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Cytotoxic flavonoids and isoflavonoids from Erythrina sigmoidea towards multi-factorial drug resistant cancer cells

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Summary

Introduction Continuous efforts from scientists of diverse fields are necessary not only to better understand the mechanism by which multidrug resistant (MDR) cancer cells occur, but also to boost the discovery of new cytotoxic compounds. This work was designed to assess the cytotoxicity and the mechanism of action of flavonoids abyssinone IV (1), atalantoflavone (3) and neocyclomorusin (6) and isoflavonoids sigmoidin I (2), sophorapterocarpan A (4), bidwillon A (5) and 6α-hydroxyphaseollidin (7) isolated from Erythrina sigmoidea against nine drug sensitive and multidrug resistant (MDR) cancer cell lines. Methods The resazurin reduction assay was used to evaluate the cytotoxicity of the studied compounds whilst caspase-Glo assay was used to detect the activation of caspases enzymes by 1, 2, 4 and 7. Cell cycle, mitochondrial membrane potential and levels of reactive oxygen species were all analyzed via flow cytometry. Results The pterocarpan isoflavonoid 7 displayed the best antiproliferative activity with the IC50 values below 10 μM obtained on the nine tested cancer cell lines. The IC50 values below 50 μM were also recorded with compounds 1, 2 and 4 against the nine cancer cell lines whilst 3, 5 and 6 showed selective activities. The IC50 values varied from 14.43 μM (against MDA-MB-231-pcDNA cells) to 20.65 μM [towards HCT116 (p53 +/+) cells] for compound 1, from 4.24 μM (towards CCRF-CEM cells) to 30.98 μM (towards MDA-MB-231-BCRP cells) for 2, from 3.73 μM (towards CCRF-CEM cells) to 14.81 μM (against U87MG.ΔEGFR cells) for 4, from 3.36 μM (towards CCRF-CEM cells) to 6.44 μM (against HepG2 cells) for 7, and from 0.20 μM (against CCRF-CEM cells) and 195.12 μM (against CEM/ADR5000 cells) for the positive control drug, doxorubicin. Compared to their corresponding sensitive cell lines, collateral sensitivity was observed with HCT116 (p53 −/−) to 1, 2, 4, 5, and 7 and with U87MG.ΔEGFR to 1 to 6. Compound 7 induced apoptosis in CCRF-CEM cells mediated by the activation of caspases 3/7, 8 and 9 and breakdown of MMP and increase in ROS production, whereas the apoptotic process induced by 1, 2 and 4 was mediated by the loss of MMP as well as increase in ROS production. Conclusions Compounds from Erythrina sigmoidea and mostly 6α-hydroxyphaseollidin are potential antiproliferative natural products that deserve more investigations to develop novel anticancer drugs against sensitive and otherwise drug-resistant phenotypes.

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Acknowledgments

Authors acknowledge the Cameroon National Herbarium (Yaoundé) for the plant identification. VK is very grateful to the Alexander von Humboldt Foundation for an 18 months’ fellowship in Germany through the ''Georg Foster Research Fellowship for Experienced Researcher'' program. Authors also acknowledge the DAAD for a stipend to MZ.

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Authors and Affiliations

  1. Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, University of Mainz, Staudinger Weg 5, 55128, Mainz, Germany

    Victor Kuete, Maen Zeino & Thomas Efferth

  2. Department of Biochemistry, Faculty of Science, University of Dschang, Dschang, Cameroon

    Victor Kuete & Doriane E. Djeussi

  3. Department of Organic Chemistry, Faculty of Science, University of Yaoundé I, Yaoundé, Cameroon

    Louis P. Sandjo, Guy M. N. Kwamou & Bonaventure Ngadjui

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  1. Victor Kuete
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Correspondence to Thomas Efferth.

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Authors’ Contribution

VK and MZ carried out the experiments; VK, LPS and DED contributed to plant’s collection, compound’s isolation and/or identification. VK wrote the manuscript. VK, BTN and TE designed the experiments; TE supervised the work, provided the facilities for the study. All authors read the manuscript and approved the final version.

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Kuete, V., Sandjo, L.P., Djeussi, D.E. et al. Cytotoxic flavonoids and isoflavonoids from Erythrina sigmoidea towards multi-factorial drug resistant cancer cells. Invest New Drugs 32, 1053–1062 (2014). https://doi.org/10.1007/s10637-014-0137-y

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