_:b415462811 . _:b415462788 "2"^^ . _:b415462812 . _:b415462813 . _:b415462814 . _:b415462815 . _:b415462791 "2"^^ . _:b415462800 . _:b415462801 . _:b415462802 . _:b415462803 . _:b415462790 "2"^^ . _:b415462804 . . . _:b415462805 . _:b415462806 . . _:b415462785 "2"^^ . _:b415462807 . _:b415462824 . _:b6156089 "the use of piperine, nanoparticles, liposomes, phospholipid complexes and structurally altered derivatives and analogues that dramatically improve the biological activity of curcumin (Shoba et al, 1998; Mishra et al, 2005; Liu et al, >>2006<<; Anand et al, 2007; Li et al, 2007; Mosley et al, 2007)." . . _:b6156052 . _:b415462825 . _:b415462826 . _:b415462845 . . _:b415462827 . _:b415462784 "2"^^ . _:b415462828 . _:b415462829 . _:b415462830 . _:b415462831 . _:b415462787 "2"^^ . _:b415462816 . . _:b415462817 . . . _:b415462818 . _:b6156080 "At least three different Phase I clinical trials have indicated that curcumin is safe and well tolerated even at doses as high as 12\u2009g\u2009day\u22121 (Cheng et al, >>2001<<). However, despite its well-documented efficacy and safety in both animals and humans in vivo and in vitro, its poor bioavailability has been cited as a major concern and has probably delayed its development as a therapeutic agent. Serum" . _:b415462819 . _:b415462786 "2"^^ . . _:b415462707 . _:b415462820 . _:b415462821 . _:b415462800 . _:b415462822 . _:b415462823 . _:b415462847 . _:b415462797 "2"^^ . _:b415462840 . . _:b415462841 . _:b415462827 . _:b415462842 . _:b415462843 . _:b415462796 "2"^^ . _:b415462844 . _:b415462845 . _:b415462846 . _:b415462847 . _:b415462799 "2"^^ . _:b415462832 . _:b415462833 . _:b415462834 . _:b415462835 . _:b415462798 "2"^^ . _:b415462836 . _:b6156071 "Other authors have recently reported exclusive autophagic cell death after curcumin treatment and this was associated with the activation of ERK signalling (Aoki et al, >>2007<<; Shinojima et al, 2007)." . . _:b415462837 . _:b415462838 . _:b415462839 . _:b415462793 "2"^^ . _:b415462760 . _:b415462792 "2"^^ . _:b415462850 . _:b415462795 "2"^^ . _:b6156069 . _:b415462779 . _:b415462839 . . _:b415462794 "2"^^ . _:b6156087 . _:b6156065 . _:b415462814 . _:b415462805 "2"^^ . _:b415462804 "2"^^ . . _:b415462807 "2"^^ . _:b415462722 . _:b415462813 . _:b415462806 "2"^^ . . _:b415462885 . _:b415462801 "2"^^ . _:b415462811 . . _:b415462809 . _:b415462800 "2"^^ . _:b6156080 . . _:b415462803 "2"^^ . _:b415462802 "2"^^ . _:b415462886 . _:b415462813 "2"^^ . _:b415462734 . . _:b415462812 "2"^^ . _:b6156068 "Other authors have reported biochemical features of apoptosis in cell populations showing MC morphology \u2013 primarily caspase activation, although indeed with minimal caspase 3 cleavage (Rashmi et al, >>2004<<, 2005). Another study also reported that caspase activation was not required for MC and that activation of caspases varied in different cell lines (Mansilla et al, 2006). Clearly, limited caspase activation in a heterogeneous population" . _:b415462901 . _:b415462895 . _:b415462815 "2"^^ . _:b415462833 . _:b415462763 . _:b6156090 "nanoparticles, liposomes, phospholipid complexes and structurally altered derivatives and analogues that dramatically improve the biological activity of curcumin (Shoba et al, 1998; Mishra et al, 2005; Liu et al, 2006; Anand et al, >>2007<<; Li et al, 2007; Mosley et al, 2007)." . _:b415462814 "2"^^ . _:b415462798 . . _:b415462809 "2"^^ . . _:b415462897 . _:b6156087 "have gained attention, such as the use of piperine, nanoparticles, liposomes, phospholipid complexes and structurally altered derivatives and analogues that dramatically improve the biological activity of curcumin (Shoba et al, >>1998<<; Mishra et al, 2005; Liu et al, 2006; Anand et al, 2007; Li et al, 2007; Mosley et al, 2007)." . _:b415462807 . _:b415462808 "2"^^ . _:b415462709 . . _:b6156079 . _:b415462811 "2"^^ . _:b415462708 . . _:b415462810 "2"^^ . . _:b415462711 . . "PMC0" . . _:b415462821 "2"^^ . _:b415462710 . . _:b415462820 "2"^^ . _:b415462823 "2"^^ . _:b6156049 . _:b6156045 "materials and methods" . _:b6156062 . _:b415462822 "2"^^ . _:b415462707 . _:b415462843 . _:b415462817 "2"^^ . _:b415462890 . _:b415462816 "2"^^ . _:b415462717 . . _:b415462819 "2"^^ . _:b415462716 . _:b6156066 . _:b415462818 "2"^^ . _:b415462719 . . _:b415462829 "2"^^ . _:b415462718 . _:b6156057 . . _:b415462828 "2"^^ . _:b415462713 . _:b6156069 "Other authors have reported biochemical features of apoptosis in cell populations showing MC morphology \u2013 primarily caspase activation, although indeed with minimal caspase 3 cleavage (Rashmi et al, 2004, >>2005<<). Another study also reported that caspase activation was not required for MC and that activation of caspases varied in different cell lines (Mansilla et al, 2006). Clearly, limited caspase activation in a heterogeneous population of" . . _:b415462831 "2"^^ . _:b415462712 . _:b415462745 . _:b415462830 "2"^^ . _:b415462715 . . _:b415462825 "2"^^ . _:b415462714 . . _:b415462765 . _:b415462824 "2"^^ . _:b415462725 . . . _:b415462827 "2"^^ . _:b415462724 . . _:b415462826 "2"^^ . _:b415462727 . _:b415462872 . . _:b415462718 . _:b415462837 "2"^^ . _:b415462726 . _:b6156091 "liposomes, phospholipid complexes and structurally altered derivatives and analogues that dramatically improve the biological activity of curcumin (Shoba et al, 1998; Mishra et al, 2005; Liu et al, 2006; Anand et al, 2007; Li et al, >>2007<<; Mosley et al, 2007)." . _:b415462836 "2"^^ . _:b415462721 . . . _:b415462839 "2"^^ . _:b6156088 "such as the use of piperine, nanoparticles, liposomes, phospholipid complexes and structurally altered derivatives and analogues that dramatically improve the biological activity of curcumin (Shoba et al, 1998; Mishra et al, >>2005<<; Liu et al, 2006; Anand et al, 2007; Li et al, 2007; Mosley et al, 2007)." . _:b6156070 "Another study also reported that caspase activation was not required for MC and that activation of caspases varied in different cell lines (Mansilla et al, >>2006<<). Clearly, limited caspase activation in a heterogeneous population of cells (as in OE21 cells) does not necessarily mean that the MC cells are activating caspases. We have found minimal caspase 3 cleavage in two of our four cell lines" . _:b415462874 . _:b415462720 . _:b415462841 . _:b415462838 "2"^^ . _:b415462723 . . _:b415462833 "2"^^ . _:b415462722 . _:b415462832 "2"^^ . _:b415462733 . _:b415462835 "2"^^ . _:b415462732 . _:b415462834 "2"^^ . _:b415462735 . _:b6156060 "primary target of curcumin is unknown; however, an emerging body of evidence suggests that this compound may achieve its diverse effects through inhibition of the UPS (Henke et al, 1999; Uhle et al, 2003; Jana et al, 2004; Si et al, >>2007<<). We therefore looked for evidence of the accumulation of poly-ubiquitinated proteins after treatment." . _:b415462828 . _:b6156072 "Other authors have recently reported exclusive autophagic cell death after curcumin treatment and this was associated with the activation of ERK signalling (Aoki et al, 2007; Shinojima et al, >>2007<<). However, we found de-phosphorylation of ERK after curcumin treatment (Supplementary data). It is possible that this difference is cell-line-related \u2013 or dose-related \u2013 as our study used much lower concentrations of drug (Aoki et al 80" . _:b415462845 "2"^^ . _:b415462734 . _:b415462879 . . . _:b415462844 "2"^^ . _:b415462729 . _:b415462726 . _:b415462847 "2"^^ . _:b415462728 . . _:b415462846 "2"^^ . _:b415462731 . . _:b415462841 "2"^^ . _:b415462730 . . _:b415462840 "2"^^ . _:b415462741 . _:b415462843 "2"^^ . _:b415462740 . . _:b6156066 "The most sensitive cell lines (KYSE450, OE21 and OE33) underwent mitotic arrest with morphological features of MC (Castedo et al, 2004; Vitale et al, >>2005<<). The published literature is divided as to whether MC is an event that precedes apoptotic cell death or is a distinct mechanism of cell death (reviewed in Vakifahmetoglu et al, 2008). Although morphological analysis did show apoptotic" . _:b415462842 "2"^^ . _:b415462743 . _:b415462853 "2"^^ . _:b415462742 . _:b6156075 "Our data are therefore supportive of the view that curcumin acts as an inhibitor of