Tuttle Traci R, Takiar Vinita, Kumar Bhavna, Kumar Pawan, Ben-Jonathan Nira
Department of Cancer Biology, University of Cincinnati School of Medicine, Cincinnati, OH 45267, USA.
Department of Radiation Oncology, University of Cincinnati School of Medicine, Cincinnati, OH 45267, USA.
Cancer Lett. 2017 Mar 28;389:33-40. doi: 10.1016/j.canlet.2016.12.020. Epub 2016 Dec 23.
Head and neck squamous cell carcinoma (HNSCC) is an aggressive and often fatal disease. Cisplatin is the most common chemotherapeutic drug in the treatment of HNSCC, but intrinsic and acquired resistance are frequent, and severe side effects occur at high doses. The second messenger cyclic GMP (cGMP) is produced by soluble guanylate cyclase (sGC). We previously reported that activation of the cGMP signaling cascade caused apoptosis in HNSCC cells, while others found that this pathway enhances cisplatin efficacy in some cell types. Here we found that sGC stimulators reduced HNSCC cell viability synergistically with cisplatin, and enhanced apoptosis by cisplatin. Moreover, the sGC stimulators effectively reduced viability in cells with acquired cisplatin resistance, and were synergistic with cisplatin. The sGC stimulator BAY 41-2272 reduced expression of the survival proteins EGFR and β-catenin, and increased pro-apoptotic Bax, suggesting a potential mechanism for the anti-tumorigenic effects of these drugs. The sGC stimulator Riociguat is FDA-approved to treat pulmonary hypertension, and others are being studied for therapeutic use in several diseases. These drugs could provide valuable addition or alternative to cisplatin in the treatment of HNSCC.
头颈部鳞状细胞癌（HNSCC）是一种侵袭性且往往致命的疾病。顺铂是治疗HNSCC最常用的化疗药物，但内在和获得性耐药很常见，且高剂量时会出现严重副作用。第二信使环磷酸鸟苷（cGMP）由可溶性鸟苷酸环化酶（sGC）产生。我们之前报道过，cGMP信号级联的激活会导致HNSCC细胞凋亡，而其他人发现该途径在某些细胞类型中可增强顺铂疗效。在此我们发现，sGC刺激剂与顺铂协同降低HNSCC细胞活力，并增强顺铂诱导的凋亡。此外，sGC刺激剂可有效降低获得性顺铂耐药细胞的活力，且与顺铂具有协同作用。sGC刺激剂BAY 41-2272降低了存活蛋白表皮生长因子受体（EGFR）和β-连环蛋白的表达，并增加了促凋亡蛋白Bax的表达，提示了这些药物抗肿瘤作用的潜在机制。sGC刺激剂利奥西呱已获美国食品药品监督管理局（FDA）批准用于治疗肺动脉高压，其他药物也正在针对多种疾病的治疗用途进行研究。这些药物在HNSCC的治疗中可为顺铂提供有价值的补充或替代方案。
