Cannabidiol as a novel inhibitor of ld-1 gene expression in aggressive breast cancer cells
Cannabidiol as a novel inhibitor of ld-1 gene expression in aggressive breast cancer cells
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DOI：
10.1158/1535-7163.mct-07-0371
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发表时间：
2007-11-01
影响因子：
5.7
通讯作者：
Desprez, Pierre-Yves
中科院分区：
文献类型：
--
作者：
McAllister, Sean D.;Christian, Rigel T.;Desprez, Pierre-Yves
侵袭性乳腺癌细胞的侵袭和转移是癌症进展过程中最后也是致命的一步，也是遗传学上了解最少的。临床上，对侵袭性和转移性乳腺癌的治疗措施仍然有限。显然，迫切需要有效和无毒的治疗方法。ID-1是一种基本螺旋-环-螺旋转录因子的抑制因子，最近被证明是乳腺癌和其他癌症转移潜力的关键调节因子。使用小鼠模型，我们先前确定，当ID-1被反义LD-1稳定转导下调时，转移性乳腺癌细胞在体外侵袭性和体内转移性显著降低。然而，在这一点上，使用反义技术来减少转移性乳腺癌患者ID-1的表达是不可能的。在这里，我们报告了大麻二醇(CBD)，一种低毒的大麻素，可以下调侵袭性人类乳腺癌细胞ID-1的表达。有效抑制ID-1表达的CBD浓度与用于抑制乳腺癌细胞增殖和侵袭表型的浓度相关。CBD对ID-1的表达有抑制作用，且呈浓度依赖性。这些效应似乎是由于在启动子水平上抑制ID-1基因而产生的。重要的是，CBD不能抑制异位表达ID-1的细胞的侵袭性。总之，CBD是第一个无毒的外源性药物，可以显著降低转移性乳腺癌细胞中ID-1的表达，从而下调肿瘤的侵袭性。[摩尔癌症治疗2007；6(11)：2921-7]。
Invasion and metastasis of aggressive breast cancer cells is the final and fatal step during cancer progression, and is the least understood genetically. Clinically, there are still limited therapeutic interventions for aggressive and metastatic breast cancers available. Clearly, effective and nontoxic therapies are urgently required. Id-1, an inhibitor of basic helix-loop-helix transcription factors, has recently been shown to be a key regulator of the metastatic potential of breast and additional cancers. Using a mouse model, we previously determined that metastatic breast cancer cells became significantly less invasive in vitro and less metastatic in vivo when Id-1 was down-regulated by stable transduction with antisense ld-1. It is not possible at this point, however, to use antisense technology to reduce Id-1 expression in patients with metastatic breast cancer. Here, we report that cannabidiol (CBD), a cannabinoid with a low-toxicity profile, could down-regulate Id-1 expression in aggressive human breast cancer cells. The CBD concentrations effective at inhibiting Id-1 expression correlated with those used to inhibit the proliferative and invasive phenotype of breast cancer cells. CBD was able to inhibit Id-1 expression at the mRNA and protein level in a concentration-dependent fashion. These effects seemed to occur as the result of an inhibition of the Id-1 gene at the promoter level. Importantly, CBD did not inhibit invasiveness in cells that ectopically expressed Id-1. In conclusion, CBD represents the first nontoxic exogenous agent that can significantly decrease Id-1 expression in metastatic breast cancer cells leading to the down-regulation of tumor aggressiveness. [Mol Cancer Ther 2007;6(11):2921-7].