Abstract
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.
•Carfilzomib-induced lung injury via oxidative stress•Apremilast attenuates carfilzomib-induced lung injury via oxidative stress.•Apremilast attenuates carfilzomib-induced lung injury via inhibition of TNF-α and NF-κB activation.