Ellipticine

IC50 = 0.99 μM for L1210 lymphocytic leukemia cells [1]

Plant alkaloid ellipticine shows antitumor, mutagenic and cytotoxic activities by inhibition of DNA topoisomerase II activity. DNA topoisomerase II regulates the overwinding or underwinding of DNA by cuting DNA double helix, passing another unbroken DNA helix through it, and then reannealing the cut strands.

In vitro: Treatment mammalian DNA topoisomerase II reaction mixture with ellipticine resulted in the stimulation of DNA cleavage. The drug-stimulation of DNA cleavage is related to the formation of a ternary complex between topoisomerase II, DNA, and ellipticine. Ellipticine dose not inhibit enzyme-mediated DNA religation, however, it stimulates DNA breakage by enhancing the forward rate of cleavage [2]. Ellipticine showed growth inhibition activity on L1210 lymphocytic leukemia cells with a IC50 of 0.99 μM [1].

In vivo: Ellipticine was evaluated in P. berghei infected mice in the 4-day suppressive test. Ellipticine had a 100% inhibition versus controls on days 5 and 7 at an oral dose of 50 mg/kg/day, and the mean survival time (MST) was more than 40 days [3].

Clinical trial: Several ellipticine derivatives have been validated in clinical trials, however, due to adverse side-effects, no progress has be reported.

References:
[1] Paoletti C, Cros S, Xuong ND, Lecointe P, Moisand A.  Comparative cytotoxic and antitumoral effects of ellipticine derivatives on mouse L 1210 leukemia. Chem Biol Interact. 1979 Apr;25(1):45-58.
[2] Tewey KM, Chen GL, Nelson EM, Liu LF.  Intercalative antitumor drugs interfere with the breakage-reunion reaction of mammalian DNA topoisomerase II. J Biol Chem. 1984 Jul 25;259(14):9182-7.
[3] Rocha e Silva LF, Montoia A, Amorim RC, Melo MR, Henrique MC, Nunomura SM, Costa MR, Andrade Neto VF, Costa DS, Dantas G, Lavrado J, Moreira R, Paulo A, Pinto AC, Tadei WP, Zacardi RS, Eberlin MN, Pohlit AM.  Comparative in vitro and in vivo antimalarial activity of the indole alkaloids ellipticine, olivacine, cryptolepine and a synthetic cryptolepine analog. Phytomedicine. 2012 Dec 15;20(1):71-6.

Nuclear quantum effects in a HIV/cancer inhibitor: The case of ellipticine.[Pubmed:27908111]

J Chem Phys. 2016 Nov 28;145(20):205102.

Ellipticine is a natural product that is currently being actively investigated for its inhibitory cancer and HIV properties. Here we use path-integral molecular dynamics coupled with excited state calculations to characterize the role of nuclear quantum effects on the structural and electronic properties of Ellipticine in water, a common biological solvent. Quantum effects collectively enhance the fluctuations of both light and heavy nuclei of the covalent and hydrogen bonds in Ellipticine. In particular, for the Ellipticine-water system, where the proton donor and acceptor have different proton affinities, we find that nuclear quantum effects (NQEs) strengthen both the strong and the weak H bonds. This is in contrast to what is observed for the cases where the proton affinity of the donors and acceptors is same. These structural fluctuations cause a significant red-shift in the absorption spectra and an increase in the broadening, bringing it into closer agreement with the experiments. Our work shows that nuclear quantum effects alter both qualitatively and quantitatively the optical properties of this biologically relevant system and highlights the importance of the inclusion of these effects in the microscopic understanding of their optical properties. We propose that isotopic substitution will produce a blue shift and a reduction in the broadening of the absorption peak.

Effectiveness of human cytochrome P450 3A4 present in liposomal and microsomal nanoparticles in formation of covalent DNA adducts by ellipticine.[Pubmed:28263536]

Neuro Endocrinol Lett. 2016 Dec 18;37(Suppl1):95-102.

OBJECTIVES: Ellipticine is an anticancer agent that functions through multiple mechanisms participating in cell cycle arrest and initiation of apoptosis. This drug forms covalent DNA adducts after its enzymatic activation with cytochrome P450 (CYP), which is one of the most important Ellipticine DNA-damaging mechanisms of its cytotoxic effects. The improvements of cancer treatment are the major challenge in oncology research. Nanotransporters (nanoparticles) are promising approaches to target tumor cells, frequently leading to improve drug therapeutic index. Ellipticine has already been prepared in nanoparticle forms. However, since its anticancer efficiency depends on the CYP3A4-mediated metabolism in cancer cells, the aim of our research is to develop nanoparticles containing this enzyme that can be transported to tumor cells, thereby potentiating Ellipticine cytotoxicity. METHODS: The CYP3A4 enzyme encapsulated into two nanoparticle forms, liposomes and microsomes, was tested to activate Ellipticine to its reactive species forming covalent DNA adducts. Ellipticine-derived DNA adducts were determined by the 32P-postlabeling method. RESULTS: The CYP3A4 enzyme both in the liposome and microsome nanoparticle forms was efficient to activate Ellipticine to species forming DNA adducts. Two DNA adducts, which are formed from Ellipticine metabolites 12-hydroxy- and 13-hydroxyEllipticine generated by its oxidation by CYP3A4, were formed by both CYP3A4 nanoparticle systems. A higher effectiveness of CYP3A4 in microsomal than in liposomal nanoparticles to form Ellipticine-DNA adducts was found. CONCLUSION: Further testing in a suitable cancer cell model is encouraged to investigate whether the DNA-damaging effects of Ellipticine after its activation by CYP3A4 nanoparticle forms are appropriate for active targeting of this enzyme to specific cancer cells.

