Sarkar Fazlul H, Adsule Shreelekha, Padhye Subhash, Kulkarni Sudhir, Li Yiwei
Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA.
Mini Rev Med Chem. 2006 Apr;6(4):401-7. doi: 10.2174/138955706776361439.
Genistein, one of the predominant soy isoflavones, has been shown to compete with 17beta-estradiol for estrogen receptor binding because of its structural similarity, resulting in agonistic or antagonistic activity. It causes inhibition of cell growth in breast and prostate cancers in vivo and in vitro. From gene expression profiles, genistein has been found to regulate the genes that are critical for the control of cell proliferation, cell cycle, apoptosis, oncogenesis, transcription regulation, and cell signal transduction pathways. It has been reported that genistein induces apoptosis and inhibits activation of NF-kappaB and Akt signaling pathways, both of which are known to maintain a balance between cell survival and apoptosis. Recently, we found that genistein sensitized cancer cells to apoptosis induced by chemotherapeutic agents including docetaxel, gemcitabine and cisplatin through inactivation of NF-kappaB in multiple cancer cell lines. To enhance the anti-cancer activity of genistein, we have synthesized structurally-modified derivatives of isoflavone based on the structural requirements for optimal anti-cancer effect. We found that these synthetic derivatives of isoflavone exerted higher anti-cancer activity with lower IC50. These derivatives of isoflavone also induced more apoptosis compared to genistein. These results suggest that genistein and synthetic structurally-modified derivatives of isoflavone may be promising agents for cancer chemoprevention and therapy either alone or in combination with existing chemotherapeutic agents.
染料木黄酮是大豆中主要的异黄酮之一，因其结构相似性，已被证明可与17β-雌二醇竞争雌激素受体结合，从而产生激动或拮抗活性。它在体内和体外均可抑制乳腺癌和前列腺癌的细胞生长。从基因表达谱来看，已发现染料木黄酮可调节对细胞增殖、细胞周期、细胞凋亡、肿瘤发生、转录调控及细胞信号转导通路控制至关重要的基因。据报道，染料木黄酮可诱导细胞凋亡，并抑制NF-κB和Akt信号通路的激活，而这两条信号通路已知在细胞存活与凋亡之间维持平衡。最近，我们发现染料木黄酮通过使多种癌细胞系中的NF-κB失活，使癌细胞对包括多西他赛、吉西他滨和顺铂在内的化疗药物诱导的凋亡敏感。为增强染料木黄酮的抗癌活性，我们基于最佳抗癌效果的结构要求，合成了异黄酮的结构修饰衍生物。我们发现这些异黄酮的合成衍生物具有更高的抗癌活性和更低的IC50。与染料木黄酮相比，这些异黄酮衍生物还可诱导更多的细胞凋亡。这些结果表明，染料木黄酮和异黄酮的合成结构修饰衍生物可能是单独或与现有化疗药物联合用于癌症化学预防和治疗的有前景的药物。
