Diaz Roque, Nguewa Paul A, Redrado Miriam, Manrique Irene, Calvo Alfonso
Division of Oncology, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
Department of Microbiology and Parasitology, Instituto de Salud Tropical, University of Navarra, Pamplona, Spain.
Prostate. 2015 Aug 1;75(11):1137-49. doi: 10.1002/pros.22980. Epub 2015 Apr 20.
The need for new treatments for advanced prostate cancer has fostered the experimental use of targeted therapies. Sunitinib is a multi-tyrosine kinase inhibitor that mainly targets membrane-bound receptors of cells within the tumor microenvironment, such as endothelial cells and pericytes. However, recent studies suggest a direct effect on tumor cells. In the present study, we have evaluated both direct and indirect effects of Sunitinib in prostate cancer and how this drug regulates hypoxia, using in vitro and in vivo models.
We have used both in vitro (PC-3, DU145, and LNCaP cells) and in vivo (PC-3 xenografts) models to study the effect of Sunitinib in prostate cancer. Analysis of hypoxia based on HIF-1α expression and FMISO uptake was conducted. ALDH activity was used to analyze cancer stem cells (CSC).
Sunitinib strongly reduced proliferation of PC-3 and DU-145 cells in a dose dependent manner, and decreased levels of p-Akt, p-Erk1/2, and Id-1, compared to untreated cells. A 3-fold reduction in tumor growth was also observed (P < 0.001 with respect to controls). Depletion of Hif-1α levels in vitro and a decrease in FMISO uptake in vivo showed that Sunitinib inhibits tumor hypoxia. When combined with radiotherapy, this drug enhanced cell death in vitro and in vivo, and significantly decreased CD-31, PDGFRβ, Hif-1α, Id1, and PCNA protein levels (whereas apoptosis was increased) in tumors as compared to controls or single-therapy treated mice. Moreover, Sunitinib reduced the number of ALDH + cancer stem-like cells and sensitized these cells to radiation-mediated loss of clonogenicity.
Our results support the use of Sunitinib in prostate cancer and shows that both hypoxia and cancer stem cells are involved in the effect elicited by this drug. Combination of Sunitinib with radiotherapy warrants further consideration to reduce prostate cancer burden.
晚期前列腺癌对新治疗方法的需求推动了靶向治疗的实验性应用。舒尼替尼是一种多酪氨酸激酶抑制剂，主要靶向肿瘤微环境中细胞的膜结合受体，如内皮细胞和周细胞。然而，最近的研究表明其对肿瘤细胞有直接作用。在本研究中，我们使用体外和体内模型评估了舒尼替尼在前列腺癌中的直接和间接作用，以及该药物如何调节缺氧。
我们使用体外（PC-3、DU145和LNCaP细胞）和体内（PC-3异种移植）模型来研究舒尼替尼对前列腺癌的影响。基于缺氧诱导因子-1α（HIF-1α）表达和氟代脱氧葡萄糖（FMISO）摄取进行缺氧分析。醛脱氢酶（ALDH）活性用于分析癌症干细胞（CSC）。
与未处理的细胞相比，舒尼替尼以剂量依赖性方式强烈降低PC-3和DU-145细胞的增殖，并降低p-Akt、p-Erk1/2和Id-1的水平。还观察到肿瘤生长减少了3倍（相对于对照组，P < 0.001）。体外Hif-1α水平的降低和体内FMISO摄取的减少表明舒尼替尼抑制肿瘤缺氧。与放疗联合使用时，该药物在体外和体内均增强细胞死亡，并且与对照组或单药治疗的小鼠相比，肿瘤中CD-31、血小板衍生生长因子受体β（PDGFRβ）、Hif-1α、Id1和增殖细胞核抗原（PCNA）蛋白水平显著降低（而凋亡增加）。此外，舒尼替尼减少了ALDH +癌症干细胞样细胞的数量，并使这些细胞对辐射介导的克隆形成能力丧失敏感。
我们的结果支持舒尼替尼在前列腺癌中的应用，并表明缺氧和癌症干细胞均参与该药物引发的效应。舒尼替尼与放疗联合使用值得进一步考虑以减轻前列腺癌负担。
