A novel curcumin analog (H-4073) enhances the therapeutic efficacy of cisplatin treatment in head and neck cancer.
A novel curcumin analog (H-4073) enhances the therapeutic efficacy of cisplatin treatment in head and neck cancer.
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DOI：
10.1371/journal.pone.0093208
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Kumar P
中科院分区：
文献类型：
--
作者：
Kumar B;Yadav A;Hideg K;Kuppusamy P;Teknos TN;Kumar P
化疗是局部头颈鳞状细胞癌（HNSCC）的标准治疗方式。然而，由于获得了化疗耐药性，许多患者在这种治疗后未能做出反应并复发。因此，迫切需要开发能够逆转耐药表型的新药。姜黄素是香料姜黄的成分，已被证明对多种肿瘤类型具有抗炎、抗氧化和抗增殖特性。然而，姜黄素的使用由于其生物吸收差而受到限制。最近，通过将哌啶酮连接到β-二酮结构和苯基上的氟取代，开发出了基于二芳基哌啶酮（DAP）的新型姜黄素类似物。在这项研究中，我们使用体外和体内头颈癌模型评估了 H-4073（DAP 的一种全氟变体）的有效性。我们的结果表明，H-4073 是一种有效的抗肿瘤剂，它以剂量依赖性方式显着抑制所有测试的 HNSCC 细胞系的细胞增殖。此外，通过细胞活力测定 (MTT)、细胞凋亡测定（Annexin V 结合）和 cleaved caspase-3（Western blot）观察到，用 H-4073 预处理顺铂耐药的 HNSCC 细胞系可显着逆转化疗耐药性。 H-4073 通过抑制 JAK/STAT3、FAK、Akt 和 VEGF 信号通路介导其抗肿瘤作用，这些信号通路在细胞增殖、迁移、存活和血管生成中发挥重要作用。在SCID小鼠异种移植模型中，H-4073显着增强了顺铂的抗肿瘤和抗血管生成作用，且没有增加全身毒性。有趣的是，H-4073 通过阻断肿瘤细胞产生 VEGF 以及直接抑制内皮细胞功能来抑制肿瘤血管生成。综上所述，我们的结果表明 H-4073 是一种有效的抗肿瘤药物，可用于克服 HNSCC 的化疗耐药性。
Chemotherapy constitutes the standard modality of treatment for localized head and neck squamous cell carcinomas (HNSCC). However, many patients fail to respond and relapse after this treatments due to the acquisition of chemo-resistance. Therefore, there is an urgent need to develop novel drugs that could reverse the resistant phenotype. Curcumin, the constituent of the spice turmeric has been shown to have anti-inflammatory, anti-oxidant and anti-proliferative properties in several tumor types. However, use of curcumin has been limited due to its poor bio-absorption. Recently, a novel class of curcumin analogs, based on diarylidenylpiperidones (DAP), has been developed by incorporating a piperidone link to the beta-diketone structure and fluoro substitutions on the phenyl groups. In this study, we evaluated the effectiveness of H-4073, a parafluorinated variant of DAP, using both in vitro and in vivo head and neck cancer models. Our results demonstrate that H-4073 is a potent anti-tumor agent and it significantly inhibited cell proliferation in all the HNSCC cell lines tested in a dose-dependent manner. In addition, pretreatment of cisplatin-resistant HNSCC cell lines with H-4073 significantly reversed the chemo-resistance as observed by cell viability assay (MTT), apoptosis assay (Annexin V binding) and cleaved caspase-3 (Western blot). H-4073 mediated its anti-tumor effects by inhibiting JAK/STAT3, FAK, Akt and VEGF signaling pathways that play important roles in cell proliferation, migration, survival and angiogenesis. In the SCID mouse xenograft model, H-4073 significantly enhanced the anti-tumor and anti-angiogenesis effects of cisplatin, with no added systemic toxicity. Interestingly, H-4073 inhibited tumor angiogenesis by blocking VEGF production by tumor cells as well as directly inhibiting endothelial cell function. Taken together, our results suggest that H-4073 is a potent anti-tumor agent and it can be used to overcome chemotherapy resistance in HNSCC.
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影响因子：
8
作者：
Bourguignon, L. Y. W.;Earle, C.;Wong, G.;Spevak, C. C.;Krueger, K.
通讯作者：
Krueger, K.
影响因子：
5.7
作者：
Kumar B;Yadav A;Lang JC;Cipolla MJ;Schmitt AC;Arradaza N;Teknos TN;Kumar P
通讯作者：
Kumar P
影响因子：
16
作者：
Lim, Ssang-Taek;Chen, Xiao Lei;Llic, Dusko
通讯作者：
Llic, Dusko
Stat3和Notch1的表达与头颈鳞癌顺铂耐药相关
影响因子：
4.2
作者：
Gu, Feng;Ma, Yongjie;Fu, Li
通讯作者：
Fu, Li
DOI：
10.1002/hed.10274
发表时间：
2003-08-01
影响因子：
2.9
作者：
Bradford, CR;Zhu, SB;Carey, TE
通讯作者：
Carey, TE