Al-Howail Huda A, Hakami Hana A, Al-Otaibi Basem, Al-Mazrou Amer, Daghestani Maha H, Al-Jammaz Ibrahim, Al-Khalaf Huda H, Aboussekhra Abdelilah
Department of Molecular Oncology, King Faisal Specialist Hospital and Research Center, MBC # 03, PO BOX 3354, Riyadh, 11211, Kingdom of Saudi Arabia.
Department of Zoology, College of Science, King Saud University, Riyadh, 11451, Kingdom of Saudi Arabia.
BMC Cancer. 2016 Jul 27;16:540. doi: 10.1186/s12885-016-2583-8.
Triple-negative breast cancer (TNBC) is an aggressive histological subtype with limited treatment options and very poor prognosis following progression after standard chemotherapeutic regimens. Therefore, novel molecules and therapeutic options are urgently needed for this category of patients. Recently, we have identified PAC as a curcumin analogue with potent anti-cancer features.
HPLC was used to evaluate the stability of PAC and curcumin in PBS and also in circulating blood. Cytotoxicity/apoptosis was assessed in different breast cancer cell lines using propidium iodide/annexinV associated with flow cytometry. Furthermore, immunoblotting analysis determined the effects of PAC on different oncogenic proteins and pathways. Additionally, the real time xCELLigence RTCA technology was applied to investigate the effect of PAC on the cellular proliferation, migration and invasion capacities.
PAC is more stable than curcumin in PBS and in circulating blood. Furthermore, we have shown differential sensitivity of estrogen receptor-alfa positive (ERα(+)) and estrogen receptor alfa negative (ERα(-)) breast cancer cells to PAC, which down-regulated ERα in both cell types. This led to complete disappearance of ERα in ERα(-) cells, which express very low level of this receptor. Interestingly, specific down-regulation of ERα in receptor positive cells increased the apoptotic response of these cells to PAC, confirming that ERα inhibits PAC-dependent induction of apoptosis, which could be mediated through ERα down-regulation. Additionally, PAC inhibited the proliferation and suppressed the epithelial-to-mesenchymal transition process in breast cancer cells, with higher efficiency on the TNBC subtype. This effect was also observed in vivo on tumor xenografts. Additionally, PAC suppressed the expression/secretion of 2 important cytokines IL-6 and MCP-1, and consequently inhibited the paracrine procarcinogenic effects of breast cancer cells on breast stromal fibroblasts.
These results indicate that PAC could be considered as important candidate for future therapeutic options against the devastating TNBC subtype.
三阴性乳腺癌（TNBC）是一种侵袭性组织学亚型，治疗选择有限，在标准化疗方案进展后的预后非常差。因此，这类患者迫切需要新的分子和治疗选择。最近，我们已确定PAC是一种具有强大抗癌特性的姜黄素类似物。
使用高效液相色谱法（HPLC）评估PAC和姜黄素在磷酸盐缓冲盐水（PBS）以及循环血液中的稳定性。使用碘化丙啶/膜联蛋白V结合流式细胞术在不同乳腺癌细胞系中评估细胞毒性/凋亡。此外，免疫印迹分析确定了PAC对不同致癌蛋白和信号通路的影响。此外，应用实时xCELLigence RTCA技术研究PAC对细胞增殖、迁移和侵袭能力的影响。
PAC在PBS和循环血液中比姜黄素更稳定。此外，我们已表明雌激素受体α阳性（ERα(+)）和雌激素受体α阴性（ERα(-)）乳腺癌细胞对PAC的敏感性存在差异，PAC在两种细胞类型中均下调ERα。这导致ERα(-)细胞中ERα完全消失，这些细胞中该受体表达水平极低。有趣的是，受体阳性细胞中ERα的特异性下调增加了这些细胞对PAC的凋亡反应，证实ERα抑制PAC依赖性凋亡诱导，这可能通过ERα下调介导。此外，PAC抑制乳腺癌细胞的增殖并抑制上皮-间质转化过程，对TNBC亚型的效率更高。在体内对肿瘤异种移植也观察到了这种效果。此外，PAC抑制两种重要细胞因子IL-6和MCP-1的表达/分泌，因此抑制乳腺癌细胞对乳腺基质成纤维细胞的旁分泌促癌作用。
这些结果表明，PAC可被视为未来针对具有破坏性的TNBC亚型的治疗选择的重要候选药物。
