Siddiqui Rafat A, Harvey Kevin A, Xu Zhidong, Natarajan Selvamuthu K, Davisson V Jo
Cellular Biochemistry Laboratory, Methodist Research Institute, Indiana University Health, 1800 N. Capitol Ave., Room E504, Indianapolis, IN 46202, USA; Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Cellular Biochemistry Laboratory, Methodist Research Institute, Indiana University Health, 1800 N. Capitol Ave., Room E504, Indianapolis, IN 46202, USA.
Bioorg Med Chem. 2014 Mar 15;22(6):1899-908. doi: 10.1016/j.bmc.2014.01.051. Epub 2014 Feb 6.
Lovastatin (LOV) and docosahexaenoic acid (DHA), besides improving cardiovascular functions, are also known for their anticancer activities. However, use of these compounds for treating or preventing cancer is limited because of their efficacies. The approach pursued involved chemical linkage of these two chemotypes. A lovastatin-docosahexaenoate (LOV-DHA) conjugate was prepared and tested against selected breast tumor cells lines with differential expression of estrogen receptors (ER) and Heregulin-2 (Her-2). The LOV-DHA conjugate exhibited superior cytotoxic effects against ER(-)/Her-2(-) cell lines (MDA-MB-231 and MDA-MB-468), which were not observed with DHA or lovastatin alone, or in combination. Lovastatin supplementation arrested cells in the G₀/G₁ phase and enhanced expression levels of p21, whereas the conjugate did not demonstrate cell cycle arrest nor increased p21 expression. The LOV-DHA conjugate induced significant (P<0.05) apoptosis as low as 1 μM, whereas DHA and lovastatin were ineffective at this concentration. The growth inhibitory effects of lovastatin were reversed by the addition of mevalonate, whereas mevalonate had no effect on the LOV-DHA conjugate-induced growth inhibition in MDA-MB-231 cells. Furthermore, the LOV-DHA conjugates were stable in mouse serum and intracellularly in MDA-MB-231 cells. These data suggest that the LOV-DHA conjugate mediated its effects through a HMG-CoA reductase-independent pathway and exerted significantly (P<0.05) higher anticancer effects in breast cancer cells than lovastatin or DHA alone.
洛伐他汀（LOV）和二十二碳六烯酸（DHA）除了能改善心血管功能外，还因其抗癌活性而闻名。然而，由于它们的疗效，这些化合物在治疗或预防癌症方面的应用受到限制。所采用的方法涉及将这两种化学类型进行化学连接。制备了一种洛伐他汀 - 二十二碳六烯酸酯（LOV - DHA）缀合物，并针对具有不同雌激素受体（ER）和人表皮生长因子受体 - 2（Her - 2）表达的选定乳腺癌细胞系进行了测试。LOV - DHA缀合物对ER（-）/ Her - 2（-）细胞系（MDA - MB - 231和MDA - MB - 468）表现出卓越的细胞毒性作用，单独使用DHA或洛伐他汀，或两者联合使用时均未观察到这种作用。补充洛伐他汀使细胞停滞在G₀/G₁期并提高p21的表达水平，而该缀合物未表现出细胞周期停滞，也未增加p21的表达。LOV - DHA缀合物在低至1μM时即可诱导显著（P<0.05）的细胞凋亡，而在此浓度下DHA和洛伐他汀无效。添加甲羟戊酸可逆转洛伐他汀的生长抑制作用，而甲羟戊酸对MDA - MB - 231细胞中LOV - DHA缀合物诱导的生长抑制没有影响。此外，LOV - DHA缀合物在小鼠血清和MDA - MB - 231细胞内是稳定的。这些数据表明，LOV - DHA缀合物通过一条不依赖HMG - CoA还原酶的途径介导其作用，并且在乳腺癌细胞中比单独使用洛伐他汀或DHA具有显著（P<0.05）更高的抗癌效果。
