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β-Elemene Inhibits Cell Proliferation by Regulating the Expression and Activity of Topoisomerases I and IIα in Human Hepatocarcinoma HepG-2 Cells.

Gong M, Liu Y, Zhang J, Gao YJ, Zhai PP, Su X, Li X, Li Y, Hou L, Cui XN - Biomed Res Int (2015)

Bottom Line: To investigate the effects of β-Elemene (β-ELE) on the proliferation, apoptosis, and topoisomerase I (TOPO I) and topoisomerase IIα (TOPO IIα) expression and activity of human hepatocarcinoma HepG-2 cells.After treatment with β-ELE, morphological alterations of HepG-2 cells were observed under an inverted microscope.Supercoiled pBR322 and kDNA were also used to determine the direct effect of β-ELE on DNA breaks. β-ELE significantly inhibited HepG-2 cell proliferation in a dose- and time-dependent manner. β-ELE also induced tumor cell arrest at S phase, induced cell apoptosis, and downregulated the protein expression of TOPO I and TOPO IIα in a dose-dependent manner. β-ELE also inhibited TOPO I- and TOPO IIα-mediated DNA relaxation but did not directly induce DNA breakage at any concentration. β-ELE could inhibit the proliferation of HepG-2 cells and interfere with the expression and activity of TOPO I and TOPO IIα.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, China.

ABSTRACT

Objective: To investigate the effects of β-Elemene (β-ELE) on the proliferation, apoptosis, and topoisomerase I (TOPO I) and topoisomerase IIα (TOPO IIα) expression and activity of human hepatocarcinoma HepG-2 cells.

Methods: After treatment with β-ELE, morphological alterations of HepG-2 cells were observed under an inverted microscope. Cell proliferation was assessed using an MTT assay, cell cycles were analyzed using flow cytometry, and apoptosis was detected by Annexin V/PI staining. The expression of TOPO I and TOPO IIα was analyzed by Western blot techniques, and their activity was measured using the TOPO I-mediated, supercoiled pBR322 DNA relaxation and TOPO IIα-mediated Kinetoplast DNA (kDNA) decatenation assays, respectively. Supercoiled pBR322 and kDNA were also used to determine the direct effect of β-ELE on DNA breaks.

Results: β-ELE significantly inhibited HepG-2 cell proliferation in a dose- and time-dependent manner. β-ELE also induced tumor cell arrest at S phase, induced cell apoptosis, and downregulated the protein expression of TOPO I and TOPO IIα in a dose-dependent manner. β-ELE also inhibited TOPO I- and TOPO IIα-mediated DNA relaxation but did not directly induce DNA breakage at any concentration.

Conclusion: β-ELE could inhibit the proliferation of HepG-2 cells and interfere with the expression and activity of TOPO I and TOPO IIα.

No MeSH data available.


Related in: MedlinePlus

Structure of β-Elemene.
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Related In: Results  -  Collection


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fig1: Structure of β-Elemene.

Mentions: β-Elemene (beta-1-methyl-1-vinyl-2,4-di-isopropenyl-cyclohexane; β-ELE), a noncytotoxic antitumor element isolated from the traditional Chinese herbal medicine Rhizoma Zedoariae (Figure 1), has been approved by the State Food and Drug Administration of China for tumor therapy for decades. As a noncytotoxic agent with high antitumor efficacy and low cellular toxicity to normal tissues, β-ELE has been commonly used in Chinese clinical practice and has exhibited a broad spectrum of antitumor activity. Furthermore, β-ELE demonstrates efficacy in tumors that are unresponsive to chemotherapy, such as hepatocarcinoma, brain gliomas, lung cancer, ovarian carcinoma, and breast cancer [4–8]. No bone marrow suppression or drug resistance has been reported in clinical observations; on the contrary, the immunity and quality of life of patients improved during β-ELE therapy [9]. Clinical data also showed synergistic effects of β-ELE in combination with chemotherapy. β-ELE is now being evaluated in clinical trials in the United States [10]. Basic studies illustrated that β-ELE could pass through the blood-brain barrier [11] and increase tumor cell immunogenicity, at least in part, by inducing elevated expression of heat shock protein 70 on the tumor cell surface [9] and circumventing chemoresistance [12]. However, no data have shown the effect of β-ELE on topoisomerases. Topoisomerases, including TOPO I and TOPO II, are key enzymes in the regulation of nucleic acid topology configurations, and topoisomerases have become important targets for antitumor drugs [13]. Mammalian cells express two types of TOPO II enzymes, TOPO IIα and TOPO IIβ, but only TOPO IIα is essential for cellular viability due to its fundamental role in DNA metabolism and chromatin organization during interphase and mitosis. Moreover, TOPO IIα is one of the most important drug targets in cancer chemotherapy [1, 2, 14].


