4-oxo-fenretinide, a recently identified fenretinide metabolite, induces marked G2-M cell cycle arrest and apoptosis in fenretinide-sensitive and fenretinide-resistant cell lines.
4-oxo-fenretinide, a recently identified fenretinide metabolite, induces marked G2-M cell cycle arrest and apoptosis in fenretinide-sensitive and fenretinide-resistant cell lines.
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DOI：
10.1158/0008-5472.can-05-3362
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发表时间：
2006-03
期刊：
影响因子：
11.2
通讯作者：
M. G. Villani;V. Appierto;E. Cavadini;A. Bettiga;A. Prinetti;M. Clagett-Dame;R. Curley;F. Formelli
中科院分区：
文献类型：
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作者：
M. G. Villani;V. Appierto;E. Cavadini;A. Bettiga;A. Prinetti;M. Clagett-Dame;R. Curley;F. Formelli
4-氧代-N-（4-羟基苯基）维甲酰胺（4-oxo-4-HPR）是芬维A胺（4-HPR）的一种代谢产物。我们探讨了4-oxo-4-HPR在卵巢、乳腺和神经母细胞瘤肿瘤细胞系中诱导细胞生长抑制的有效性;此外，我们研究了两种卵巢癌细胞系中介导这种效应的分子事件，一种对4-HPR敏感（A2780），一种对4-HPR耐药（A2780/HPR）。4-氧代-4-HPR在大多数细胞系中比4-HPR有效2至4倍，在4-HPR敏感和4-HPR抗性细胞中均有效，并且与4-HPR组合引起协同效应。4-oxo-4-HPR的肿瘤生长抑制作用似乎不依赖于核维甲酸受体（RAR），如RAR拮抗剂抑制其作用的失败以及其结合和反式激活RAR的能力差所示。与4-HPR不同，4-oxo-4-HPR仅轻微影响细胞周期的G（1）期，4-oxo-4-HPR导致细胞在G（2）-M期显著蓄积。这种效应与G（2）-M（细胞周期蛋白依赖性激酶1和cdc 25 c）和S（细胞周期蛋白A）期调节蛋白表达的减少以及凋亡相关蛋白（如p53和p21）表达的增加有关。4-oxo-4-HPR在4-HPR敏感和4-HPR抗性细胞中诱导凋亡，并涉及caspase-3和caspase-9的激活，但不涉及caspase-8。我们还表明，4-氧代-4-HPR，类似于4-HPR，增加活性氧的产生和神经酰胺的从头合成水平。总之，4-氧代-4-HPR是一种有效的4-HPR代谢物，其本身可能充当治疗剂，并且当与4-HPR组合时，可能改善4-HPR活性或克服4-HPR抗性。
4-oxo-N-(4-hydroxyphenyl)retinamide (4-oxo-4-HPR) is a recently identified metabolite of fenretinide (4-HPR). We explored the effectiveness of 4-oxo-4-HPR in inducing cell growth inhibition in ovarian, breast, and neuroblastoma tumor cell lines; moreover, we investigated the molecular events mediating this effect in two ovarian carcinoma cell lines, one sensitive (A2780) and one resistant (A2780/HPR) to 4-HPR. 4-oxo-4-HPR was two to four times more effective than 4-HPR in most cell lines, was effective in both 4-HPR-sensitive and 4-HPR-resistant cells, and, in combination with 4-HPR, caused a synergistic effect. The tumor growth-inhibitory effects of 4-oxo-4-HPR seem to be independent of nuclear retinoid receptors (RAR), as indicated by the failure of RAR antagonists to inhibit its effects and by its poor ability to bind and transactivate RARs. Unlike 4-HPR, which only slightly affected the G(1) phase of the cell cycle, 4-oxo-4-HPR caused a marked accumulation of cells in G(2)-M. This effect was associated with a reduction in the expression of regulatory proteins of G(2)-M (cyclin-dependent kinase 1 and cdc25c) and S (cyclin A) phases, and with an increase in the expression of apoptosis-related proteins, such as p53 and p21. Apoptosis was induced by 4-oxo-4-HPR in both 4-HPR-sensitive and 4-HPR-resistant cells and involved activation of caspase-3 and caspase-9 but not caspase-8. We also showed that 4-oxo-4-HPR, similarly to 4-HPR, increased reactive oxygen species generation and ceramide levels by de novo synthesis. In conclusion, 4-oxo-4-HPR is an effective 4-HPR metabolite that might act as therapeutic agent per se and, when combined with 4-HPR, might improve 4-HPR activity or overcome 4-HPR resistance.