The College of Staten Island, City University of New York, Staten Island, NY, USA.
Int J Cancer. 2012 Aug 15;131(4):E569-78. doi: 10.1002/ijc.26479. Epub 2012 Jan 3.
In vitro studies have shown that curcumin, a polyphenol from the culinary component turmeric, has strong anticancer properties. However, there is no consensus on its therapeutic effect in human. Our earlier experiments involving implanted murine melanoma B16F10 cells in the neck or brain of syngeneic C57BL6 mice showed that tail vein injection of curcumin blocks formation of lesions and tumor in these mice. However, such treatment was ineffective in eliminating established tumors that already occupied ≤10% of brain volume. Possible reasons include low solubility and rapid metabolism of curcumin in vivo. To increase its efficacy, we have linked curcumin through a cleavable arm to an antibody (Ab) against the melanoma surface antigen Muc18. The antibody-coupled curcumin was 230-fold more effective in eliminating B16F10 cells in vitro, and in vivo, it rapidly decimated established, B16F10-evoked brain tumors, enabling the rescued mice to live normally far beyond 90 days from implantation of cancer cells. In contrast, mice treated with Muc18 Ab alone died of brain tumor within a month. In B16F10 cells, curcumin-Ab (adduct) treatment caused a dramatic inhibition of NF-kB: a transcription factor that is constitutively activated in cancer cells. Furthermore, overexpression of NF-kB in the B16F10 cells blocked adduct-evoked stimulation of caspase-3/7 activity. Thus, by suppressing NF-kB, the curcumin adduct inhibits other downstream tumor-promoting proteins, thereby eliminating the B16F10 cells. Our study submits a novel yet generally applicable strategy of converting curcumin into a potent anticancer agent and provides a mechanistic framework for its action.
体外研究表明，姜黄素是来自烹饪用姜黄的多酚，具有很强的抗癌特性。然而，其在人类中的治疗效果尚无定论。我们之前的实验涉及将植入性鼠黑色素瘤 B16F10 细胞注射到同种系 C57BL6 小鼠的颈部或脑部，结果显示尾静脉注射姜黄素可阻止这些小鼠的病变和肿瘤形成。然而，这种治疗方法对于消除已占据≤10%脑容量的已建立肿瘤无效。可能的原因包括姜黄素在体内的低溶解度和快速代谢。为了提高其疗效，我们通过可裂解臂将姜黄素与针对黑色素瘤表面抗原 Muc18 的抗体（Ab）连接起来。抗体偶联的姜黄素在体外消除 B16F10 细胞的效果提高了 230 倍，在体内，它迅速消灭了已建立的、由 B16F10 引起的脑肿瘤，使获救的小鼠在植入癌细胞后能正常存活 90 天以上。相比之下，单独用 Muc18 Ab 治疗的小鼠在一个月内死于脑肿瘤。在 B16F10 细胞中，姜黄素-Ab（加合物）处理导致 NF-kB 的强烈抑制：一种在癌细胞中持续激活的转录因子。此外，B16F10 细胞中 NF-kB 的过表达阻断了加合物诱导的 caspase-3/7 活性的刺激。因此，通过抑制 NF-kB，姜黄素加合物抑制了其他下游促进肿瘤的蛋白质，从而消除了 B16F10 细胞。我们的研究提出了一种将姜黄素转化为有效抗癌剂的新颖但普遍适用的策略，并为其作用提供了一个机制框架。
