Modulatory effect of sodium butyrate on anticancer activity of abemaciclib in MDA-MB- 231 human breast cancer cells

Abstract Triple negative is the most aggressive subtype of breast cancer with its treatment limited only to chemotherapy and radiotherapy. The effect of abemaciclib and /or sodium butyrate on MDA-MB-231 triple negative breast cancer cells was investigated. Using MTT assay, IC50 for the growth inhibitory effect of abemaciclib, sodium butyrate, and their combination were 14.55 µM, 7.08 mM, 3.743 mM, respectively. The combination showed a synergistic interaction with a decrease in IC50 to 2.55 µM of abemaciclib and 3.74 mM of butyrate. Three replica of four groups of cancer cells were treated for 48hr with IC50 of either abemaciclib or butyrate or their high or low doses combinations. A fifth group was treated with complete medium and served as control. Cell migration, protein expression level of cyclinD1, E2F2 transcription factor, phosphorylated AKT, nuclear factor kabba B (NF-κB), cyclin dependent kinase-2 (CDK2), retinoblastoma (Rb), p16INK4a, p53 and mRNA level of CDK2, p16INK4a and p53 were assessed in all treated groups. Combination treatment of abemaciclib and butyrate showed a significant attenuation of cell metastasis. The combination treatment was associated with a decrease in E2F2, CDK2, and NF-κB protein level together with an attenuation in AKT phosphorylation level. The combination also showed an elevation in Rb, p16INK4a, together with a reversal of DNA hypo-methylated state. Although abemaciclib monotherapy failed to alter CD1 or P53 levels, the combination significantly reduced CD1 level together with an increase in P53 level. In conclusion, combining butyrate with abemaciclib augmented its antiproliferative and antimetastatic effect and induced apoptotic activity.