Panda Siva S, Tran Queen L, Rajpurohit Pragya, Pillai Girinath G, Thomas Sean J, Bridges Allison E, Capito Jason E, Thangaraju Muthusamy, Lokeshwar Bal L
Department of Chemistry and Physics, Augusta University, Augusta, GA 30912, USA.
Department of Biochemistry and Molecular Biology, Augusta University, Augusta, GA 30912, USA.
Pharmaceuticals (Basel). 2022 Apr 6;15(4):451. doi: 10.3390/ph15040451.
Curcumin (CUR) has received great attention over the past two decades due to its anticancer, anti-inflammatory, and antioxidant properties. Similarly, Dichloroacetate (DCA), an pyruvate dehydrogenase kinase 1 (PKD1) inhibitor, has gained huge attention as a potential anticancer drug. However, the clinical utility of these two agents is very limited because of the poor bioavailability and unsolicited side effects, respectively. We have synthesized fusion conjugates of CUR and DCA with an amino acids linker to overcome these limitations by utilizing the molecular hybridization approach. The molecular docking studies showed the potential targets of Curcumin-Modified Conjugates (CMCs) in breast cancer cells. We synthesized six hybrid conjugates named . These six CMC conjugates do not show any significant toxicity in a human normal immortalized mammary epithelial cell line (MCF10A) in vitro and C57BL/6 mice in vivo. However, treatment with and significantly reduced the growth and clonogenic survival by colony-formation assays in several human breast cancer cells (BC). Treatment by oral gavage of a transgenic mouse BC and metastatic BC tumor-bearing mice with significantly reduced tumor growth and metastasis. Overall, our study provides strong evidence that CUR and DCA conjugates have a significant anticancer properties at a sub-micromolar concentration and overcome the clinical limitation of using CUR and DCA as potential anticancer drugs.
姜黄素（CUR）在过去二十年中因其抗癌、抗炎和抗氧化特性而备受关注。同样，二氯乙酸（DCA）作为一种丙酮酸脱氢酶激酶1（PKD1）抑制剂，作为一种潜在的抗癌药物也受到了极大关注。然而，由于生物利用度差和副作用，这两种药物的临床应用非常有限。我们通过氨基酸连接体合成了CUR和DCA的融合共轭物，以利用分子杂交方法克服这些限制。分子对接研究显示了姜黄素修饰共轭物（CMC）在乳腺癌细胞中的潜在靶点。我们合成了六种名为 的杂合共轭物。这六种CMC共轭物在体外人正常永生化乳腺上皮细胞系（MCF10A）和体内C57BL/6小鼠中均未显示出任何显著毒性。然而，用 和 处理通过集落形成试验显著降低了几种人乳腺癌细胞（BC）的生长和克隆形成存活率。通过对转基因小鼠BC和转移性BC荷瘤小鼠口服灌胃 显著降低了肿瘤生长和转移。总体而言,我们的研究提供了强有力的证据，表明CUR和DCA共轭物在亚微摩尔浓度下具有显著的抗癌特性，并克服了将CUR和DCA用作潜在抗癌药物的临床局限性。
