ABSTRACT
OBJECTIVE: Inhibition of tumor metastasis is a useful strategy to improve the efficacy of cancer therapy. Ventilagolin, a natural 1, 4-naphthoquinone derivative extracted from Ventilago leiocarpa Benth, has shown promising antitumor effects in previous studies. However, the effects and underlying mechanisms of Ventilagolin against migration, invasion and epithelial-mesenchymal transition (EMT) of hepatocellular carcinoma (HCC) remain unclear. The present study has examined these effects and determined whether the proto-oncogene Pim-1 is involved. METHODS: The effects of Ventilagolin on migration, invasion, Pim-1 and EMT-related proteins (eg, E-cadherin, N-cadherin, Vimentin) expression were assessed by scratch wound healing, Transwell, qRT-PCR and Western blot assays, respectively. Pim-1 stably overexpressed HepG2 and SMMC-7721 cells were generated to explore whether Ventilagolin inhibited migration, invasion and EMT of HCC cells via regulating Pim-1. Subcutaneous xenograft tumor model in nude mice was established. Histopathological changes of tumor tissues were examined by H&E staining and expressions of Pim-1 and EMT-related proteins were detected by immunohistochemistry. RESULTS: Ventilagolin significantly (P < 0.01) reduced the expression of Pim-1 levels in HepG2 and SMMC-7721 cells. Compared with the control group, the migration and invasion abilities of Pim-1-overexpressing HepG2 and SMMC-7721 cells were significantly (P < 0.05, P < 0.01) enhanced, the expression of E-cadherin was decreased (P < 0.01), and the levels of N-cadherin and Vimentin were upregulated (P < 0.05, P < 0.01). Ventilagolin treatment effectively reversed these effects of Pim-1 overexpression. In vivo experiments showed that Ventilagolin could effectively suppress HCC tumor growth, downregulate Pim-1, N-cadherin and Vimentin expression, and upregulate E-cadherin expression. CONCLUSION: Ventilagolin suppresses HCC cell proliferation, migration and invasion and reverses EMT process by downregulating Pim-1, suggesting Ventilagolin is a potential therapeutic agent for treatment of HCC.
Subject(s)
Antineoplastic Agents/pharmacology , Carcinoma, Hepatocellular/drug therapy , Epithelial-Mesenchymal Transition/drug effects , Liver Neoplasms/drug therapy , Naphthoquinones/pharmacology , Proto-Oncogene Proteins c-pim-1/antagonists & inhibitors , Animals , Antineoplastic Agents/chemistry , Carcinoma, Hepatocellular/metabolism , Carcinoma, Hepatocellular/pathology , Cell Movement/drug effects , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Down-Regulation/drug effects , Drug Screening Assays, Antitumor , Female , Humans , Liver Neoplasms/metabolism , Liver Neoplasms/pathology , Liver Neoplasms, Experimental/drug therapy , Liver Neoplasms, Experimental/metabolism , Liver Neoplasms, Experimental/pathology , Mice , Mice, Inbred BALB C , Mice, Nude , Molecular Structure , Naphthoquinones/chemistry , Proto-Oncogene Proteins c-pim-1/genetics , Proto-Oncogene Proteins c-pim-1/metabolism , RNA, Messenger/antagonists & inhibitors , RNA, Messenger/genetics , RNA, Messenger/metabolism , Structure-Activity Relationship , Tumor Cells, Cultured , Wound Healing/drug effectsABSTRACT
Breast cancer (BC) is a major contributor of cancer-associated mortality in women. It is essential to find new therapeutic targets and drugs. Polyrhachis vicina Rogers is one of the Traditional Chinese Medicine (TCM). Our previous studies have shown an active fraction of Polyrhachis vicina Rogers (AFPR) has significant anti-inflammatory activity, suggesting its anti-cancer effect. Here, we aimed to explore the inhibitory effects of AFPR on BC and reveal its mechanism. The effects of AFPR on BC were examined by cell proliferation assay, wound healing assay, invasion assay and xenograft assay. Microarray sequencing, qRT-PCR, Western blot, chromatin immunoprecipitation assay and luciferase reporter assay were performed to investigate the regulation of AFPR on related genes and underlying mechanisms. As a result, AFPR suppressed BC cell growth, migration and invasion and inhibited tumor growth. LncRNA NKILA was most prominently upregulated in AFPR-treated MCF7 cells. AFPR inactivated NF-κB signaling pathway via regulating NKILA. Furthermore, AFPR regulated the expression of NKILA by inhibiting its transcript suppressor EGR1. This study firstly indicated that AFPR was a potential inhibitor of BC development via regulating EGR1/NKILA/NF-κB axis.