the UPS (Henke et al, >>1999<<; Jana et al, 2004; Si et al, 2007)." . _:b415462852 "2"^^ . _:b415462737 . . _:b415462713 . _:b415462855 "2"^^ . _:b6156064 . . _:b6156096 . . _:b415462736 . _:b415462787 . _:b415462806 . _:b415462854 "2"^^ . _:b415462739 . _:b415462849 "2"^^ . _:b415462738 . . _:b415462848 "2"^^ . _:b415462749 . _:b415462851 "2"^^ . _:b415462857 . _:b415462748 . . _:b415462850 "2"^^ . _:b415462751 . _:b6156053 . _:b6156074 . . _:b415462861 "2"^^ . _:b415462750 . _:b415462755 . . _:b415462860 "2"^^ . _:b415462745 . _:b415462863 "2"^^ . _:b415462744 . _:b415462862 "2"^^ . _:b415462747 . _:b415462896 . _:b415462857 "2"^^ . _:b6156092 "complexes and structurally altered derivatives and analogues that dramatically improve the biological activity of curcumin (Shoba et al, 1998; Mishra et al, 2005; Liu et al, 2006; Anand et al, 2007; Li et al, 2007; Mosley et al, >>2007<<). Combination studies so far in both in vitro and in vivo have highlighted promising combinations of curcumin with oxaliplatin (Howells et al, 2007; Li et al, 2007; Patel et al, 2008) and paclitaxel (Aggarwal et al, 2005), suggesting" . _:b415462746 . _:b415462856 "2"^^ . _:b6156085 "shown curcumin has low bioavailability, limited tissue distribution, short half-life and a rapid metabolism irrespective of its route of administration (Ravindranath and Chandrasekhara, 1981; Garcea et al, 2004, 2005; Hoehle et al, >>2006<<; Anand et al, 2007). The fact that curcumin has poor systemic bioavailability would suggest that the gastrointestinal tract is the most promising site for use in prevention or therapy." . . _:b415462757 . _:b415462815 . _:b6156058 "The primary target of curcumin is unknown; however, an emerging body of evidence suggests that this compound may achieve its diverse effects through inhibition of the UPS (Henke et al, 1999; Uhle et al, >>2003<<; Jana et al, 2004; Si et al, 2007)." . _:b415462859 "2"^^ . _:b415462756 . _:b415462858 "2"^^ . _:b415462759 . . _:b415462873 . . _:b415462869 "2"^^ . _:b415462758 . . _:b415462750 . _:b6156068 . _:b415462868 "2"^^ . _:b415462753 . . _:b415462871 "2"^^ . _:b415462752 . . . _:b415462870 "2"^^ . _:b415462755 . _:b415462865 "2"^^ . _:b415462754 . _:b415462864 "2"^^ . _:b415462887 . _:b415462876 . _:b415462765 . _:b415462870 . . _:b415462867 "2"^^ . _:b415462764 . _:b415462866 "2"^^ . _:b415462767 . _:b415462880 . _:b415462877 "2"^^ . _:b415462766 . _:b415462876 "2"^^ . . _:b6156051 "The dramatic vacuolisation of the cytoplasm without apparent loss of nuclear material is consistent with the described macrostructure of autophagy (F) (Figure 3A) (Kroemer et al, >>2009<<). This type of autophagic morphology in the KYSE450 cell line has also been observed by our group in response to treatment with cytotoxic drugs such as 5-fluorouracil and cisplatin (unpublished data). Interestingly, the features of MC and" . _:b415462761 . _:b415462879 "2"^^ . _:b415462760 . _:b415462878 "2"^^ . _:b415462763 . . _:b415462877 . _:b415462873 "2"^^ . _:b415462762 . _:b415462872 "2"^^ . _:b415462773 . _:b415462875 "2"^^ . _:b415462772 . _:b6156096 "Combination studies so far in both in vitro and in vivo have highlighted promising combinations of curcumin with oxaliplatin (Howells et al, 2007; Li et al, 2007; Patel et al, 2008) and paclitaxel (Aggarwal et al, >>2005<<), suggesting there is a very definite potential for curcumin to be used as part of mainstream clinical regimes." . . _:b6156089 . _:b415462874 "2"^^ . _:b415462775 . _:b415462885 "2"^^ . _:b415462774 . . _:b415462884 "2"^^ . _:b415462769 . . _:b415462736 . _:b415462865 . _:b415462741 . _:b415462887 "2"^^ . _:b415462768 . . _:b415462817 . _:b415462886 "2"^^ . _:b415462771 . . _:b415462881 "2"^^ . . _:b415462770 . _:b6156093 "Combination studies so far in both in vitro and in vivo have highlighted promising combinations of curcumin with oxaliplatin (Howells et al, >>2007<<; Li et al, 2007; Patel et al, 2008) and paclitaxel (Aggarwal et al, 2005), suggesting there is a very definite potential for curcumin to be used as part of mainstream clinical