Goyal Navneet, Do Camilla, Hill-Odom Miriam, Beamon Teresa, Ponnapakkam Tulasi, Liu Jiawang, Sridhar Jayalakshmi, Huckaba Thomas, Foroozesh Maryam
Department of Chemistry, Xavier University of Louisiana, New Orleans, LA, USA.
University of Tennessee Health Sciences Center, Memphis, TN, USA.
J Oncol Res Ther. 2023;8(2). doi: 10.29011/2574-710x.10172.
Many current anti-cancer drugs used to treat breast cancer mediate tumor cell death through the induction of apoptosis. Cancer cells, however, often acquire multidrug-resistance following prolonged exposure to chemotherapeutics. Consequently, molecular pathways involved in tumor cell proliferation have become potential targets for pharmacological intervention. Ceramides are tumor suppressor lipids naturally found in the cell membrane, and are central molecules in the sphingolipid signalling pathway.
Our lab has targeted the ceramide signaling pathway for potential pharmacological intervention in the treatment of breast cancer. Previously, we have shown that certain ceramide analogs have therapeutic potential in the treatment of chemo-sensitive and multidrug-resistant breast cancers. Using the most active analog from our previous studies as the lead compound, new analogs containing a flavone moiety were designed and synthesized. In general, flavone derivatives often show interesting pharmacological properties, and compounds based on these molecules have been found useful in many different therapeutic areas including anti-tumor, anti-coagulants, and anti-HIV therapy.
Synthesis and biological evaluation of five new flavonoid ceramide analogs are reported here. These compounds were also shown to be self-fluorescent, which can be useful when investigating their distribution and action in cancer cells.
Four out of the five flavone ceramide analogs in this study showed significant anti-proliferation activities in the three cell lines studied, MDA-MB-232, MCF-7, and MCF-7TN-R; some showing varying degrees of selectivity. The mechanisms involved in cell proliferation inhibition are complicated and further studies are needed.
目前许多用于治疗乳腺癌的抗癌药物通过诱导细胞凋亡来介导肿瘤细胞死亡。然而，癌细胞在长期接触化疗药物后常常会产生多药耐药性。因此，参与肿瘤细胞增殖的分子途径已成为药物干预的潜在靶点。神经酰胺是天然存在于细胞膜中的肿瘤抑制性脂质，是鞘脂信号通路的核心分子。
我们实验室已将神经酰胺信号通路作为乳腺癌治疗中潜在的药物干预靶点。此前，我们已表明某些神经酰胺类似物在治疗化疗敏感型和多药耐药型乳腺癌方面具有治疗潜力。以我们之前研究中活性最高的类似物作为先导化合物，设计并合成了含有黄酮部分的新类似物。一般来说，黄酮衍生物常常表现出有趣的药理特性，基于这些分子的化合物已被发现在许多不同的治疗领域有用，包括抗肿瘤、抗凝血和抗HIV治疗。
本文报道了五种新的黄酮类神经酰胺类似物的合成及生物学评价。这些化合物还显示出自身荧光性，这在研究它们在癌细胞中的分布和作用时可能会有用。
本研究中的五种黄酮神经酰胺类似物中有四种在研究的三种细胞系MDA-MB-232、MCF-7和MCF-7TN-R中显示出显著的抗增殖活性；有些表现出不同程度的选择性。细胞增殖抑制所涉及的机制很复杂，需要进一步研究。
