promising, this technology will not have a full impact on routine clinical practice until there is further standardization of techniques and optimal clinical trial design. Due to substantial disease heterogeneity and the number of genes being analyzed, collaborative, multi-institutional studies are required to accrue enough patients for sufficient statistical power. Newer bioinformatic approaches are being developed to assist with the analysis of this important data.
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http://dx.doi.org/10.1039/b618163eDOI Listing
July 2007

The retinoid X receptor-selective ligand, LGD1069, inhibits tumor-induced angiogenesis via suppression of VEGF in human non-small cell lung cancer.

Cancer Lett 2007 Apr 5;248(1):153-63. Epub 2006 Oct 5.

Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Xian Nong Tan Street, Beijing 100050, China.

The present study determined the influence of a retinoid X receptor agonist LGD1069 on angiogenesis in non-small cell lung cancer. In A549 xenograft models, treatment with LGD1069 inhibited the growth and CD31 expression compared with control. In vivo angiogenesis assay utilizing hollow fiber, LGD1069 reduced density of capillary network induced by tumor cells. To determine the basis of these observations, we examined the expression of VEGF and activation of JNK and ERK in A549 cells exposed to LGD1069. Our data showed that LGD1069 decrease the VEGF expression of tumor cells in a dose-dependent manner. Furthermore, it was demonstrated that the decreasing expression of VEGF was consist with inhibition of JNK and ERK activation induced by LGD1069. Collectively, our results suggest a role of LGD1069 in treatment for non-small cell lung cancer by inhibition of tumor-induced angiogenesis.
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http://dx.doi.org/10.1016/j.canlet.2006.06.012DOI Listing
April 2007

Growth inhibition and differentiation induced by peroxisome proliferator activated receptor gamma ligand rosiglitazone in human melanoma cell line A375.

Med Oncol 2006 ;23(3):393-402

Institute of Materia Medica, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100050 China.

Background: Ligands of peroxisome proliferator-activated receptors (PPARs) have been demonstrated to be antitumorgenic in vitro and in vivo due to their antiproliferative, prodifferential, and antiangiogenic effects. The aim of this study is to evaluate the effects and mechanisms of PPARgamma ligand rosiglitazone (ROZ) on the growth, apoptosis, and differentiation in human melanoma cancer cell line A375.

Methods: The effects of ROZ on A375 cell proliferation were measured by clonogenic assay, apoptosis and cell cycle kinetics by FACS with ROZ for 72 h, PPARgamma protein was detected by Western blot analysis and immunocytochemical staining, and PPARgamma mRNA expression by RT-PCR. The differentiation effect of ROZ was determined by measurement of melanin content and tyrosinase activity. The levels of Bcl-2, P53, p-ERK, and ERK were also detected by Western blot analysis. Inhibition of tumorigensis was observed in nude mice.

Results: ROZ inhibited colony formation and induced apoptosis in A375 cells, and the cells were arrested in G1 phase. This effect was associated with a decrease of the expression of Bcl-2 and increase of the expression of P53. ROZ also induced the differentiation in A375 cells. ROZ increased expression of PPARgamma and decreased the expression of ERK and p-ERK. Data in vivo showed that ROZ could inhibit tumorigensis in nude mice.

Conclusion: These results demonstrated that ROZ inhibited growth of A375 cells via the induction of apoptosis, necrosis, and differentiation in a PPARgamma-dependent manner and might present a promising therapeutic approach in certain human maligancies.
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http://dx.doi.org/10.1385/mo:23:3:393DOI Listing
January 2010
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