Dietary administration of the proapoptotic vitamin E analogue α-tocopheryloxyacetic acid inhibits metastatic murine breast cancer
Dietary administration of the proapoptotic vitamin E analogue α-tocopheryloxyacetic acid inhibits metastatic murine breast cancer
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DOI：
10.1158/0008-5472.can-06-2403
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发表时间：
2006-10-01
期刊：
影响因子：
11.2
通讯作者：
Akporiaye, Emmanuel T.
中科院分区：
文献类型：
--
作者：
Hahn, Tobias;Szabo, Lajos;Akporiaye, Emmanuel T.
维生素E（RRR-a-生育酚）衍生物a-生育酚琥珀酸酯（alpha-TOS）和a-生育酚氧基乙酸（alpha-TEA）在临床前动物模型中抑制肿瘤生长的能力最近引起了对其治疗人类癌症的潜在用途的兴趣。为了使这些维生素E类似物的使用更具有临床相关性，我们比较了口服和腹膜内递送形式的α-TEA和α-TOS对鼠乳腺癌（4 T1）的抗肿瘤功效，所述鼠乳腺癌由于其不良免疫原性和高转移潜力而与人乳腺癌相似。在细胞培养研究中，我们发现，这两种化合物抑制肿瘤集落形成和诱导肿瘤细胞凋亡死亡。为了避免与α-TEA和α-TOS的疏水性相关的溶解度问题，我们将囊泡形式的α-TEA（V α-TEA）和α-TOS（V α-TOS）用于体内肿瘤研究。这两种化合物抑制预先建立的4 T1肿瘤的生长时，给予腹腔注射。然而，当通过口服管饲法，只有酯酶抗性V α-TEA能够抑制原发性肿瘤的生长和减少肺转移。为了使这种方法更适用于临床，将α-TEA掺入饮食中并喂给荷瘤小鼠。我们在此首次报道，在预防和治疗环境中，饮食α-TEA递送显著抑制原发性肿瘤生长并显著减少自发转移性扩散至肺。这项研究表明，饮食中的α-TEA可以证明是一种相对简单有效的治疗转移性乳腺癌的方法。
The ability of the vitamin E (RRR-alpha-tocopherol) derivatives a-tocopheryl succinate (alpha-TOS) and alpha-tocopheryloxyacetic acid (alpha-TEA) to suppress tumor growth in preclinical animal models has recently led to increased interest in their potential use for treating human cancer. To make the use of these vitamin E analogues more clinically relevant, we compared the antitumor efficacy of orally and i.p. delivered forms of alpha-TEA and alpha-TOS against a murine mammary cancer (4T1) that bears resemblance to human breast cancer because of its poor immunogenicity and high metastatic potential. In cell culture studies, we showed that both compounds inhibited tumor colony formation and induced apoptotic death of tumor cells. To avoid solubility concerns associated with the hydrophobicity of alpha-TEA and alpha-TOS, we used the vesiculated forms of alpha-TEA (V alpha-TEA) and alpha-TOS (V alpha-TOS) for the in vivo tumor studies. Both compounds inhibited the growth of preestablished 4T1 tumors when given i.p. However, when given by oral gavage, only the esterase-resistant V alpha-TEA was able to suppress primary tumor growth and reduce lung metastasis. To make this approach more translatable to the clinic, a-TEA was incorporated into the diet and fed to tumor-bearing mice. We report here for the first time that dietary alpha-TEA delivery significantly inhibited primary tumor growth and dramatically reduced spontaneous metastatic spread to the lung in prophylactic and therapeutic settings. This study suggests that dietary alpha-TEA could prove useful as a relatively easy and effective modality for treating metastatic breast cancer.