Ellipticine induces apoptosis in human endometrial cancer cells: The potential involvement of reactive oxygen species and mitogen-activated protein kinases

Kim, Ji Young; Lee, Seung Gee; Chung, Jin Yong; Kim, Yoon Jae; Park, Ji Eun; Koh, Hyungjong; Han, Myoungseok; Park, Young Chul; Yoo, Young Hyun; Kim, Jong Min

doi:10.1016/j.tox.2011.07.014

Cited by 51 publications

(35 citation statements)

References 41 publications

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“…This is consistent with published results on the distribution of ellipticine [34]. Many chemotherapeutics, including ellipticine [24] increase oxidative stress in cells [35]. Several studies have demonstrated that ROS cause a G2/M arrest [20,[36][37][38][39].…”

Section: Discussionsupporting

confidence: 91%

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Ellipticine derivative induces potent cytostatic effect in acute myeloid leukaemia cells

Russell

O'Sullivan²,

Miller³

et al. 2014

Invest New Drugs

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A panel of novel ellipticine isomers were designed and synthesised with the aim of evaluating their anti-cancer effects on selected leukaemia cell lines. A preliminary NCI 60-cell screen demonstrated that these compounds display promising anti-tumour activity across a number of different cell types. We have consequently examined the effect of these derivatives in detail on the Acute Myeloid Leukaemia (AML) cell line, MV4-11. Cell cycle analyses revealed that the compounds had a range of distinctive cell cycle effects. 7-Hydroxyisoellipticine showed the most promise with respect to cytostatic activity. We demonstrated that this compound inhibited proliferation of leukaemia cells by preventing cells from progressing from G2 phase into mitosis over a period of 24 h at a concentration of 5 μM. Our research suggests that this is mediated by an induction of reactive oxygen species (ROS), which in turn activates the DNA damage response pathway. As a result of the activation of p53, cyclin B1 is inhibited. The induction of this pathway leads to apoptosis which is seen at 48 h using the same dose of 7-hydroxyisoellipticine. This study provides for the first time detailed cellular information on the potential use of isoellipticines as chemotherapeutic agents.

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Section: Discussionsupporting

confidence: 91%

“…6a). Recently, ellipticine has been shown to elevate intracellular reactive oxygen species (ROS) levels [24], and so ROS levels post 7-hydroxyisoellipticine treatment were measured. Dihydroethidium has been used extensively in cell culture experiments to evaluate ROS production [25].…”

Section: Resultsmentioning

confidence: 99%

Ellipticine derivative induces potent cytostatic effect in acute myeloid leukaemia cells

Russell

O'Sullivan²,

Miller³

et al. 2014

Invest New Drugs

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“…The cell viability inhibition analysis on A431 cells at doses ranging from 10 µM to 150 µM, reported IC 50 concentrations of 36 µM and 28 µM for NBQ 38 and NBQ 95 respectively and although lower than those reported for ellipticine, in other cell lines (up to 10 µM) [36,37] we consider this to be in close (µM) range. In terms of the mode of action similarities where also observed between ellipticine and the NBQs.…”

Section: Discussioncontrasting

confidence: 48%

Novel Nitrobenzazolo[3,2-a]quinolinium Salts Induce Cell Death through a Mechanism Involving DNA Damage, Cell Cycle Changes, and Mitochondrial Permeabilization

Vélez¹,

Cox²,

Rosado-Berrios³

et al. 2013

OJApo

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This study reports the capacity of three nitro substituted benzazolo[3,2-a]quinolinium salts NBQs: NBQ 95 (NSC-763304), NBQ 38 (NSC 763305), and NBQ 97 (NSC-763306) as potential antitumor agents. NBQ’s are unnatural alkaloids possessing a positive charge that could facilitate interaction with cell organelles. The anticancer activities of these compounds were evaluated through the National Cancer Institute (NCI) 60 cell line screening which represents diverse histologies. The screening was performed at 10 µM on all cell lines. Results from the NCI screening indicated cytotoxicity activity on six cell lines. In order to explore a possible mechanism of action, a detailed biological activity study of NBQ 95 and NBQ 38 was performed on A431 human epidermoid carcinoma cells to determine an apoptotic pathway involving, cell cycle changes, DNA fragmentation, mutations, mitochondrial membrane permeabilization and caspases activation. DNA fragmentation, cell cycle effects, mutagenesis, mitochondrial permeabilization and activation of caspases were determined by fluorimetry and differential imaging. Our data showed that A431 growth was inhibited with an average IC50 of 30 µM. In terms of the mechanism, these compounds interacted with DNA causing fragmentation and cell cycle arrest at sub G0/G1 stage. Mutagenesis was higher for NBQ 38 and moderate for NBQ 95 Mitochon-drial permeabilization was observed with NBQ 38 and slightly for NBQ 95. Both compounds caused activation of Caspases 3 and 7 suggesting an apoptotic cell death pathway through an intrinsic mechanism. This study reports evidence of the toxicity of these novel compounds with overlapping structural and mechanistic similarities to ellipticine, a known anti-tumor compound.

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“…This effect was attributed to various activities of ellipticines including antitopoisomerase activity (48), Fas ligand stimulatory activity (47), induction of reactive-oxygen species (42), and DNA adduct formation (49). Pol-I inhibition induces cell cycle arrest and apoptosis (6,7,40,50,51) and our findings that ellipticines inhibit rDNA transcription in cells, suggest that this is the main, underlying reason for the ellipticines anti-proliferative activity.…”

Section: Discussionmentioning

confidence: 65%

“…It has been shown previously that ellipticines induce cell cycle arrest and apoptosis in cells (20,42,(45)(46)(47). This effect was attributed to various activities of ellipticines including antitopoisomerase activity (48), Fas ligand stimulatory activity (47), induction of reactive-oxygen species (42), and DNA adduct formation (49).…”

Section: Discussionmentioning

confidence: 90%

Old Drug, New Target

Andrews

Panova

Normand

et al. 2013

Journal of Biological Chemistry

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Background: rRNA synthesis by Pol-I is a key and rate-limiting stage of ribosome biogenesis. Results: Ellipticines selectively inhibit Pol-I transcription both in vitro and in cells. Conclusion: Interactions of essential transcription factor SL1 with the promoter is the primary target of the drugs. Significance: This study reveals a novel class of Pol-I inhibitors and analyses their mechanism of action.

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Ellipticine induces apoptosis in human endometrial cancer cells: The potential involvement of reactive oxygen species and mitogen-activated protein kinases

Cited by 51 publications

References 41 publications

Ellipticine derivative induces potent cytostatic effect in acute myeloid leukaemia cells

Ellipticine derivative induces potent cytostatic effect in acute myeloid leukaemia cells

Novel Nitrobenzazolo[3,2-a]quinolinium Salts Induce Cell Death through a Mechanism Involving DNA Damage, Cell Cycle Changes, and Mitochondrial Permeabilization

Old Drug, New Target

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