ATM participates in the regulation of viability and cell cycle via ellipticine in bladder cancer.[Pubmed:28138703]

Mol Med Rep. 2017 Mar;15(3):1143-1148.

Ellipticine, an alkaloid isolated from Apocyanaceae plants, has been demonstrated to exhibit antitumor activity in several cancers. However, the effect and the mechanisms underlying its action have not been investigated in human bladder cancer cells. The aim of the present study was to investigate the effect and mechanism of Ellipticine on the behavior of T24 bladder cancer cells. T24 cells were treated with varying concentrations and durations of Ellipticine. Cell viability was evaluated by Cell Counting Kit8 assay. Cell motility was analyzed by Transwell migration assay. Flow cytometry, reverse transcriptionquantitative polymerase chain reaction and western blot analyses were performed to detect the cell cycle and signaling pathways involved. The results demonstrated that Ellipticine suppressed proliferation and inhibited the migration ability of T24 bladder cancer cells in a dose and timedependent manner, and resulted in G2/M cell cycle arrest. The mechanism of this action was demonstrated to be due to Ellipticinetriggered activation of the ATM serine/threonine kinase pathway. These data therefore suggest that Ellipticine may be effective towards treating human bladder cancer.

Inhibition of p53 protein phosphorylation by 9-hydroxyellipticine: a possible anticancer mechanism.[Pubmed:7591958]

Jpn J Cancer Res. 1995 Sep;86(9):819-27.

Abnormality of p53, a tumor suppressor gene, is considered to be a potential cause of malignancy. We found that Ellipticine and 9-hydroxyEllipticine (9HE), antitumor alkaloids, caused selective inhibition of p53 protein phosphorylation in Lewis lung carcinoma and SW480 (human colon cancer cell line) in a concentration-dependent manner from 0.1 to 100 microM. 9HE suppressed cdk2 kinase activity concentration-dependently from 1 to 100 microM. By contrast, the inhibition of p53 protein phosphorylation by elliptinium and elliprabin (N2 substituted derivatives of 9HE) was very weak. A good correlation was observed between p53 phosphorylation inhibition and cytotoxic activity of these agents in terms of concentration-response relationships, suggesting that inhibition of p53 protein phosphorylation via kinase inhibition may be involved in the anticancer mechanism of these agents. In addition, this study demonstrated that brief exposure to 9HE caused apoptosis of cancer cells. It is suggested that accumulation of dephosphorylated mutant p53 may induce apoptosis.

Intercalative antitumor drugs interfere with the breakage-reunion reaction of mammalian DNA topoisomerase II.[Pubmed:6086625]

J Biol Chem. 1984 Jul 25;259(14):9182-7.

Many intercalative antitumor drugs have been shown to induce reversible protein-linked DNA breaks in cultured mammalian cells. Using purified mammalian DNA topoisomerase II, we have demonstrated that the antitumor drugs Ellipticine and 2-methyl-9-hydroxyEllipticine (2-Me-9-OH-E+) can produce reversible protein-linked DNA breaks in vitro. 2-Me-9-OH-E+ which is more cytotoxic toward L1210 cells and more active against experimental tumors than Ellipticine is also more effective in stimulating DNA cleavage in vitro. Similar to the effect of 4'-(9-acridinylamino)-methanesulfon-m-anisidide (m-AMSA) on topoisomerase II in vitro, the mechanism of DNA breakage induced by Ellipticines is most likely due to the drug stabilization of a cleavable complex formed between topoisomerase II and DNA. Protein denaturant treatment of the cleavable complex results in DNA breakage and covalent linking of one topoisomerase II subunit to each 5'-end of the cleaved DNA. Cleavage sites on pBR322 DNA produced by Ellipticine or 2-Me-9-OH-E+ treatment mapped at the same positions. However, many of these cleavage sites are distinctly different from those produced by the antitumor drug m-AMSA which also targets at topoisomerase II. Our results thus suggest that although mammalian DNA topoisomerase II may be a common target of these antitumor drugs, drug-DNA-topoisomerase interactions for different antitumor drugs may be different.