Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria (C1428EGA), Buenos Aires, Argentina; IFIBYNE, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria (C1428EGA), Buenos Aires, Argentina.
Departamento de Química Orgánica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria (C1428EGA), Buenos Aires, Argentina; IFIBYNE, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria (C1428EGA), Buenos Aires, Argentina.
Biochem Pharmacol. 2014 Jun 15;89(4):526-35. doi: 10.1016/j.bcp.2014.04.006. Epub 2014 Apr 13.
Glucocorticoids (GCs) are steroid hormones widely used as coadjuvants in the treatment of solid tumors due to their anti-inflammatory effects. However, evidence show that they also may induce chemotherapy resistance, probably through their capacity to inhibit apoptosis triggered by antineoplastic drugs. GCs exert their action by regulating gene expression throughout two main mechanisms: transactivation, where the activated glucocorticoid receptor (GR) directly binds to certain genes; and transrepression, an indirect mechanism by which GR regulates other transcription factors activities. Recently, our group has shown that the rigid steroid 21-hydroxy-6,19-epoxyprogesterone (21OH-6,19OP) is a selective GR ligand that behaves as an agonist in transrepression assays and as an antagonist in transactivation ones. Here, we have evaluated the anti-inflammatory activity of 21OH-6,19OP, its capacity to generate chemoresistance, as well as its mechanism of action. We found that 21OH-6,19OP inhibits nitrites formation and the inducible nitric oxide synthase (Nos-2) expression in macrophages. It also blocks the expression of both cyclooxygenase-2 (COX-2) and interleukin-8 (IL-8) triggered by tumor necrosis factor-alpha (TNF-α) in epithelial lung cancer cells. However, contrary to dexamethasone (DEX), 21OH-6,19OP neither reverts the paclitaxel-induced caspase-3 activity, nor induces the anti-apoptotic Bcl-X(L) gene expression in murine tumor mammary epithelial cells; and importantly, it lacks GCs-associated chemoresistance in a mouse mammary tumor model. Together, our findings suggest that 21OH-6,19OP behaves as a dissociated GC that keeps anti-inflammatory action without affecting the apoptotic process triggered by chemotherapeutic drugs. For these reasons, this steroid may become a putative novel coadjuvant in the treatment of breast cancer.
糖皮质激素（GCs）是一种广泛应用于治疗实体瘤的甾体激素，因其具有抗炎作用。然而，有证据表明，它们也可能诱导化疗耐药，这可能是由于它们抑制抗肿瘤药物触发的细胞凋亡的能力。GCs 通过两种主要机制调节基因表达来发挥作用：反式激活，其中激活的糖皮质激素受体（GR）直接与某些基因结合；反式阻遏，GR 通过这种间接机制调节其他转录因子的活性。最近，我们的研究小组表明，刚性甾体 21-羟-6,19-环氧孕酮（21OH-6,19OP）是一种选择性 GR 配体，在反式阻遏测定中表现为激动剂，在反式激活测定中表现为拮抗剂。在这里，我们评估了 21OH-6,19OP 的抗炎活性、产生化疗耐药的能力以及其作用机制。我们发现，21OH-6,19OP 抑制巨噬细胞中亚硝酸盐的形成和诱导型一氧化氮合酶（Nos-2）的表达。它还能阻断肿瘤坏死因子-α（TNF-α）触发的上皮肺癌细胞中环氧化酶-2（COX-2）和白细胞介素-8（IL-8）的表达。然而，与地塞米松（DEX）相反，21OH-6,19OP 既不能逆转紫杉醇诱导的 caspase-3 活性，也不能诱导鼠肿瘤乳腺上皮细胞中抗凋亡的 Bcl-X（L）基因表达；而且，它在小鼠乳腺肿瘤模型中缺乏与 GC 相关的化疗耐药性。总之，我们的研究结果表明，21OH-6,19OP 表现为一种分离的 GC，它保持抗炎作用而不影响化疗药物触发的凋亡过程。由于这些原因，这种甾体可能成为治疗乳腺癌的一种新型辅助药物。