regimes." . . _:b415462880 "2"^^ . _:b415462781 . . _:b415462883 "2"^^ . _:b415462780 . _:b415462863 . _:b415462770 . _:b415462882 "2"^^ . . _:b415462783 . _:b415462777 . _:b6156086 . _:b415462893 "2"^^ . . _:b415462782 . . _:b6156092 . . _:b415462894 . _:b6156081 . _:b415462892 "2"^^ . . _:b415462777 . . . . _:b415462782 . _:b415462895 "2"^^ . _:b415462776 . _:b6156056 . _:b415462894 "2"^^ . . _:b415462779 . . _:b415462889 "2"^^ . _:b415462778 . _:b415462862 . _:b415462888 "2"^^ . _:b6156077 "Our data are therefore supportive of the view that curcumin acts as an inhibitor of the UPS (Henke et al, 1999; Jana et al, 2004; Si et al, >>2007<<). This is likely to have marked effects on the cell cycle, but effects may differ in different cell lines because of differences in their existing proteome. For example, cells of a similar type that have lost transcription of tumour" . _:b415462789 . _:b6156056 "To investigate whether autophagy coexisted in the cell lines after curcumin treatment, we used the MDC assay, which is a selective fluorescent marker of autophagic vesicles (Biederbick et al, >>1995<<). The dye shows diffuse staining in non-autophagic cells, but is sequestered into punctate vesicular staining when autophagy is induced. We therefore examined distribution of the dye in the three curcumin-sensitive cell lines (OE21, OE33" . _:b6156083 "Various studies have shown curcumin has low bioavailability, limited tissue distribution, short half-life and a rapid metabolism irrespective of its route of administration (Ravindranath and Chandrasekhara, 1981; Garcea et al, >>2004<<, 2005; Hoehle et al, 2006; Anand et al, 2007)." . . _:b415462891 "2"^^ . _:b415462788 . _:b415462758 . _:b6156061 . _:b415462801 . . _:b415462890 "2"^^ . . _:b415462791 . . _:b415462901 "2"^^ . . _:b415462790 . _:b415462900 "2"^^ . _:b415462785 . . _:b415462769 . _:b415462784 . _:b6156073 . . _:b415462787 . _:b415462881 . _:b6156090 . _:b415462860 . _:b415462897 "2"^^ . _:b415462786 . _:b415462896 "2"^^ . _:b415462797 . _:b6156067 . . _:b415462899 "2"^^ . _:b415462796 . _:b415462883 . _:b415462731 . _:b6156073 "A number of studies have also linked downregulation of survivin with MC (Magalska et al, >>2006<<; Wolanin et al, 2006)." . . _:b415462740 . _:b415462898 "2"^^ . _:b415462799 . _:b6156063 "discussion" . _:b415462798 . _:b6156052 "Various papers have suggested that MC is an independent death process, whereas others have proposed that MC is just a consequence of mitotic failure that leads to apoptosis (Castedo et al, >>2004<<; Vakifahmetoglu et al, 2008). We therefore looked for the presence of active caspase-3, which is an indicator of classical apoptosis." . _:b415462805 . _:b6156082 . . _:b6156070 . _:b415462747 . _:b415462793 . . _:b415462792 . _:b415462775 . . _:b415462795 . _:b415462792 . . . _:b415462794 . _:b415462829 . _:b6156055 "This can promote cell survival during cell stress; however, excessive autophagy can also lead to cell death (Degterev and Yuan, >>2008<<). To investigate whether autophagy coexisted in the cell lines after curcumin treatment, we used the MDC assay, which is a selective fluorescent marker of autophagic vesicles (Biederbick et al, 1995). The dye shows diffuse staining in" . . _:b415462805 . _:b415462892 . . _:b415462804 . . _:b415462900 . _:b415462807 . . _:b6156086 "low bioavailability, limited tissue distribution, short half-life and a rapid metabolism irrespective of its route of administration (Ravindranath and Chandrasekhara, 1981; Garcea et al, 2004, 2005; Hoehle et al, 2006; Anand et al, >>2007<<). The fact that curcumin has poor systemic bioavailability would suggest that the gastrointestinal tract is the most promising site for use in prevention or therapy." . _:b415462806 . . _:b415462801 . _:b415462861 . . _:b415462893 . _:b415462773 . _:b6156067 "The published literature is divided as to whether MC is an event that precedes apoptotic cell death or is a distinct mechanism of cell death (reviewed in Vakifahmetoglu et al, >>2008<<). Although morphological analysis did show apoptotic cells in OE21 and OE33, these