A metabolite of nobiletin, 4'-demethylnobiletin and atorvastatin synergistically inhibits human colon cancer cell growth by inducing G0/G1 cell cycle arrest and apoptosis.
A metabolite of nobiletin, 4'-demethylnobiletin and atorvastatin synergistically inhibits human colon cancer cell growth by inducing G0/G1 cell cycle arrest and apoptosis.
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DOI：
10.1039/c7fo01155e
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发表时间：
2018-01-24
期刊：
影响因子：
6.1
通讯作者：
Xiao H
中科院分区：
文献类型：
--
作者：
Wu X ;Song M ;Qiu P ;Li F ;Wang M ;Zheng J ;Wang Q ;Xu F ;Xiao H
由于这些药物之间潜在的协同相互作用，结合不同的化学预防药物是降低癌症发病率和死亡率的一种有前途的策略。此前，我们证明口服0.05%（w/w，饮食中）川陈皮素（NBT，一种柑橘类黄酮）与0.02%（w/w，饮食中）阿托伐他汀（ATST，一种降脂药）对大鼠结肠癌的抑制作用比NBT（饮食中0.1% w/w）或ATST（饮食中0.1% w/w）更强。 0.04% w/w (饮食中)单独使用较高剂量。为了进一步阐明NBT和ATST之间这种有希望的协同作用的机制，本文中，我们测量了喂食NBT（饮食中0.05％w/w）+ ATST（饮食中0.02％w/w）的大鼠结肠组织中NBT及其主要代谢物和ATST的水平，并确定了NBT主要代谢物和ATST在抑制结肠癌细胞生长中的相互作用模式。 HPLC-MS分析显示4’-去甲基川陈皮素(4DN)是NBT最丰富的代谢物，在结肠组织中的水平约为NBT的5倍，这表明4DN在介导NBT在结肠中的生物学效应中具有潜在意义。我们发现，4DN/ATST以2:1浓度比共同处理对人结肠癌HT-29细胞产生比单独4DN或ATST更强的生长抑制作用，等效线图分析证实4DN/ATST组合的这种增强的抑制作用是高度协同的。 4DN/ATST 共同处理导致 G0/G1 细胞周期停滞并诱导 HT-29 细胞广泛凋亡。此外，4DN/ATST 联合治疗深刻调节与细胞周期和细胞凋亡调节相关的关键信号蛋白。我们的结果表明，4DN/ATST 联合治疗在抑制结肠癌细胞生长方面产生了强大的协同作用，这为 NBT/ATST 联合协同抑制结肠癌的发生提供了新的机制。
Combining different chemopreventive agents is a promising strategy to reduce cancer incidence and mortality due to potential synergistic interactions between these agents. Previously, we demonstrated that oral administration of nobiletin (NBT, a citrus flavonoid) at 0.05% (w/w, in diet) together with atorvastatin (ATST, a lipid-lowering drug) at 0.02% (w/w, in diet) produced much stronger inhibition on colon carcinogenesis in rats in comparision with that produced by NBT (at 0.1% w/w in diet) or ATST (at 0.04% w/w in diet) alone at higher doses. To further elucidate the mechanism of this promising synergy between NBT and ATST, herein, we measured the levels of NBT, its major metabolites and ATST in the colonic tissue of rats fed NBT (0.05% w/w, in diet) + ATST (0.02% w/w, in diet), and determined the mode of interation between the major NBT metabolite and ATST in inihibiting colon cancer cell growth. HPLC-MS analysis showed that 4’-demethylnobiletin (4DN) is the most abundant metabolite of NBT with a level about 5-fold as high as that of NBT in the colonic tissue, which indicated potential significance of 4DN in mediating biological effects of NBT in the colon . We found that co-treatments of 4DN/ATST at 2: 1 concentration ratio produced much stronger growth inhibitory effect on human colon cancer HT-29 cells than 4DN or ATST alone, and isobologram analysis confirmed that this enhanced inhibitory effect by 4DN/ATST combination was highly synergistic. Co-treatment of 4DN/ATST led to G0/G1 cell cycle arrest and induced extensive apoptosis in HT-29 cells. Furthermore, 4DN/ATST co-treatment profoundly modulated key signaling proteins related with regulation of cell cycle and apoptosis. Our results demonstrated a strong synergy produced by 4DN/ATST co-treatment in inhibiting colon cancer cell growth, which provided a novel mechanism by which NBT/ATST in combination synergistically inhibit colon carcinogenesis.
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影响因子：
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