Debreli Coskun Melis, Sudha Thangirala, Bharali Dhruba J, Celikler Serap, Davis Paul J, Mousa Shaker A
Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, NY, United States.
Department of Biology, Faculty of Arts and Sciences, Uludag University, Bursa, Turkey.
Front Pharmacol. 2020 Feb 27;11:95. doi: 10.3389/fphar.2020.00095. eCollection 2020.
Pancreatic cancer decreases survival time and quality of life because of drug resistance and peripheral neuropathy during conventional treatment. This study was undertaken to investigate whether αvβ3 integrin receptor antagonist compounds NDAT and XT199 can suppress the development of cisplatin resistance and cisplatin-induced peripheral neuropathy in an orthotopic pancreatic SUIT2-luc cancer cell mouse model. Anticancer effects of these compounds and their combination with cisplatin were assessed in this tumor mouse model with bioluminescent signaling and histopathology, and a cytokine assay was used to examine expression of inflammatory cytokines IL-1β, IL-6, IL-10, and TNF-α from plasma samples. To determine the neuroprotective effects of the compounds on cisplatin-induced peripheral neuropathy, behavioral hind-limb posture of the mice was evaluated. The combination therapy of NDAT or XT199 with cisplatin elicited greater inhibition of tumor growth and increased tumor necrosis compared to cisplatin alone. NDAT and XT199 in combination with cisplatin significantly decreased expression of pro-inflammatory cytokines IL-1β, IL-6, and TNF-α and significantly increased expression of anti-inflammatory cytokine IL-10 in comparison to cisplatin alone. Cisplatin-treated groups showed stocking-glove hind-limb posture, whereas NDAT and XT199 with cisplatin-treated groups displayed normal hind-limb posture. Results clearly suggest that NDAT and XT199 treatment with cisplatin that inactivates NF-κB may contribute to increased antitumor and anti-inflammatory efficacy as well as alleviate cisplatin-mediated loss of motor function in this pancreatic tumor mouse model.
由于传统治疗过程中存在耐药性和周围神经病变，胰腺癌会降低生存时间和生活质量。本研究旨在调查αvβ3整合素受体拮抗剂化合物NDAT和XT199是否能在原位胰腺SUIT2-luc癌细胞小鼠模型中抑制顺铂耐药性的发展和顺铂诱导的周围神经病变。在该肿瘤小鼠模型中，通过生物发光信号和组织病理学评估了这些化合物及其与顺铂联合使用的抗癌效果，并使用细胞因子检测法检测血浆样本中炎性细胞因子IL-1β、IL-6、IL-10和TNF-α的表达。为了确定这些化合物对顺铂诱导的周围神经病变的神经保护作用，评估了小鼠的行为性后肢姿势。与单独使用顺铂相比，NDAT或XT199与顺铂的联合治疗对肿瘤生长的抑制作用更强，肿瘤坏死增加。与单独使用顺铂相比，NDAT和XT199与顺铂联合使用显著降低了促炎细胞因子IL-1β、IL-6和TNF-α的表达，并显著增加了抗炎细胞因子IL-10的表达。顺铂治疗组表现出袜套样后肢姿势，而NDAT和XT199与顺铂治疗组表现出正常的后肢姿势。结果清楚地表明，在该胰腺肿瘤小鼠模型中，用NDAT和XT199与顺铂联合治疗使NF-κB失活，可能有助于提高抗肿瘤和抗炎疗效，并减轻顺铂介导的运动功能丧失。
