用CDK4 / 6抑制剂palbociclib预处理可提高紫杉醇在TNBC细胞中的功效。,Scientific Reports

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用CDK4 / 6抑制剂palbociclib预处理可提高紫杉醇在TNBC细胞中的功效。
Scientific Reports ( IF 3.8 ) Pub Date : 2019-09-10 , DOI: 10.1038/s41598-019-49484-4
Daniele Cretella ₁ , Claudia Fumarola ₁ , Mara Bonelli ₁ , Roberta Alfieri ₁ , Silvia La Monica ₁ , Graziana Digiacomo ₁ , Andrea Cavazzoni ₁ , Maricla Galetti _{2,

3} , Daniele Generali _{4,

5} , Pier Giorgio Petronini ₁

Affiliation

三阴性乳腺癌（TNBC）由于缺乏药物靶向性而成为具有挑战性的疾病。因此，化学疗法仍然是治疗的标准，并且确定新的靶点是临床的高度优先事项。在癌症中经常报道细胞周期机制的组成发生改变。鉴于CDK4 / 6抑制剂palbocicib在ER阳性BC中获得了成功，我们探索了在Rb阳性TNBC细胞模型中将该药物与化疗结合的潜力。palbociclib与紫杉醇的同时使用具有拮抗作用。相比之下，序贯治疗比单次治疗更有效地抑制细胞增殖并增加细胞死亡。通过下调E2F目标c-myc，palbociclib降低了HIF-1α和GLUT-1的表达，因此在常氧和低氧条件下葡萄糖的摄取和消耗。重要的是，palbociclib / paclitaxel顺序联合可增强这些对葡萄糖代谢的抑制作用。这种组合的优越功效归因于紫杉醇抑制palbociclib介导的AKT诱导并进一步下调Rb / E2F / c-myc信号传导的能力。我们的结果表明，通过用palbociclib进行预处理可以显着提高标准化学疗法的疗效，从而为Rb熟练的TNBC提供更好的治疗选择。这种组合的优越功效归因于紫杉醇抑制palbociclib介导的AKT诱导并进一步下调Rb / E2F / c-myc信号传导的能力。我们的结果表明，通过用palbociclib进行预处理可以显着提高标准化学疗法的疗效，从而为Rb熟练的TNBC提供更好的治疗选择。这种组合的优越功效归因于紫杉醇抑制palbociclib介导的AKT诱导并进一步下调Rb / E2F / c-myc信号传导的能力。我们的结果表明，通过用palbociclib进行预处理可以显着提高标准化学疗法的疗效，从而为Rb熟练的TNBC提供更好的治疗选择。

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Pre-treatment with the CDK4/6 inhibitor palbociclib improves the efficacy of paclitaxel in TNBC cells.

Triple Negative Breast Cancer (TNBC) is a challenging disease due to the lack of druggable targets; therefore, chemotherapy remains the standard of care and the identification of new targets is a high clinical priority. Alterations in the components of the cell cycle machinery have been frequently reported in cancer; given the success obtained with the CDK4/6 inhibitor palbocicib in ER-positive BC, we explored the potential of combining this drug with chemotherapy in Rb-positive TNBC cell models. The simultaneous combination of palbociclib with paclitaxel exerted an antagonistic effect; by contrast, the sequential treatment inhibited cell proliferation and increased cell death more efficaciously than single treatments. By down-regulating the E2F target c-myc, palbociclib reduced HIF-1α and GLUT-1 expression, and hence glucose uptake and consumption both under normoxic and hypoxic conditions. Importantly, these inhibitory effects on glucose metabolism were enhanced by palbociclib/paclitaxel sequential combination; the superior efficacy of such combination was ascribed to the ability of paclitaxel to inhibit palbociclib-mediated induction of AKT and to further down-regulate the Rb/E2F/c-myc signaling. Our results suggest that the efficacy of standard chemotherapy can be significantly improved by a pre-treatment with palbociclib, thus offering a better therapeutic option for Rb-proficient TNBC.

更新日期：2019-09-10

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