Curcumin induces proapoptotic effects against human melanoma cells and modulates the cellular response to immunotherapeutic cytokines.
Curcumin induces proapoptotic effects against human melanoma cells and modulates the cellular response to immunotherapeutic cytokines.
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DOI：
10.1158/1535-7163.mct-09-0377
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发表时间：
2009-09
影响因子：
5.7
通讯作者：
Lesinski GB
中科院分区：
文献类型：
--
作者：
Bill MA;Bakan C;Benson DM Jr;Fuchs J;Young G;Lesinski GB
姜黄素具有作为化学预防剂和化学治疗剂的潜力，然而其与临床相关细胞因子的相互作用的特征很差。由于细胞因子免疫疗法是治疗恶性黑色素瘤的主要手段，我们假设姜黄素可以调节细胞对干扰素和白细胞介素的反应。作为单一药物，姜黄素诱导人黑色素瘤细胞系凋亡的剂量依赖性增加，这在>10 µM的剂量下最突出。免疫印迹分析证实，姜黄素诱导细胞凋亡，并揭示caspase-3加工，PARP切割，减少Bcl-2和减少基础磷酸化STAT 3。尽管姜黄素具有促凋亡作用，但姜黄素预处理人黑色素瘤细胞系抑制了IFN-α和IFN-γ后STAT 1蛋白的磷酸化和下游基因的转录，分别通过免疫印迹分析和真实的时间PCR测定。用姜黄素预处理来自健康供体的外周血单核细胞（PBMC）还抑制IFN-α、IFN-γ和IL-2磷酸化STAT蛋白的能力，所述STAT蛋白对于它们的抗肿瘤活性（分别为STAT 1和STAT 5）及其各自的下游基因表达至关重要，如通过真实的时间PCR测量的。最后，用姜黄素刺激自然杀伤（NK）细胞降低了IL-12诱导的IFN-γ分泌水平，以及在与作为靶标的A375黑素瘤细胞或NK敏感性K562细胞共培养时颗粒酶B或IFN-γ的产生。这些数据表明，虽然姜黄素可以诱导黑色素瘤细胞的凋亡，但它也可以不利地影响免疫效应细胞对具有抗肿瘤特性的临床相关细胞因子的反应性。
Curcumin has potential as a chemopreventative and chemotherapeutic agent however its interactions with clinically relevant cytokines are poorly characterized. Since cytokine immunotherapy is a mainstay of treatment for malignant melanoma, we hypothesized that curcumin could modulate the cellular responsiveness to interferons and interleukins. As a single agent, curcumin induced a dose-dependent increase in apoptosis of human melanoma cell lines, which was most prominent at doses >10 µM. Immunoblot analysis confirmed that curcumin induced apoptosis and revealed caspase-3 processing, PARP cleavage, reduced Bcl-2 and decreased basal phosphorylated STAT3. Despite its pro-apoptotic effects, curcumin pre-treatment of human melanoma cell lines inhibited the phosphorylation of STAT1 protein and downstream gene transcription following IFN-α and IFN-γ as determined by immunoblot analysis and Real Time PCR, respectively. Pre-treatment of peripheral blood mononuclear cells (PBMCs) from healthy donors with curcumin also inhibited the ability of IFN-α, IFN-γ and IL-2 to phosphorylate STAT proteins critical for their anti-tumor activity (STAT1 and STAT5, respectively) and their respective downstream gene expression as measured by Real Time PCR. Finally, stimulation of natural killer (NK) cells with curcumin reduced the level of IL-12-induced IFN-γ secretion, and production of granzyme b or IFN-γ upon co-culture with A375 melanoma cells or NK sensitive K562 cells as targets. These data demonstrate that although curcumin can induce apoptosis of melanoma cells, it can also adversely affect the responsiveness of immune effector cells to clinically relevant cytokines that possess anti-tumor properties.