Devapatla Bharat, Sharma Ankur, Woo Sukyung
Department of Pharmaceutical Sciences, College of Pharmacy, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States of America.
PLoS One. 2015 Sep 28;10(9):e0139237. doi: 10.1371/journal.pone.0139237. eCollection 2015.
Antiangiogenic therapy is important for the treatment of gynecological cancer. However, the therapeutic benefit derived from these treatments is transient, predominantly due to the selective activation of compensatory proangiogenic pathways that lead to rapid development of resistance. We aimed to identify and target potential alternative signaling to anti-vascular endothelial growth factor (VEGF) therapy, with a view toward developing a combination of antiangiogenic agents to provide extended therapeutic benefits. We developed a preclinical in vivo phenotypic resistance model of ovarian cancer resistant to antiangiogenic therapy. We measured dynamic changes in secreted chemokines and angiogenic signaling in tumors and plasma in response to anti-VEGF treatment, as tumors advanced from the initial responsive phase to progressive disease. In tumors that progressed following sorafenib treatment, gene and protein expression levels of proangiogenic CXC chemokines and their receptors were significantly elevated, compared with responsive tumors. The chemokine (C-X-C motif) ligand 8 (CXCL8), also known as interleukin-8 (IL-8) increase was time-dependent and coincided with the dynamics of tumor progression. We used SB225002, a pharmacological inhibitor of chemokine (C-X-C motif) receptor 2 (CXCR2), to disrupt the CXC chemokine-mediated functions of ovarian cancer cells in in vitro assays of cell growth inhibition, spheroid formation, and cell migration. The combination of CXCR2 inhibitor with sorafenib led to a synergistic inhibition of cell growth in vitro, and further stabilized tumor progression following sorafenib in vivo. Our results suggest that CXCR2-mediated chemokines may represent an important compensatory pathway that promotes resistance to antiangiogenic therapy in ovarian cancer. Thus, simultaneous blockage of this proangiogenic cytokine pathway using CXCR2 inhibitors and the VEGF receptor (VEGFR) pathway could improve the outcomes of antiangiogenic therapy.
抗血管生成疗法对妇科癌症的治疗至关重要。然而，这些治疗所带来的治疗益处是短暂的，主要原因是代偿性促血管生成途径的选择性激活导致耐药性迅速发展。我们旨在识别并靶向抗血管内皮生长因子（VEGF）治疗的潜在替代信号通路，以期开发抗血管生成药物组合以提供延长的治疗益处。我们建立了对抗血管生成疗法耐药的卵巢癌临床前体内表型耐药模型。随着肿瘤从初始反应期发展为进展性疾病，我们测量了抗VEGF治疗后肿瘤和血浆中分泌趋化因子和血管生成信号的动态变化。与反应性肿瘤相比，在索拉非尼治疗后进展的肿瘤中，促血管生成CXC趋化因子及其受体的基因和蛋白表达水平显著升高。趋化因子（C-X-C基序）配体8（CXCL8），也称为白细胞介素-8（IL-8）的增加是时间依赖性的，且与肿瘤进展动态一致。我们使用趋化因子（C-X-C基序）受体2（CXCR2）的药理学抑制剂SB225002，在细胞生长抑制、球体形成和细胞迁移的体外试验中破坏卵巢癌细胞的CXC趋化因子介导的功能。CXCR2抑制剂与索拉非尼联合使用在体外导致细胞生长的协同抑制，并在体内索拉非尼治疗后进一步稳定肿瘤进展。我们的结果表明，CXCR2介导的趋化因子可能代表促进卵巢癌抗血管生成治疗耐药性的重要代偿途径。因此，使用CXCR2抑制剂同时阻断这一促血管生成细胞因子途径和VEGF受体（VEGFR）途径可改善抗血管生成治疗的效果。
