Curcumin circumvents chemoresistance in vitro and potentiates the effect of thalidomide and bortezomib against human multiple myeloma in nude mice model.
Curcumin circumvents chemoresistance in vitro and potentiates the effect of thalidomide and bortezomib against human multiple myeloma in nude mice model.
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DOI：
10.1158/1535-7163.mct-08-0905
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发表时间：
2009-04
影响因子：
5.7
通讯作者：
Aggarwal BB
中科院分区：
文献类型：
--
作者：
Sung B;Kunnumakkara AB;Sethi G;Anand P;Guha S;Aggarwal BB
姜黄素（二阿魏酰甲烷）是姜黄中的一种黄色色素，已被证明可抑制NF-κB的活化，NF-κ B是一种与多发性骨髓瘤（MM）细胞的化疗耐药性密切相关的转录因子。姜黄素是否可以克服化疗耐药性和增强沙利度胺和硼替佐米的活性，用于治疗MM患者，在体外和裸鼠异种移植模型中进行了研究。我们的研究结果表明，姜黄素抑制人MM细胞的增殖，而不管它们对地塞米松、阿霉素或美法仑的敏感性如何。姜黄素还通过下调NF-κB B和Akt的组成性激活增强沙利度胺和硼替佐米的凋亡作用;这与NF-κ B调节的基因产物的抑制相关，包括细胞周期蛋白D1、Bcl-xL、Bcl-2、TRAF 1、cIAP-1、XIAP、生存素和VEGF。此外，在裸鼠模型中，我们发现姜黄素增强硼替佐米的抗肿瘤作用（P < 0.001，载体相对于硼替佐米加姜黄素; P < 0.001，硼替佐米vs.硼替佐米+姜黄素），这与Ki-67抑制相关001相对于对照）、⑶ 31（P < 0.001相对于媒介物）和VEGF（P < 0.001相对于媒介物）表达。总的来说，我们的研究结果表明，姜黄素通过下调NF-κB和NF-κ B调节的基因产物克服了化疗耐药性，并使MM细胞对沙利度胺和硼替佐米敏感。
Curcumin (diferuloylmethane), a yellow pigment in turmeric, has been shown to inhibit the activation of NF-κB, a transcription factor closely linked to chemoresistance in multiple myeloma (MM) cells. Whether curcumin can overcome chemoresistance and enhance the activity of thalidomide and bortezomib, used to treat patients with MM, was investigated in vitro and in xenograft model in nude mice. Our results show that curcumin inhibited the proliferation of human MM cells regardless of their sensitivity to dexamethasone, doxorubicin, or melphalan. Curcumin also potentiated the apoptotic effects of thalidomide and bortezomib by downregulating the constitutive activation of NF-κB and Akt; and this correlated with the suppression of NF-κB-regulated gene products, including cyclin D1, Bcl-xL, Bcl-2, TRAF1, cIAP-1, XIAP, survivin, and VEGF. Furthermore, in a nude mice model, we found that curcumin potentiated the antitumor effects of bortezomib (P < 0.001, vehicle vs. bortezomib plus curcumin; P < 0.001, bortezomib vs. bortezomib plus curcumin), and this correlated with suppression of Ki-67 (P < 0.001 vs. control), CD31 (P < 0.001 vs. vehicle), and VEGF (P < 0.001 vs. vehicle) expression. Collectively, our results suggest that curcumin overcomes chemoresistance and sensitizes MM cells to thalidomide and bortezomib by downregulating NF-κB and NF-κB-regulated gene products.