The spice-derived phenolic, malabaricone B (mal B) showed selective toxicity to human lung cancer (A549), malignant melanoma (A375) and T cell leukemia (Jurkat) cell lines, without showing toxicity to human normal intestinal (INT407), human kidney (HEK293) and lung fibroblast (WI-38) cells. Among the chosen cancer cell lines, mal B showed maximum cytotoxicity to the A549 cells (IC₅₀ = 8.1 ± 1.0 μM), which was significantly better than that of curcumin (IC₅₀ = 26.7 ± 3.1 μM). Further morphological studies by phase contrast microscopy and a clonogenic assay of the A549 cells revealed that mal B treatment increased the number of shrinking cells and also abolished the clonal proliferation of the cells. Mal B induced apoptotic cell death was confirmed by DNA laddering and quantified by cytoplasmic oligonucleosome formation and annexin V/PI assays. The mal B-induced apoptosis was mediated by an increase in the intracellular reactive oxygen species (ROS), because the cell-permeable antioxidants, N-acetylcysteine (NAC) and PEG-SOD, strongly inhibited its cytotoxicity to the A549 cells. Mal B increased the BAX level while simultaneously decreasing the BCL-2 and BCL-X_L levels in the A549 cells, triggering the mitochondrial apoptotic pathway as revealed from the release of cytochrome c, and the activation of caspase-9 and caspase-3. Pre-treatment of cells with caspase-9, caspase-3 and pan-caspase inhibitors made them more resistant to mal B treatment. This effect of mal B was strongly associated with the concomitant decrease in anti-apoptotic (IAP1, IAP2 and survivin), angiogenic (growth factors) and cancer invasiveness (matrix metalloproteinase-9, COX-2) modulating proteins. Mal B induced cytotoxicity was unaffected by the shRNA-mediated depletion of p53 in A549 cells. Most importantly, mal B sensitized a wide range of human carcinoma cells regardless of their p53 status. Finally, mal B (100 mg kg⁻¹) also inhibited lung tumor (xenograft) growth in SCID mice.

中文翻译：

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香料衍生的酚类，马拉巴酮B通过非p53途径诱导肺癌细胞的线粒体损伤†

香料衍生的酚类，马拉巴酮B（mal B）对人肺癌（A549），恶性黑色素瘤（A375）和T细胞白血病（Jurkat）细胞系表现出选择性毒性，而对人正常肠道（INT407）无毒性肾（HEK293）和肺成纤维细胞（WI-38）细胞。在所选的癌细胞系中，mal B对A549细胞表现出最大的细胞毒性（IC ₅₀ = 8.1±1.0μM），明显优于姜黄素（IC _50）。= 26.7±3.1μM）。通过相差显微镜和对A549细胞的克隆形成分析的进一步形态学研究显示，mal B处理增加了收缩细胞的数量，也消除了细胞的克隆增殖。DNA梯形证实了Mal B诱导的凋亡细胞死亡，并通过胞质寡核小体形成和膜联蛋白V / PI分析进行了定量。mal B诱导的细胞凋亡是由细胞内活性氧（ROS）的增加介导的，因为细胞可渗透的抗氧化剂N-乙酰半胱氨酸（NAC）和PEG-SOD强烈抑制了其对A549细胞的细胞毒性。Mal B增加了BAX的水平，同时降低了BCL-2和BCL-X _L从细胞色素c的释放以及caspase-9和caspase-3的激活所揭示的水平来看，A549细胞中A549的水平升高，触发了线粒体凋亡途径。用caspase-9，caspase-3和pan-caspase抑制剂预处理细胞后，它们对mal B治疗的抵抗力就会增强。mal B的这种作用与抗凋亡（IAP1，IAP2和survivin），血管生成（生长因子）和癌症侵袭性（基质金属蛋白酶9，COX-2）调节蛋白的降低密切相关。Mal B诱导的细胞毒性不受A549细胞中shRNA介导的p53消耗的影响。最重要的是，无论B53处于何种状态，mal B都能使多种人类癌细胞敏感。最后，mal B（100 mg kg ^-1）也抑制了SCID小鼠的肺肿瘤（异种移植）生长。