Antitumor Effect of <i>Glandora rosmarinifolia</i> (Boraginaceae) Essential Oil through Inhibition of the Activity of the Topo II Enzyme in Acute Myeloid Leukemia
It was previously shown that the antitumor and cytotoxic activity of the essential oil (EO) extracted from the aerial parts of <i>Glandora rosmarinifolia</i> appears to involve a pro-oxidant mechanism in hepatocellular carcinoma (HCC) and in triple-negative breast cancer (TNBC) cell line...
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MDPI AG
2022-06-01
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| author | Manuela Labbozzetta Paola Poma Chiara Occhipinti Maurizio Sajeva Monica Notarbartolo |
| author_facet | Manuela Labbozzetta Paola Poma Chiara Occhipinti Maurizio Sajeva Monica Notarbartolo |
| author_sort | Manuela Labbozzetta |
| collection | DOAJ |
| description | It was previously shown that the antitumor and cytotoxic activity of the essential oil (EO) extracted from the aerial parts of <i>Glandora rosmarinifolia</i> appears to involve a pro-oxidant mechanism in hepatocellular carcinoma (HCC) and in triple-negative breast cancer (TNBC) cell lines. Its most abundant compound is a hydroxy-methyl-naphthoquinone isomer. Important pharmacological activities, such as antitumor, antibacterial, antifungal, antiviral and antiparasitic activities, are attributed to naphthoquinones, probably due to their pro-oxidant or electrophilic potential; for some naphthoquinones, a mechanism of action of topoisomerase inhibition has been reported, in which they appear to act both as catalytic inhibitors and as topoisomerase II poisons. Our aim was to evaluate the cytotoxic activity of the essential oil on an acute myeloid leukemia cell line HL-60 and on its multidrug-resistant (MDR) variant HL-60R and verify its ability to interfere with topoisomerase II activity. MTS assay showed that <i>G. rosmarinifolia</i> EO induced a decrease in tumor cell viability equivalent in the two cell lines; this antitumor effect could depend on the pro-oxidant activity of EO in both cell lines. Furthermore, <i>G. rosmarinifolia</i> EO reduced the activity of Topo II in the nuclear extracts of HL-60 and HL-60R cells, as inferred from the inability to convert the kinetoplast DNA into the decatenated form and then not inducing linear kDNA. Confirming this result, flow cytometric analysis proved that EO induced a G<sub>0</sub>-G<sub>1</sub> phase arrest, with cell reduction in the S-phase. In addition, the combination of EO with etoposide showed a good potentiation effect in terms of cytotoxicity in both cell lines. Our results highlight the antitumor activity of EO in the HL-60 cell line and its MDR variant with a peculiar mechanism as a Topo II modulator. Unlike etoposide, EO does not cause stabilization of a covalent Topo II-DNA intermediate but acts as a catalytic inhibitor. These data make <i>G. rosmarinifolia</i> EO a potential anticancer drug candidate due to its cytotoxic action, which is not affected by multidrug resistance. |
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| spelling | doaj.art-8547277b93ef40f2bca5ac95a55943192023-12-03T14:13:47ZengMDPI AGMolecules1420-30492022-06-012713420310.3390/molecules27134203Antitumor Effect of <i>Glandora rosmarinifolia</i> (Boraginaceae) Essential Oil through Inhibition of the Activity of the Topo II Enzyme in Acute Myeloid LeukemiaManuela Labbozzetta0Paola Poma1Chiara Occhipinti2Maurizio Sajeva3Monica Notarbartolo4Department of Biological, Chemical and Pharmaceutical Science and Technology (STEBICEF), University of Palermo, 90128 Palermo, ItalyDepartment of Biological, Chemical and Pharmaceutical Science and Technology (STEBICEF), University of Palermo, 90128 Palermo, ItalyDepartment of Biological, Chemical and Pharmaceutical Science and Technology (STEBICEF), University of Palermo, 90128 Palermo, ItalyDepartment of Biological, Chemical and Pharmaceutical Science and Technology (STEBICEF), University of Palermo, 