Background/Aim: Oleuropein belongs to the potent polyphenols of olive oil. Notably, it is considered as a potentially active anticancer agent. Herein, the anticancer efficiency of oleuropein, when used separately and in combination with the chemotherapeutic agent, 2-methoxyestradiol (2-ME), was investigated in highly metastatic osteosarcoma (OS) cells. Materials and Methods: Human OS cells (143B OS cell line) were incubated with oleuropein and 2-ME, alone or in combination. Cell viability was determined by the MTT assay. Cell migration assays were used in order to determine the anti-migratory potential of the compounds, while their impact on autophagy was evaluated via the LC3-antibody-based detection assay. The interaction between oleuropein and 2-ME was determined via the CalcuSyn software. Results: Both anti-migratory and antiproliferative effects of oleuropein were demonstrated on human OS cells. Anticancer effects of oleuropein were significantly enhanced after 2-ME addition. Treatment of 143B OS cell with oleuropein, alone or in combination with 2-ME resulted in induction of autophagy. Conclusion: The obtained data suggest an anticancer effect of oleuropein, alone and in combination with 2-ME, on highly metastatic 143B OS cells. Notably, a synergism between oleuropein and 2-ME towards 143B OS cells was detected. The exact mechanism of this synergism needs to be further investigated; nonetheless, induction of nitro-oxidative stress and/or induction of autophagy are suggested.
Abbreviations used: ATCC -American Type Culture Collection; CHX -cycloheximide; DCF -2,7-dichlorofluorescin; DHCF-DA -2',7'-dihydrodichlorofluorescein diacetate; DHE -dihydroethidium; MMP -mitochondrial membrane potential; · O¯2 -superoxide anion; PS -phosphatidylserine; TMRM -tramethylrhodamine methyl ester; TNFα -tumor necrosis factor; U937 V -a variant of the U937 cell line; VP-16 -etoposide Abstract: The variant cell line U937 V was originally identified by a higher sensitivity to the cytocidal action of tumor necrosis factor alpha (TNFα) than that of its reference cell line, U937. We noticed that a typical morphological feature of dying U937 V cells was the lack of cellular disintegration, which contrasts to the formation of apoptotic bodies seen with dying U937 cells. We found that both TNFα, which induces the extrinsic apoptotic pathway, and etoposide (VP-16), which induces the intrinsic apoptotic pathway, stimulated U937 V cell death without cell disintegration. In spite of the distinct morphological differences between the U937 and U937 V cells, the basic molecular events of apoptosis, such as internucleosomal DNA degradation, phosphatidylserine exposure on the outer leaflet of the plasma membrane, caspase activation and cytochrome c release, were evident in both cell types when stimulated with both types of apoptosis inducer. In the U937 V cells, we noted an accelerated release of cytochrome c, an accelerated decrease in mitochondrial membrane potential, and a more pronounced generation of reactive oxygen species compared to the reference cells. We propose that the U937 and U937 V cell lines could serve as excellent comparison models for studies on the mechanisms regulating the processes of cellular disintegration during apoptosis, such as blebbing (zeiosis) and apoptotic body formation.
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