Subject(s)
Ants/chemistry , Early Growth Response Protein 1/metabolism , Gene Expression Regulation, Neoplastic/drug effects , NF-kappa B/metabolism , RNA, Long Noncoding/metabolism , Animals , Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , Cell Movement/drug effects , Chemical Fractionation , Early Growth Response Protein 1/genetics , Female , Humans , MCF-7 Cells , Male , Medicine, Chinese Traditional , Mice, Nude , NF-kappa B/genetics , Neoplasm Invasiveness , Neoplasms, Experimental , RNA, Long Noncoding/genetics , Up-RegulationABSTRACT
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have become the standard first-line treatment for advanced lung adenocarcinoma (LUAD) cancer patients with activating EGFR mutations. However, most patients show acquired resistance to EGFR-TKIs, thereby resulting in a modest overall survival benefit. Here, we found that expression level of APE1 was closely associated with TKI resistance in LUAD. Our clinical data show that level of APE1 was inversely correlated with progression-free survival rate and median time to progression in EGFR-mutated LUAD patients. Additionally, we observed increased expression of APE1 in TKI-resistant LUAD cell lines compared to their parental cell lines. Overexpression of APE1-protected TKI-sensitive LUAD cells from TKI-induced cell growth inhibition and cell death. In contrast, inhibition of APE1-enhanced TKI-induced apoptosis, cell growth inhibition and tumor growth inhibition in TKI-resistant LUAD. In addition, we identified that APE1 positively regulates Akt activation and APE1 overexpression-induced TKI resistance was attenuated by inhibition of Akt activity. Finally, we demonstrated that inhibition of the redox function of APE1 enhances the sensitivity of TKI-resistant LUAD cells to TKI treatment and inhibits Akt phosphorylation in TKI-resistant LUAD cells, but not by inhibition of the APE1 DNA repair function. Taken together, our data show that increased expression of APE1 significantly contributes to TKI resistance development in LUAD, and targeting APE1 may reverse acquired resistance of LUAD cells to TKI treatment. Additionally, our data show that APE1 regulates TKI resistance in LUAD cells by activating Akt signaling through a redox-dependent mechanism.
Subject(s)
Adenocarcinoma of Lung/genetics , DNA-(Apurinic or Apyrimidinic Site) Lyase/genetics , Gene Expression Regulation, Neoplastic , Lung Neoplasms/genetics , Neovascularization, Pathologic/genetics , Proto-Oncogene Proteins c-akt/genetics , Adenocarcinoma of Lung/drug therapy , Adenocarcinoma of Lung/mortality , Adenocarcinoma of Lung/pathology , Aged , Animals , Antineoplastic Agents/therapeutic use , Apoptosis/drug effects , Apoptosis/genetics , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , DNA-(Apurinic or Apyrimidinic Site) Lyase/antagonists & inhibitors , DNA-(Apurinic or Apyrimidinic Site) Lyase/metabolism , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/genetics , ErbB Receptors/metabolism , Female , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/mortality , Lung Neoplasms/pathology , Male , Mice , Mice, Nude , Middle Aged , Neoplasm Staging , Neovascularization, Pathologic/mortality , Neovascularization, Pathologic/pathology , Neovascularization, Pathologic/surgery , Oxidation-Reduction , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogene Proteins c-akt/metabolism , RNA, Small Interfering/genetics , RNA, Small Interfering/metabolism , Signal Transduction , Survival Analysis , Tumor Burden , Xenograft Model Antitumor AssaysABSTRACT
OBJECTIVE: To study the chemical constituents from Macaranga denticulata Root. METHODS: The chemical constituents were isolated and purified by silica-gel column chromatography and recrystallization, and their structures were identified by physicochemical properties and spectral data. RESULTS: Nine compounds were isolated and identified as: gheddic acid (1), aleuritolic acid-3-acetate (2), ß-sitosterol (3), stigmast-4-en-6ß-ol-3 -one (4), 2α-hydroxyaleuritolic acid 3-p-hydroxybenzoate (5), scopoletin (6), daucosterol (7), 2, 6-dimethoxy-1,4-benzoquinone (8) and maslinic acid(9). CONCLUSION: Compounds 1-9 are obtained from this plant for the first time.
Subject(s)
Euphorbiaceae/chemistry , Phytochemicals/analysis , Plant Roots/chemistry , Plants, Medicinal/chemistry , Benzoquinones , Parabens , Scopoletin , Sitosterols , Stigmasterol/analogs & derivatives , TriterpenesABSTRACT
OBJECTIVE: To study the chemical constituents of Desmodium caudatum. METHODS: Silica column chromatography, Sephadex LH-20 column chromatography and recrystallization were used to separate and purify the chemical composition of Desmodium caudatum. Their chemical structures were identified by infrared spectrum (IR), mass spectrum (MS), nuclear magnetic resonance (NMR) and other physicochemical methods. RESULTS: Twelve compounds were isolated and identified as lacceroic acid(1), gheddic acid(2), stigmasterol(3), betulin(4), citrusinol(5), yukovanol(6), kaempferol(7), protocatechuic acid(8), sophocarpine(9), matrine(10), N, Ndimethyltryptamine(11) and 5-hydroxy-N,N-dimethyltryptamine(12). CONCLUSION: Compounds 1, 2, 4 and 8-12 are isolated from this plant for the first time.