90128 Palermo, ItalyDepartment of Biological, Chemical and Pharmaceutical Science and Technology (STEBICEF), University of Palermo, 90128 Palermo, ItalyIt was previously shown that the antitumor and cytotoxic activity of the essential oil (EO) extracted from the aerial parts of <i>Glandora rosmarinifolia</i> appears to involve a pro-oxidant mechanism in hepatocellular carcinoma (HCC) and in triple-negative breast cancer (TNBC) cell lines. Its most abundant compound is a hydroxy-methyl-naphthoquinone isomer. Important pharmacological activities, such as antitumor, antibacterial, antifungal, antiviral and antiparasitic activities, are attributed to naphthoquinones, probably due to their pro-oxidant or electrophilic potential; for some naphthoquinones, a mechanism of action of topoisomerase inhibition has been reported, in which they appear to act both as catalytic inhibitors and as topoisomerase II poisons. Our aim was to evaluate the cytotoxic activity of the essential oil on an acute myeloid leukemia cell line HL-60 and on its multidrug-resistant (MDR) variant HL-60R and verify its ability to interfere with topoisomerase II activity. MTS assay showed that <i>G. rosmarinifolia</i> EO induced a decrease in tumor cell viability equivalent in the two cell lines; this antitumor effect could depend on the pro-oxidant activity of EO in both cell lines. Furthermore, <i>G. rosmarinifolia</i> EO reduced the activity of Topo II in the nuclear extracts of HL-60 and HL-60R cells, as inferred from the inability to convert the kinetoplast DNA into the decatenated form and then not inducing linear kDNA. Confirming this result, flow cytometric analysis proved that EO induced a G<sub>0</sub>-G<sub>1</sub> phase arrest, with cell reduction in the S-phase. In addition, the combination of EO with etoposide showed a good potentiation effect in terms of cytotoxicity in both cell lines. Our results highlight the antitumor activity of EO in the HL-60 cell line and its MDR variant with a peculiar mechanism as a Topo II modulator. Unlike etoposide, EO does not cause stabilization of a covalent Topo II-DNA intermediate but acts as a catalytic inhibitor. These data make <i>G. rosmarinifolia</i> EO a potential anticancer drug candidate due to its cytotoxic action, which is not affected by multidrug resistance.https://www.mdpi.com/1420-3049/27/13/4203EOsnapthoquinoneTopo IImultidrug resistance |
| spellingShingle | Manuela Labbozzetta Paola Poma Chiara Occhipinti Maurizio Sajeva Monica Notarbartolo Antitumor Effect of <i>Glandora rosmarinifolia</i> (Boraginaceae) Essential Oil through Inhibition of the Activity of the Topo II Enzyme in Acute Myeloid Leukemia Molecules EOs napthoquinone Topo II multidrug resistance |
| title | Antitumor Effect of <i>Glandora rosmarinifolia</i> (Boraginaceae) Essential Oil through Inhibition of the Activity of the Topo II Enzyme in Acute Myeloid Leukemia |
| title_full | Antitumor Effect of <i>Glandora rosmarinifolia</i> (Boraginaceae) Essential Oil through Inhibition of the Activity of the Topo II Enzyme in Acute Myeloid Leukemia |
| title_fullStr | Antitumor Effect of <i>Glandora rosmarinifolia</i> (Boraginaceae) Essential Oil through Inhibition of the Activity of the Topo II Enzyme in Acute Myeloid Leukemia |
| title_full_unstemmed | Antitumor Effect of <i>Glandora rosmarinifolia</i> (Boraginaceae) Essential Oil through Inhibition of the Activity of the Topo II Enzyme in Acute Myeloid Leukemia |
| title_short | Antitumor Effect of <i>Glandora rosmarinifolia</i> (Boraginaceae) Essential Oil through Inhibition of the Activity of the Topo II Enzyme in Acute Myeloid Leukemia |
| title_sort | antitumor effect of i glandora rosmarinifolia i boraginaceae essential oil through inhibition of the activity of the topo ii enzyme in acute myeloid leukemia |
| topic | EOs napthoquinone Topo II multidrug resistance |
| url | https://www.mdpi.com/1420-3049/27/13/4203 |
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