| Ispinesib is a potent allosteric small-molecule inhibitor of kinesin spindle protein (KSP, also known as HsEg5). In a panel of 50 human breast tumor cell lines and in three normal mammary epithelial lines: MCF10A, MCF10F, and MCF12A, the GI50 values of ispinesib are between 7.4 and 600 nM. Ispinesib (150 nM) transiently increases the proportion of cells within G2 or M phases of the cell cycle in both cell lines, BT-474, a HER2-positive luminal cell line, and MDA-MB-468, a basal A triple-negative cell line. Maximal accumulation of mitotic cells occurs after 16 hours of ispinesib treatment in MDA-MB-468 cells and 48 hours in BT-474 cells.[1] Ispinesib (15 and 30 nM) has a time and dose related effect on the growth of prostate cancer cell line PC-3 cells. Over the course of 72 hours, ispinesib causes an average increase in cell growth inhibition of 48.65% at 15 nM and 52.16% at 30 nM with respect to control samples. Ispinesib (15 nM) induces about 10-fold increase in apoptosis in PC-3 cells and ispinesib (30 nM) induces about 15-fold increase in apoptosis in PC-3 cells. Besides, ispinesib is further found to regulate the expression of genes related to the control of cell proliferation, cell cycle, cell signaling pathways, and apoptosis. Ispinesib (10 nM) also decreases the expression of epidermal growth factor receptor (EGFR) and increases in the expression of p27 (CDKN2B) and p15 (CDKN1B). 7.5 nM of ispinesib has growth inhibition of 29.83% and 10 nM of ispinesib has growth inhibition of 36.99% over 72 hours treatment. However, when the PC-3 cells are treated with 7.5 nM ispinesib plus 30 µM of genistein, the growth inhibition increases to 48.73%.[2] In the triple-negative xenograft model MDA-MB-468, ispinesib (SCID, 8 mg/kg; nude, 10 mg/kg) produces completely regression in all mice. In the ER-positive model MCF7, ispinesib causes tumor regressions in five of nine mice [one partial regression (PR) and four complete regression (CR), two of which are tumor-free survivor (TFS) at study end] and a tumor growth inhibition (TGI) of 92%. In the HER2-positive models KPL4, all 10 ispinesib-treated mice exhibit regressions (four PR, six CR, and four TFS). In the HCC1954 model, ispinesib causes regressions in four of the five treated mice. However, in both of these models, tumor regrowth begins 35 days after treatment in the less responsive tumors. In the HER2-positive model BT-474, ispinesib causes a CR in 2 of 8 mice, a lower TGI (61%) than that observed in the other models, and tumors have regrown in all mice by the end (mean tumor volume, 875 mm3).[1] |
