| In vitro: |
| Biochimica et biophysica acta, 2011, 1814(1):175-185. | | Cytochrome P450- and peroxidase-mediated oxidation of anticancer alkaloid ellipticine dictates its anti-tumor efficiency.[Reference: WebLink] | An antineoplastic alkaloid Ellipticine is a prodrug, whose pharmacological efficiency is dependent on its cytochrome P450 (CYP)- and/or peroxidase-mediated activation in target tissues. The aim of this review was to summarize our knowledge on the molecular mechanisms of Ellipticine action in the cancer cells.
METHODS AND RESULTS:
The CYP-mediated Ellipticine metabolites 9-hydroxy- and 7-hydroxyEllipticine and the product of Ellipticine oxidation by peroxidases, the Ellipticine dimer, are the detoxication metabolites of this compound. In contrast, two carbenium ions, Ellipticine-13-ylium and Ellipticine-12-ylium, derived from two activation Ellipticine metabolites, 13-hydroxyEllipticine and 12-hydroxyEllipticine, generate two major deoxyguanosine adducts in DNA found in the human breast adenocarcinoma MCF-7 cells, leukemia HL-60 and CCRF-CEM cells, neuroblastoma IMR-32, UKF-NB-3, and UKF-NB-4 cells and glioblastoma U87MG cells in vitro and in rat breast carcinoma in vivo. Formation of these covalent DNA adducts by Ellipticine is the predominant mechanism of its cytotoxicity and anti-tumor activity to these cancer cell lines. Ellipticine is also an inducer of CYP1A, 1B1, and 3A4 enzymes in the cancer cells and/or in vivo in rats exposed to this compound, thus modulating its own pharmacological efficiencies.
CONCLUSIONS:
The study forms the basis to further predict the susceptibility of human cancers to Ellipticine and suggests that this alkaloid for treatment in combination with CYP and/or peroxidase gene transfer increasing the anticancer potential of this prodrug. It also suggests Ellipticine reactive metabolites 13-hydroxyEllipticine and 12-hydroxyEllipticine to be good candidates for targeting to tumors absent from the CYP and peroxidase activation enzymes. | | Anti Cancer Drugs, 2005, 16(7):789-795. | | The anti-proliferative inhibition of ellipticine in human breast mda-mb-231 cancer cells is through cell cycle arrest and apoptosis induction.[Reference: WebLink] | Ellipticine, a cytotoxic plant alkaloid, is known to inhibit topoisomerase II.
METHODS AND RESULTS:
Here we report the mechanism of apoptosis induction and cell cycle arrest by Ellipticine in human breast MDA-MB-231 cancer cells. Ellipticine treatment arrested MDA-MB-231 cells at the G2/M phase after 6 h of treatment. This effect was strongly associated with a concomitant decrease in the level of cyclin B1, Cdc25 and Cdc2, and increase in phospho-Cdc2 (Tyr15). In addition, Ellipticine also induced apoptosis in MDA-MB-231 cells, as determined by using both DNA fragmentation and Annexin-V staining assay. Ellipticine increased the expression of Bax, but decreased the level of Bcl-2, Bcl-XL and X-linked inhibitor of apoptosis protein (XIAP), and subsequently triggered the mitochondrial apoptotic pathway (release of cytochrome c, and activation of caspase-9 and -3). In addition, pre-treatment of cells with caspase-9 inhibitor inhibited Ellipticine-induced cell proliferation and apoptosis, indicating that caspase-9 activation was involved in MDA-MB-231 cell apoptosis induced by Ellipticine.
CONCLUSIONS:
Taken together, our study suggests that the inhibition of cell cycle progression signaling and initiation of the mitochondrial apoptotic system may participate in the anti-proliferative activity of Ellipticine in MDA-MB-231 cells. |
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Cell. 2018 Jan 11;172(1-2):249-261.e12. doi: 10.1016/j.cell.2017.12.019.IF=36.216(2019)
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