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  • br stages during cell cycle progression Walker and


    stages during cell cycle progression (Walker and Assoian, 2005). Sev-eral newer agents have been developed that selectively target one or more CDKs, rather than disrupting the cytoskeleton, to inhibit tumour cell proliferation and some have entered clinical trials (Law et al., 2015). Thus, the CDK4/6 inhibitor palbociclib is an effective anti-pro-liferative agent in estrogen receptor-positive breast cancer and ovarian cancer cell lines (Finn et al., 2009) and produced a clinical response in some hormone receptor positive patients when used as a single agent (Rocca et al., 2017).
    There is evidence that amplification of cell cycle regulatory proteins diminishes the clinical efficacy of CDK inhibitors. Cyclins D1 and E1 are commonly overexpressed in primary breast cancer and are associated with more aggressive disease and adverse patient outcomes. This may be because overexpression of these genes confers resistance to standard therapies (Butt et al., 2008). Cyclins may be useful targets for anti-cancer drug design. Although palbociclib is a promising agent in pre-clinical and clinical settings, it appears to be less effective in cell lines that over-express cyclin E1, which occurs commonly in tumours (Kanska et al., 2016). Accordingly, instead of selective targeting of CDKs, agents that target multiple cell cycle regulatory proteins may have advantages over CDK inhibitors.
    Although there are no established therapeutic agents that selectively target cyclin proteins that are dysregulated in cancer a number of natural product chemicals reportedly impair the expression of one or more cell cycle regulatory proteins, including cyclins. The fungal pro-duct bassiatin selectively targeted cyclin D1 to induce cell cycle arrest in MCF-7 breast cancer cells (Meng et al., 2011), and the flavonoid
    myricetin and the morphinan alkaloid 6,7-di-O-acetyl-sinococuline in-duced anti-proliferative cell cycle arrest in T24 Zinc protoporphyrin IX carcinoma cells, and MDA-MB-231 and MCF-7, respectively, in part by down-regulation of cyclin B1 (Sun et al., 2012; Li et al., 2015). The lignin erythro-aus-trobailignan-6 down-regulated the cyclin D1/CDK4 functional complex in MCF-7 cells (Han et al., 2017) and the glycoalkaloid solanine in-hibited prostate cancer cell proliferation by targeting several cyclins and CDKs (Pan et al., 2016). Similarly, epigallocatechin gallate elicited cell cycle arrest in G1 phase in oral squamous cell carcinoma cells by down-regulating cyclins D and E (Lee et al., 2015). We found previously that ω-3-17,18-epoxy-EPA selectively decreased the expression of the cyclin D1/CDK4 complex in endothelial cells and prevented cell cycle
    progression (Cui et al., 2011). In contrast, however, cyclin E1, cyclin B1 and CDK6 were relatively refractory. The present findings that CTU and other active aryl-ureas down-regulated multiple cyclins and CDKs may offer an opportunity to efficiently decrease cancer cell viability by targeting cell cycle progression at multiple points.
    Whereas proliferative signals activate the ERK MAP kinases to promote the accumulation of cyclin D1 and accelerate cell cycle pro-gression (Mebratu and Tesfaigzi, 2009), activation of the p38 MAP ki-nase decreases cyclin D1 and cell proliferation (Conrad et al., 1999). Consistent with these findings, a number of PUFA epoxides have been found to modulate MAP kinase pathways. Thus, ω-6 AA-derived epox-yeicosatrienoic acids activate ERK MAP kinase signalling and cyclin D1
    expression (Potente et al., 2002; Chen et al., 2001). In contrast, the anti-proliferative ω-3-17,18-epoxy-EPA has been shown to activate the p38 MAP kinase and down-regulate cyclin D1 expression in endothelial cells (Cui et al., 2011). The natural products solanine, erythro-aus-trobailignan-6, epigallocatechin-3-gallate, 6,7-di-O-acetyl-sinococuline and myricetin, that have been reported to decrease the expression of cyclins and CDKs in multiple tumour cell types, have also been shown to activate the p38 MAP kinase anti-proliferative pathway (Sun et al., 2012; Li et al., 2015; Han et al., 2017; Pan et al., 2016; Lee et al., 2015). Together these findings suggest that a viable strategy for the develop-ment of novel anticancer agents could be the activation of the p38 MAP kinase to target the expression of multiple cell cycle regulatory proteins. The present study has identified a number of aryl-urea fatty acid ep-oxide bioisosteres based on ω-3-17,18-epoxy-EPA and the lead aryl-urea CTU that strongly activated the p38 MAP kinase in MDA-MB-231 cells and decreased the expression of important cyclins and CDKs to impair cancer cell viability.