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

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.