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Abstract
BackgroundKinesin spindle proteins (KSP) are motor proteins that play an essential role in mitotic spindle formation. HsEg5, a KSP, is responsible for the formation of the bipolar spindle, which is critical for proper cell division during mitosis. The function of HsEg5 provides a novel target for the manipulation of the cell cycle and the induction of apoptosis. SB715992, an experimental KSP inhibitor, has been shown to perturb bipolar spindle formation, thus making it an excellent candidate for anti-cancer agent. Our major objective was a) to investigate the cell growth inhibitory effects of SB715992 on PC-3 human prostate cancer cell line, b) to investigate whether the growth inhibitory effects of SB715992 could be enhanced when combined with genistein, a naturally occurring isoflavone and, c) to determine gene expression profile to establish molecular mechanism of action of SB715992.MethodsPC-3 cells were treated with varying concentration of SB715992, 30 μM of genistein, and SB715992 plus 30 μM of genistein. After treatments, PC-3 cells were assayed for cell proliferation, induction of apoptosis, and alteration in gene and protein expression using cell inhibition assay, apoptosis assay, microarray analysis, real-time RT-PCR, and Western Blot analysis.ResultsSB715992 inhibited cell proliferation and induced apoptosis in PC-3 cells. SB715992 was found to regulate the expression of genes related to the control of cell proliferation, cell cycle, cell signaling pathways, and apoptosis. In addition, our results showed that combination treatment with SB715992 and genistein caused significantly greater cell growth inhibition and induction of apoptosis compared to the effects of either agent alone.ConclusionOur results clearly show that SB715992 is a potent anti-tumor agent whose therapeutic effects could be enhanced by genistein. Hence, we believe that SB715992 could be a novel agent for the treatment of prostate cancer with greater success when combined with a non-toxic natural agent like genistein.
Highlights
Kinesin spindle proteins (KSP) are motor proteins that play an essential role in mitotic spindle formation
Genistein is known as a protein tyrosine kinase inhibitor and has been shown to alter the expression of genes, which are critical for the control of cell proliferation, apoptosis, and cell signalling [5]
The results obtained from the ELISA assay showed an average of 1094.88% increase in apoptosis when PC-3 cells were treated with 15 nM of
Summary
Kinesin spindle proteins (KSP) are motor proteins that play an essential role in mitotic spindle formation. Development of chemotherapeutic agents to induce apoptosis of tumor cells with lower toxicity in patients is currently being investigated by many scientists. Tyrosine kinase regulates cell-to-cell signaling that regulates growth, differentiation, adhesion, motility and programmed cell death, which play significant roles in the manifestation of human disease states such as diabetes and cancer [6]. With this information at hand, we studied the growth inhibitory effects of genistein with a new experimental anti-mitotic agent SB715992, chemically defined as n-(3amino-propyl)-n- [R-1-(3-benzyl-7-chloro-4-oxo-3, 4-dihydroquinazolin-2-yl)-2-methyl-propyl]-4-methyl-benzanide methanesulfonate (C30H33ClN4O2CH4O3S)
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