Instituto Interuniversitario de Investigación de Reconocimiento Molecular y Desarrollo Tecnológico (IDM), Universitat Politècnica de València, Universitat de València, Camino de Vera s/n, 46022, Valencia, Spain; Unidad Mixta UPV-CIPF de Investigación en Mecanismos de Enfermedades y Nanomedicina, Universitat Politècnica de València, Centro de Investigación Príncipe Felipe, C/ Eduardo Primo Yúfera 3, 46012, Valencia, Spain.
Instituto Interuniversitario de Investigación de Reconocimiento Molecular y Desarrollo Tecnológico (IDM), Universitat Politècnica de València, Universitat de València, Camino de Vera s/n, 46022, Valencia, Spain; Unidad Mixta UPV-CIPF de Investigación en Mecanismos de Enfermedades y Nanomedicina, Universitat Politècnica de València, Centro de Investigación Príncipe Felipe, C/ Eduardo Primo Yúfera 3, 46012, Valencia, Spain; CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Spain.
J Control Release. 2020 Jul 10;323:624-634. doi: 10.1016/j.jconrel.2020.04.045. Epub 2020 May 4.
The induction of senescence produces a stable cell cycle arrest in cancer cells, thereby inhibiting tumor growth; however, the incomplete immune cell-mediated clearance of senescent cells may favor tumor relapse, limiting the long-term anti-tumorigenic effect of such drugs. A combination of senescence induction and the elimination of senescent cells may, therefore, represent an efficient means to inhibit tumor relapse. In this study, we explored the antitumor efficacy of a combinatory senogenic and targeted senolytic therapy in an immunocompetent orthotopic mouse model of the aggressive triple negative breast cancer subtype. Following palbociclib-induced senogenesis and senolysis by treatment with nano-encapsulated senolytic agent navitoclax, we observed inhibited tumor growth, reduced metastases, and a reduction in the systemic toxicity of navitoclax. We believe that this combination treatment approach may have relevance to other senescence-inducing chemotherapeutic drugs and additional tumor types. SIGNIFICANCE: While the application of senescence inducers represents a successful treatment strategy in breast cancer patients, some patients still relapse, perhaps due to the subsequent accumulation of senescent cells in the body that can promote tumor recurrence. We now demonstrate that a combination treatment of a senescence inducer and a senolytic nanoparticle selectively eliminates senescent cells, delays tumor growth, and reduces metastases in a mouse model of aggressive breast cancer. Collectively, our results support targeted senolysis as a new therapeutic opportunity to improve outcomes in breast cancer patients.
衰老诱导会导致癌细胞产生稳定的细胞周期停滞，从而抑制肿瘤生长；然而，衰老细胞不能被免疫细胞完全清除，可能有利于肿瘤复发，限制了此类药物的长期抗肿瘤作用。因此，衰老诱导和衰老细胞清除的联合可能是抑制肿瘤复发的有效手段。在这项研究中，我们在侵袭性三阴性乳腺癌亚型的免疫功能正常的原位小鼠模型中探索了联合衰老诱导和靶向衰老细胞清除的抗肿瘤疗效。在用纳米封装的衰老细胞清除剂 navitoclax 进行 palbociclib 诱导的衰老和衰老细胞清除后，我们观察到肿瘤生长受到抑制、转移减少以及 navitoclax 的全身毒性降低。我们认为这种联合治疗方法可能与其他诱导衰老的化疗药物和其他肿瘤类型有关。意义：虽然衰老诱导剂的应用在乳腺癌患者中代表了一种成功的治疗策略，但一些患者仍会复发，这可能是由于体内积累的衰老细胞随后促进了肿瘤的复发。我们现在证明，衰老诱导剂和衰老细胞清除纳米颗粒的联合治疗可选择性地清除衰老细胞，延迟肿瘤生长并减少侵袭性乳腺癌小鼠模型中的转移。总的来说，我们的研究结果支持靶向衰老细胞清除作为改善乳腺癌患者预后的新治疗机会。