are coexistent but not dominant features of curcumin-treated cell populations. If apoptosis was the only death mechanism, the low level of apoptosis is not" . _:b415462800 . . _:b415462752 . _:b415462803 . . _:b415462717 . _:b415462866 . _:b415462791 . _:b415462802 . _:b415462859 . _:b415462813 . . . _:b415462836 . _:b415462802 . _:b415462812 . _:b6156084 "Various studies have shown curcumin has low bioavailability, limited tissue distribution, short half-life and a rapid metabolism irrespective of its route of administration (Ravindranath and Chandrasekhara, 1981; Garcea et al, 2004, >>2005<<; Hoehle et al, 2006; Anand et al, 2007). The fact that curcumin has poor systemic bioavailability would suggest that the gastrointestinal tract is the most promising site for use in prevention or therapy." . . _:b415462815 . _:b415462814 . _:b415462711 . . . _:b415462809 . _:b415462808 . _:b415462811 . _:b415462738 . _:b6156093 . _:b415462776 . _:b415462810 . . . _:b415462821 . . _:b415462820 . _:b415462768 . . _:b415462867 . . _:b415462823 . . . . _:b415462878 . _:b415462822 . . _:b415462757 . . _:b415462817 . _:b415462788 . _:b415462816 . _:b415462754 . _:b415462848 . _:b415462819 . _:b415462871 . _:b415462818 . _:b6156053 "Various papers have suggested that MC is an independent death process, whereas others have proposed that MC is just a consequence of mitotic failure that leads to apoptosis (Castedo et al, 2004; Vakifahmetoglu et al, >>2008<<). We therefore looked for the presence of active caspase-3, which is an indicator of classical apoptosis." . _:b415462829 . . _:b6156048 . _:b415462828 . . . _:b415462831 . . _:b415462830 . . _:b415462825 . _:b415462824 . . . _:b415462827 . . _:b415462826 . _:b415462837 . _:b415462837 . _:b415462830 . _:b415462727 . _:b6156095 "Combination studies so far in both in vitro and in vivo have highlighted promising combinations of curcumin with oxaliplatin (Howells et al, 2007; Li et al, 2007; Patel et al, >>2008<<) and paclitaxel (Aggarwal et al, 2005), suggesting there is a very definite potential for curcumin to be used as part of mainstream clinical regimes." . _:b415462836 . _:b415462819 . . . . _:b415462744 . _:b415462839 . _:b415462838 . . _:b415462833 . . _:b415462844 . _:b415462733 . _:b415462715 . _:b415462832 . _:b415462852 . _:b415462835 . . . _:b415462834 . _:b415462845 . . _:b415462844 . _:b415462847 . _:b415462835 . . _:b415462846 . . _:b415462841 . _:b415462840 . _:b415462771 . _:b415462843 . _:b415462712 . . _:b415462842 . . . _:b415462853 . _:b415462778 . _:b415462729 . _:b415462714 . . _:b415462852 . . _:b415462855 . . . _:b415462854 . _:b6156088 . . _:b415462849 . _:b415462848 . . . _:b415462869 . _:b415462851 . _:b415462795 . _:b415462850 . . . _:b6156077 . _:b415462861 . _:b415462846 . . . _:b415462860 . . _:b415462863 . . _:b415462842 . _:b415462728 . _:b415462862 . _:b415462889 . _:b6156055 . _:b415462857 . . _:b415462856 . _:b415462859 . _:b6156063 _:b6156088 . . _:b6156063 _:b6156089 . _:b6156063 _:b6156090 . _:b415462858 . . _:b6156063 _:b6156091 . _:b6156063 _:b6156092 . _:b415462749 . _:b6156063 _:b6156093 . _:b6156063 _:b6156094 . _:b415462869 . _:b6156063 _:b6156095 . _:b6156063 _:b6156080 . _:b6156063 _:b6156081 . _:b415462834 . _:b6156063 _:b6156082 . _:b415462868 . _:b6156063 _:b6156083 . _:b6156063 _:b6156084 . _:b415462780 . _:b6156063 _:b6156085 . _:b415462858 . _:b6156063 _:b6156086 . _:b415462871 . _:b6156063 _:b6156087 . _:b6156063 _:b6156072 . _:b6156063 _:b6156073 . _:b6156063 _:b6156074 . _:b415462870 . _:b6156063 _:b6156075 . _:b6156063 _:b6156076 . _:b6156063 _:b6156077 . _:b6156063 _:b6156078 . _:b415462865 . . _:b6156063 _:b6156079 . _:b6156063 _:b6156064 . _:b6156063 _:b6156065 . _:b415462725 . _:b415462864 . _:b6156063 _:b6156066 . _:b415462708 . _:b6156063 _:b6156067 . _:b6156063 _:b6156068 . _:b6156048 "MPM-2 is an antibody that recognises a group of proteins whose epitopes are exclusively phosphorylated during mitosis \u2013 particularly early prophase to metaphase (Davis et al, >>1983<<) and it is commonly used as an indicator of mitotic