Ligands for peroxisome proliferator-activated receptorγ and retinoic acid receptor inhibit growth and induce apoptosis of human breast cancer cells in vitro and in BNX mice
Ligands for peroxisome proliferator-activated receptorγ and retinoic acid receptor inhibit growth and induce apoptosis of human breast cancer cells in vitro and in BNX mice
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DOI：
10.1073/pnas.95.15.8806
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发表时间：
1998-07-21
影响因子：
11.1
通讯作者：
Koeffler, HP
中科院分区：
文献类型：
--
作者：
Elstner, E;Müller, C;Koeffler, HP
通过核激素受体（NHR）配体诱导癌细胞分化和凋亡是一种新颖且有前途的癌症治疗方法。全反式视黄酸 (ATRA) 是一种 RA 受体特异性 NHR 配体，目前用于选择性癌症的治疗。 NHR，即过氧化物酶体增殖物激活受体γ（PPARγ）在乳腺癌细胞中表达。通过合成配体曲格列酮 (TGZ) 和其他 PPAR γ 激活剂激活 PPAR γ，从而抑制培养的乳腺癌细胞的增殖和脂质积累。 TGZ (10(-5) M, 4 天) 可逆地抑制 MCF7 乳腺癌细胞的克隆生长，TGZ (10(-5) M) 和 ATRA (10(-6) M, 4 天) 的组合可协同且不可逆地抑制 MCF7 细胞的生长并诱导细胞凋亡，并与其 bcl-2 蛋白水平急剧降低相关。在体外培养的患者乳腺癌组织中也发现了类似的效果，但在正常乳腺上皮细胞中则没有。观察到的由TGZ和ATRA介导的细胞凋亡可能与bcl-2的显着下调有关，因为在用TGZ和ATRA培养的MCF7细胞中强制过度表达bcl-2会阻止细胞死亡。 TGZ 显着抑制三重免疫缺陷小鼠的 MCF7 肿瘤生长。 TGZ 和 ATRA 联合给药会导致这些肿瘤显着凋亡和纤维化，但对小鼠没有毒性作用。总而言之，这种组合可能为人类乳腺癌提供一种新颖的、无毒的、选择性的疗法。
Induction of differentiation and apoptosis in cancer cells through ligands of nuclear hormone receptors (NHRs) is a novel and promising approach to cancer therapy. All-trans-retinoic acid (ATRA), an RA receptor-specific NHR ligand, is now used for selective cancers. The NHR, peroxisome proliferator-activated receptor gamma (PPAR gamma) is expressed in breast cancer cells. Activation of PPAR gamma through a synthetic ligand, troglitazone (TGZ), and other PPAR gamma-activators cause inhibition of proliferation and lipid accumulation in cultured breast cancer cells. TGZ (10(-5) M, 4 days) reversibly inhibits clonal growth of MCF7 breast cancer cells and the combination of TGZ (10(-5) M) and ATRA (10(-6) M, 4 days) synergistically and irreversibly inhibits growth and induces apoptosis of MCF7 cells, associated with a dramatic decrease of their bcl-2 protein levels. Similar effects are noted with in vitro cultured breast cancer tissues from patients, but not with normal breast epithelial cells. The observed apoptosis mediated by TGZ and ATRA may be related to the striking down-regulation of bcl-2, because forced over-expression of bcl-2 in MCF7 cells cultured with TGZ and ATRA blocks their cell death. TGZ significantly inhibits MCF7 tumor growth in triple immunodeficient mice. Combined administration of TGZ and ATRA causes prominent apoptosis and fibrosis of these tumors without toxic effects on the mice. Taken together, this combination may provide a novel, nontoxic and selective therapy for human breast cancers.