Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.
Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.
Int Immunopharmacol. 2019 Jan;66:260-266. doi: 10.1016/j.intimp.2018.11.023. Epub 2018 Nov 28.
Acute lung injury (ALI) due to chemotherapy occurs frequently. It presents a challenge for clinicians managing therapies for different types of cancers. Carfilzomib (Kyprolis™) is a new proteasome inhibitor that shows promise for the treatment of relapsing multiple myeloma. However, several cases of severe ALI have raised concern about the use of carfilzomib against relapsed multiple myelomas. To improve the efficacy of carfilzomib, a new anti-inflammatory drug for psoriasis treatment, apremilast (Otezla™) was investigated for its protective effects against carfilzomib-induced ALI in rats. RT-PCR analyses revealed that carfilzomib administration in rats markedly increased the levels of tumor necrosis factor-alpha and nuclear factor-kappa B and myeloperoxidase activity with a concomitant increase in lipid peroxidation. The anti-inflammatory cytokine, interleukin-10, was downregulated following carfilzomib administration. Reduction in glutathione levels indicated diminished cellular antioxidant defenses in response to carfilzomib-induced ALI. ALI was confirmed by histopathological observations in lung tissue slices. Apremilast administration reduced lung inflammation in terms of reduction in myeloperoxidase activity and levels of tumor necrosis factor-alpha and alveolar infiltrating cells. Apremilast reversed all observed toxic effects of carfilzomib and prevented ALI in rats.
化疗引起的急性肺损伤（ALI）较为常见。这给管理不同类型癌症治疗方法的临床医生带来了挑战。卡非佐米（Kyprolis™）是一种新型蛋白酶体抑制剂，在治疗复发性多发性骨髓瘤方面显示出良好的前景。然而，几例严重的 ALI 引起了人们对卡非佐米治疗复发性多发性骨髓瘤的使用的关注。为了提高卡非佐米的疗效，一种用于治疗银屑病的新型抗炎药物阿普司特（Otezla™）被研究用于其对大鼠卡非佐米诱导的 ALI 的保护作用。RT-PCR 分析显示，卡非佐米给药可显著增加大鼠肿瘤坏死因子-α和核因子-κB 的水平和髓过氧化物酶活性，并伴有脂质过氧化的增加。抗炎细胞因子白细胞介素-10 的水平在卡非佐米给药后下调。谷胱甘肽水平的降低表明，细胞抗氧化防御能力在卡非佐米诱导的 ALI 中减弱。肺组织切片的组织病理学观察证实了 ALI。阿普司特给药可降低髓过氧化物酶活性和肿瘤坏死因子-α及肺泡浸润细胞水平，从而减轻肺部炎症。阿普司特逆转了卡非佐米的所有观察到的毒性作用，并预防了大鼠的 ALI。