disturbance." . _:b6156063 _:b6156069 . _:b6156063 _:b6156070 . _:b415462867 . _:b6156063 _:b6156071 . _:b6156047 _:b6156056 . . _:b6156047 _:b6156057 . . _:b415462866 . _:b6156047 _:b6156058 . _:b6156047 _:b6156059 . . _:b6156047 _:b6156060 . . _:b6156047 _:b6156061 . . _:b415462877 . _:b415462851 . _:b6156047 _:b6156062 . . _:b415462735 . _:b6156047 _:b6156048 . _:b415462746 . _:b6156047 _:b6156049 . _:b6156047 _:b6156050 . _:b415462876 . _:b6156047 _:b6156051 . _:b6156045 . _:b6156047 _:b6156052 . _:b6156047 _:b6156053 . _:b6156047 _:b6156054 . _:b415462879 . _:b6156047 _:b6156055 . _:b6156046 . _:b415462878 . _:b6156047 . . _:b415462873 . _:b6156063 _:b6156096 . _:b415462872 . . _:b415462875 . _:b6156045 _:b6156046 . . . . _:b415462874 . . _:b415462823 . . _:b6156046 "Human oesophageal squamous and adenocarcinoma cell lines OE19, OE21 and OE33 (Rockett et al, >>1997<<) were purchased from the European Collection of Cell Cultures (ECACC). KYSE450 were purchased from Die Deutsche Managementsystem Zertifizierungsgesellschaft mbH (DSMZ, Braunschweig, Germany)." . _:b415462888 . . . . _:b415462885 . . _:b6156052 . _:b415462884 . . _:b6156053 . _:b415462887 . _:b6156054 . _:b415462886 . _:b6156055 . . _:b415462881 . . _:b6156048 . . _:b415462880 . _:b415462723 . . _:b6156049 . _:b415462810 . _:b415462883 . . _:b6156050 . . _:b415462882 . _:b6156051 . _:b415462893 . _:b6156060 . _:b415462854 . _:b415462892 . _:b6156084 . _:b6156082 "Various studies have shown curcumin has low bioavailability, limited tissue distribution, short half-life and a rapid metabolism irrespective of its route of administration (Ravindranath and Chandrasekhara, >>1981<<; Garcea et al, 2004, 2005; Hoehle et al, 2006; Anand et al, 2007)." . _:b415462730 . _:b6156061 . _:b415462895 . _:b6156062 . _:b415462894 . _:b6156059 "The primary target of curcumin is unknown; however, an emerging body of evidence suggests that this compound may achieve its diverse effects through inhibition of the UPS (Henke et al, 1999; Uhle et al, 2003; Jana et al, >>2004<<; Si et al, 2007)." . _:b6156063 . . _:b415462708 "6"^^ . _:b6156072 . _:b415462889 . _:b6156056 . _:b415462711 "5"^^ . _:b415462709 "6"^^ . _:b6156078 "Another reported activity of curcumin that may explain its pleiotropic nature is its effects on histone modification (Liu et al, >>2005<<). We cannot rule this out, and clearly more mechanistic work needs to be undertaken in this area. It is also noteworthy that the UPS system can influence chromatin structure and thus transcription (O\u2019Connell and Harper, 2007)." . _:b6156061 "UPS-mediated degradation of cyclin B1 is then required for cell-cycle progression through mitosis (Kops et al, >>2005<<; Vassilev et al, 2006)." . _:b415462888 . . _:b6156057 . _:b415462821 . . . . _:b415462710 "5"^^ . _:b415462891 . _:b6156058 . . _:b415462890 . _:b6156059 . _:b415462707 "8"^^ . . _:b415462820 . _:b415462901 . . _:b6156068 . . _:b415462900 . . _:b6156069 . _:b415462743 . _:b415462772 . . _:b6156070 . _:b415462784 . _:b415462717 "5"^^ . _:b6156059 . . _:b415462774 . _:b6156071 . _:b6156049 "As a positive control, cells were treated with nocodazole, a known inducer of metaphase arrest (Vassilev et al, >>2006<<). Treatment of KYSE450 cells with nocodazole for 18\u2009h resulted in a synchronisation of the entire cell population in the G2/M phase and an increase in MPM-2 labelling from 0.15 to 23.5% (Figure 2B). In all cells treated with 25\u2009\u03BCM of" . _:b6156063 . _:b415462742 . _:b415462716 "5"^^ . _:b415462897 . _:b415462710 . _:b6156064 . _:b415462719 "4"^^ . _:b415462896 . _:b6156065 . _:b6156079 "It is also noteworthy that the UPS system can influence chromatin structure and thus transcription (O\u2019Connell and Harper, >>2007<<)." . _:b415462718 "5"^^ . . _:b415462899 . _:b415462808 . _:b6156066 . _:b415462853 . _:b415462713 "5"^^ . . _:b6156045 . _:b415462898 . _:b415462781 . _:b6156067 . _:b6156047 . _:b6156083 . _:b415462712 "5"^^ . _:b415462762 . _:b6156076 . _:b415462864 . _:b6156060 . _:b415462715 "5"^^ . . . _:b6156077 . . _:b6156071 . _:b415462714 "5"^^ . _:b415462751 . _:b6156078 . _:b415462725 "4"^^ . _:b415462759 . _:b415462818 . _:b415462783 . _:b6156079 . _:b415462724 "4"^^ . _:b415462748 . . _:b6156072 . _:b415462727 "4"^^ . _:b415462882 . _:b6156073 . _:b415462726 "4"^^ . _:b6156081 "Serum concentrations of curcumin after oral administration range from 0.013 to 11.1\u2009\u03BCM (Anand et al, >>2007<<). Various studies have shown curcumin has low bioavailability, limited tissue distribution, short half-life and a rapid metabolism irrespective of its route of administration (Ravindranath and Chandrasekhara, 1981; Garcea et al, 2004," . . . _:b6156051 . . _:b6156074 . _:b415462721 "4"^^ . . . _:b6156050 . _:b6156075 . _:b415462720 "4"^^ . _:b6156062 "UPS-mediated degradation of cyclin B1 is then required for cell-cycle progression through mitosis (Kops et al, 2005; Vassilev et al, >>2006<<). If the UPS system is inhibited in these cell lines, then cyclin B1 is likely to accumulate and may contribute to the major disturbances in mitotic checkpoints. We therefore examined expression after treatment with 15 and 25\u2009\u03BCM of" . . _:b415462875 . _:b415462724 . _:b6156084 . _:b415462723 "4"^^ . _:b415462804 . _:b6156085 . _:b415462722 "4"^^ . . _:b415462812 . _:b415462840 . _:b415462733 "3"^^ . _:b6156086 . _:b415462732 "3"^^ . _:b6156087 . . . _:b415462822 . _:b6156076 . _:b415462735 "3"^^ . _:b6156080 . _:b415462884 . . _:b415462766 . _:b6156095 . _:b415462734 "3"^^ . _:b6156081 . _:b415462728 . _:b6156082 . _:b415462729 "4"^^ . _:b415462720 . _:b415462729 . _:b415462730 . _:b415462731 . _:b415462732 . _:b6156083 . _:b415462728 "4"^^ . _:b415462733 . _:b415462734 . _:b415462735 . _:b415462731 "3"^^ . _:b6156092 . _:b6156054 "Autophagy is a process that sequesters cytoplasmic proteins or organelles into a lytic compartment that facilitates degradation and re-cycling (Xie and Klionsky, >>2007<<). This can promote cell survival during cell stress; however, excessive autophagy can also lead to cell death (Degterev and Yuan, 2008). To investigate whether autophagy coexisted in the cell lines after curcumin treatment, we used the" . _:b415462803 . _:b415462720 . _:b415462721 . _:b6156050 "Other studies have reported that curcumin can induce MC, which is currently defined primarily by morphology (Kroemer et al, >>2009<<). We therefore examined the morphology of curcumin-treated cells. Figure 3A shows representative examples of both treated and untreated cell lines. After 24\u2009h treatment with concentrations as low as 15\u2009\u03BCM, a marked elevation in the number" . _:b415462722 . _:b415462723 . _:b415462796 . . _:b415462724 . _:b6156093 . _:b415462730 "4"^^ . _:b415462725 . _:b415462726 . _:b415462816 . . _:b415462891 . _:b415462727 . _:b415462741 "3"^^ . _:b6156094 . . _:b415462744 . _:b415462745 . _:b415462746 . _:b415462747 . _:b415462740 "3"^^ . _:b6156095 . _:b415462748 . _:b415462749 . _:b415462750 . _:b415462899 . _:b415462751 . . _:b6156088 . . _:b415462736 . _:b415462743 "3"^^ . _:b415462737 . _:b415462738 . _:b415462739 . _:b415462824 . _:b415462742 "3"^^ . _:b6156089 . _:b415462740 . _:b415462741 . _:b415462719 . _:b415462742 . _:b415462743 . _:b415462737 "3"^^ . _:b6156090 . . _:b415462760 . _:b415462761 . _:b415462762 . _:b415462763 . _:b415462736 "3"^^ . _:b6156091 . . _:b415462764 . _:b415462765 . _:b6156074 "A number of studies have also linked downregulation of survivin with MC (Magalska et al, 2006; Wolanin et al, >>2006<<). We did not see a correlation between low survivin expression and induction of MC in the oesophageal cancer cells (Supplementary data)." . _:b415462793 . . _:b415462766 . _:b415462767 . . _:b415462739 "3"^^ . _:b415462752 . _:b415462753 . _:b415462754 . _:b6156078 . _:b415462721 . _:b415462755 . _:b415462738 "3"^^ . _:b415462756 . _:b415462757 . _:b415462758 . _:b415462794 . . _:b415462759 . _:b415462749 "3"^^ . _:b415462776 . . _:b415462777 . _:b415462778 . _:b6156064 "Curcumin has shown potential as both a chemopreventive agent and a chemotherapeutic agent in various gastrointestinal cancers, and initial studies