Arsenic trioxide and breast cancer: Analysis of the apoptotic, differentiative and immunomodulatory effects
Arsenic trioxide and breast cancer: Analysis of the apoptotic, differentiative and immunomodulatory effects
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DOI：
10.1023/a:1015272401822
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发表时间：
2002-05-01
影响因子：
3.8
通讯作者：
Ferrero, E
中科院分区：
文献类型：
--
作者：
Baj, G;Arnulfo, A;Ferrero, E
三氧化二砷（As 2 O3）在临床上用于治疗急性早幼粒细胞白血病，并在体外对几种实体瘤细胞系具有活性，其中诱导分化和凋亡是主要作用。为了探讨As 2 O3对乳腺癌的潜在治疗应用，我们分析了As 2 O3对四种人乳腺癌细胞系：MCF 7，MDA-MB-231，T-47 D和BT-20生长的影响。将细胞培养在0.5、2和5 μ M的As 2 O3中，As 2 O3的浓度范围是可实现的。当浓度大于或等于2 μ M时，As 2 O3通过细胞凋亡迅速诱导MCF 7和MDA-MB-231细胞死亡，而T-47 D和BT-20则部分抵抗。在0.5 μ M时，As 2 O3是亚凋亡的，但诱导分化的特征在于ICAM-1（CD 54）的上调，乳腺上皮分化的标志物，细胞培养物在形态上出现更多的有机化。此外，我们表明，通过标准的细胞毒性试验，As 2 O3治疗可以增加乳腺癌细胞溶解淋巴因子激活的杀伤细胞，并证明了在这个过程中的ICAM-1/LFA-1的相互作用的重要作用。As 2 O3的这种额外活性可以转化为体内改善的抗肿瘤免疫监视。总之，As 2 O3诱导不同程度的分化，凋亡和溶解在这些模型细胞系，并可能是一个有前途的佐剂，目前的治疗乳腺癌凭借其三重凋亡，分化和免疫调节作用。
Arsenic trioxide (As2O3) is used clinically to treat acute promyelocytic leukemia and has activity in vitro against several solid tumour cell lines, where induction of differentiation and apoptosis are the prime effects. To investigate the potential therapeutic application of As2O3 to breast cancer, we analysed the effects of As2O3 on the growth of four human breast cancer cell lines: MCF7, MDA-MB-231, T-47D and BT-20. Cells were cultured in 0.5, 2 and 5 muM As2O3, a range of pharmacologically achievable concentrations of As2O3. At greater than or equal to2 muM, As2O3 rapidly induced cell death by apoptosis in MCF7 and MDA-MB-231 while T-47D and BT-20 were partially resistant. At 0.5 muM, As2O3 was subapoptotic but induced features of differentiation consisting in upregulation of ICAM-1 (CD54), a marker of mammary epithelial differentiation, and cell cultures appeared morphologically more orga-nized. Furthermore, we demonstrate by standard cytotoxicity assays that As2O3 treatment can augment breast cancer cell lysis by lymphokine-activated killer cells and demonstrate an important role of the ICAM-1/LFA-1 interaction in this process. This additional activity of As2O3 could translate into improved antitumour immunosurveillance in vivo. In conclusion, As2O3 induced varying degrees of differentiation, apoptosis and lysis in these model cell lines, and may be a promising adjuvant to current treatments of breast cancer by virtue of its triple apoptotic, differentiative and immunomodulatory effects.