Eltrombopag olamine induces apoptosis in human breast adenocarcinoma and hepatocellular carcinoma cells through modulation of multiple apoptotic pathways

Cancer remains a global health challenge, driving the search for more effective therapeutic agents due to the limitations of existing treatments. We evaluated the anticancer potential of Eltrombopag olamine on MCF-7 (breast adenocarcinoma) and SMMC-7721 (hepatocellular carcinoma) cell lines. Eltrombopag olamine demonstrated dose-dependent antiproliferative effects, with IC₅₀ values of 31, 154, and 127 µg/ml for MCF-7, SMMC-7721, and non-cancer HEK293T cell lines, respectively. Apoptosis induction in MCF-7 and SMMC-7721 cell lines was confirmed through Hoechst 33342 staining-assisted detection of condensed nuclei. FITC-annexin V/PI staining showed a significant increase in late apoptosis in both MCF-7 and SMMC-7721 cells, as well as necrosis in SMMC-7721 cells. The cell cycle analysis revealed S-phase arrest in both MCF-7 and SMMC-7721 cell lines and a remarkable increase of sub-G1 phase in SMMC-7721 cells. Caspase-dependent apoptosis was evidenced by reduced cell death in the presence of Caspase-3/7, -8, and - 9 inhibitors. In MCF-7 cells, FAS, TP53, BAX, TNFα, and cytochrome-C were upregulated, while ERK expression was downregulated. In SMMC-7721 cells, TP53, BAX, and TNFα were similarly upregulated, whereas ERK, STAT3, MAPK, NOTCH, PARP1, and EGFR expression levels were reduced. The results show the involvement of mitochondrial (intrinsic), EGFR-MAPK-ERK, WNT1, and death receptor signaling pathways in the apoptosis process. Interactions of Eltrombopag with EGFR, FAS, p53, and TNFα proteins were detected through molecular docking simulations. These findings highlight the potential of Eltrombopag olamine as a repurposed, multi-targeted therapeutic candidate for the treatment of breast and liver cancer.