in oesophageal cancer have been encouraging (Ushida et al, >>2000<<). In this study, we have investigated the effects of curcumin on panel of genetically and phenotypically heterogeneous oesophageal cancer cell lines." . _:b415462898 . _:b415462779 . _:b415462748 "3"^^ . _:b415462780 . _:b415462781 . _:b415462782 . . _:b415462783 . _:b415462751 "3"^^ . _:b6156096 . _:b415462768 . _:b415462769 . _:b415462770 . _:b415462771 . _:b415462750 "3"^^ . _:b415462772 . _:b415462773 . _:b415462774 . _:b415462831 . _:b415462775 . _:b415462745 "3"^^ . _:b415462737 . _:b415462739 . _:b415462744 "3"^^ . _:b415462753 . _:b415462799 . _:b415462747 "3"^^ . . _:b415462746 "3"^^ . . _:b415462757 "2"^^ . _:b415462756 . _:b415462756 "2"^^ . _:b415462732 . . _:b415462759 "2"^^ . . _:b415462758 "2"^^ . . _:b6156058 . _:b415462753 "3"^^ . _:b415462752 "3"^^ . _:b6156085 . . _:b415462755 "2"^^ . _:b415462754 "2"^^ . . _:b415462765 "2"^^ . _:b415462709 . . _:b415462712 . . _:b415462713 . _:b415462714 . _:b415462764 "2"^^ . _:b6156065 "The most sensitive cell lines (KYSE450, OE21 and OE33) underwent mitotic arrest with morphological features of MC (Castedo et al, >>2004<<; Vitale et al, 2005)." . _:b415462715 . _:b415462716 . _:b415462717 . . _:b415462718 . _:b415462767 "2"^^ . _:b415462719 . . _:b415462825 . _:b415462766 "2"^^ . _:b415462707 . _:b415462708 . _:b415462709 . _:b415462856 . _:b415462710 . _:b415462761 "2"^^ . _:b415462789 . _:b415462711 . _:b415462856 . _:b415462832 . . _:b415462857 . _:b415462858 . _:b6156057 "The primary target of curcumin is unknown; however, an emerging body of evidence suggests that this compound may achieve its diverse effects through inhibition of the UPS (Henke et al, >>1999<<; Uhle et al, 2003; Jana et al, 2004; Si et al, 2007)." . _:b6156046 . . _:b415462859 . _:b415462760 "2"^^ . _:b415462860 . _:b6156047 "results" . _:b415462861 . _:b415462862 . _:b415462763 "2"^^ . _:b415462863 . _:b415462848 . . _:b415462849 . _:b415462850 . _:b415462762 "2"^^ . _:b415462851 . _:b415462852 . _:b415462853 . _:b415462849 . _:b415462854 . _:b415462773 "2"^^ . _:b415462855 . _:b415462872 . _:b415462786 . _:b415462873 . . . _:b415462874 . _:b415462772 "2"^^ . _:b415462875 . _:b415462876 . _:b415462877 . _:b415462878 . _:b415462775 "2"^^ . _:b415462855 . _:b415462879 . _:b415462864 . _:b6156094 . _:b415462764 . _:b415462865 . _:b415462866 . . _:b415462774 "2"^^ . _:b415462867 . _:b415462868 . _:b415462869 . _:b415462870 . _:b415462838 . _:b415462769 "2"^^ . _:b415462871 . _:b415462888 . _:b415462889 . _:b415462890 . _:b415462768 "2"^^ . _:b415462891 . "10.1038%2Fsj.bjc.6605308" . _:b415462892 . _:b415462893 . _:b415462894 . _:b415462771 "2"^^ . _:b415462895 . _:b415462880 . _:b415462767 . _:b415462881 . _:b415462882 . _:b415462770 "2"^^ . _:b415462883 . _:b415462884 . _:b6156091 . _:b415462885 . _:b6156054 . . . _:b415462886 . _:b415462887 . _:b415462781 "2"^^ . _:b415462780 "2"^^ . _:b415462785 . _:b415462868 . _:b415462797 . _:b415462783 "2"^^ . _:b415462896 . _:b6156075 . _:b415462897 . _:b415462898 . _:b415462899 . _:b415462782 "2"^^ . _:b415462900 . _:b415462901 . _:b6156076 "Our data are therefore supportive of the view that curcumin acts as an inhibitor of the UPS (Henke et al, 1999; Jana et al, >>2004<<; Si et al, 2007)." . _:b415462790 . _:b415462777 "2"^^ . _:b415462792 . _:b415462793 . _:b415462794 . . _:b415462776 "2"^^ . _:b415462761 . _:b415462795 . . _:b415462826 . _:b415462796 . . _:b415462797 . _:b415462798 . _:b415462799 . _:b415462779 "2"^^ . _:b415462784 . _:b415462785 . _:b415462786 . _:b415462778 "2"^^ . _:b415462787 . _:b415462788 . _:b415462716 . _:b415462789 . _:b415462790 . _:b415462791 . _:b415462789 "2"^^ . _:b415462808 . _:b6156094 "Combination studies so far in both in vitro and in vivo have highlighted promising combinations of curcumin with oxaliplatin (Howells et al, 2007; Li et al, >>2007<<; Patel et al, 2008) and paclitaxel (Aggarwal et al, 2005), suggesting there is a very definite potential for curcumin to be used as part of mainstream clinical regimes." . _:b415462809 . . _:b415462810 .