β-Elemene Inhibits Cell Proliferation by Regulating the Expression and Activity of Topoisomerases I and IIα in Human Hepatocarcinoma HepG-2 Cells.

Gong M, Liu Y, Zhang J, Gao YJ, Zhai PP, Su X, Li X, Li Y, Hou L, Cui XN - Biomed Res Int (2015)

Structure of β-Elemene.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4499621&req=5

fig1: Structure of β-Elemene.
Mentions: β-Elemene (beta-1-methyl-1-vinyl-2,4-di-isopropenyl-cyclohexane; β-ELE), a noncytotoxic antitumor element isolated from the traditional Chinese herbal medicine Rhizoma Zedoariae (Figure 1), has been approved by the State Food and Drug Administration of China for tumor therapy for decades. As a noncytotoxic agent with high antitumor efficacy and low cellular toxicity to normal tissues, β-ELE has been commonly used in Chinese clinical practice and has exhibited a broad spectrum of antitumor activity. Furthermore, β-ELE demonstrates efficacy in tumors that are unresponsive to chemotherapy, such as hepatocarcinoma, brain gliomas, lung cancer, ovarian carcinoma, and breast cancer [4–8]. No bone marrow suppression or drug resistance has been reported in clinical observations; on the contrary, the immunity and quality of life of patients improved during β-ELE therapy [9]. Clinical data also showed synergistic effects of β-ELE in combination with chemotherapy. β-ELE is now being evaluated in clinical trials in the United States [10]. Basic studies illustrated that β-ELE could pass through the blood-brain barrier [11] and increase tumor cell immunogenicity, at least in part, by inducing elevated expression of heat shock protein 70 on the tumor cell surface [9] and circumventing chemoresistance [12]. However, no data have shown the effect of β-ELE on topoisomerases. Topoisomerases, including TOPO I and TOPO II, are key enzymes in the regulation of nucleic acid topology configurations, and topoisomerases have become important targets for antitumor drugs [13]. Mammalian cells express two types of TOPO II enzymes, TOPO IIα and TOPO IIβ, but only TOPO IIα is essential for cellular viability due to its fundamental role in DNA metabolism and chromatin organization during interphase and mitosis. Moreover, TOPO IIα is one of the most important drug targets in cancer chemotherapy [1, 2, 14].

Bottom Line: To investigate the effects of β-Elemene (β-ELE) on the proliferation, apoptosis, and topoisomerase I (TOPO I) and topoisomerase IIα (TOPO IIα) expression and activity of human hepatocarcinoma HepG-2 cells.After treatment with β-ELE, morphological alterations of HepG-2 cells were observed under an inverted microscope.Supercoiled pBR322 and kDNA were also used to determine the direct effect of β-ELE on DNA breaks. β-ELE significantly inhibited HepG-2 cell proliferation in a dose- and time-dependent manner. β-ELE also induced tumor cell arrest at S phase, induced cell apoptosis, and downregulated the protein expression of TOPO I and TOPO IIα in a dose-dependent manner. β-ELE also inhibited TOPO I- and TOPO IIα-mediated DNA relaxation but did not directly induce DNA breakage at any concentration. β-ELE could inhibit the proliferation of HepG-2 cells and interfere with the expression and activity of TOPO I and TOPO IIα.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, China.

ABSTRACT

Objective: To investigate the effects of β-Elemene (β-ELE) on the proliferation, apoptosis, and topoisomerase I (TOPO I) and topoisomerase IIα (TOPO IIα) expression and activity of human hepatocarcinoma HepG-2 cells.

Methods: After treatment with β-ELE, morphological alterations of HepG-2 cells were observed under an inverted microscope. Cell proliferation was assessed using an MTT assay, cell cycles were analyzed using flow cytometry, and apoptosis was detected by Annexin V/PI staining. The expression of TOPO I and TOPO IIα was analyzed by Western blot techniques, and their activity was measured using the TOPO I-mediated, supercoiled pBR322 DNA relaxation and TOPO IIα-mediated Kinetoplast DNA (kDNA) decatenation assays, respectively. Supercoiled pBR322 and kDNA were also used to determine the direct effect of β-ELE on DNA breaks.

Results: β-ELE significantly inhibited HepG-2 cell proliferation in a dose- and time-dependent manner. β-ELE also induced tumor cell arrest at S phase, induced cell apoptosis, and downregulated the protein expression of TOPO I and TOPO IIα in a dose-dependent manner. β-ELE also inhibited TOPO I- and TOPO IIα-mediated DNA relaxation but did not directly induce DNA breakage at any concentration.

Conclusion: β-ELE could inhibit the proliferation of HepG-2 cells and interfere with the expression and activity of TOPO I and TOPO IIα.

No MeSH data available.


Related in: MedlinePlus