Acetovanillone prevents cyclophosphamide-induced acute lung injury by modulating PI3K/Akt/mTOR and Nrf2 signaling in rats

Cyclophosphamide (CP) is a medication used as an anticancer drug and to suppress
the immune system. However, its clinical applications are restricted because of the
toxic and adverse side effects. The present study investigated the protective effect
of acetovanillone (AV), a natural NADPH oxidase inhibitor, against acute lung injury
(ALI) induced by CP. Rats were administered AV (100 mg/kg) for 10 days and a single
injection of CP (200 mg/kg) at day 7. At the end of the experiment, the animals were
sacrificed, and lung samples were collected for analyses. CP caused ALI manifested
by the histopathological alterations. Lipid peroxidation and NADPH oxidase activity
were increased, whereas GSH and antioxidant enzymes were decreased in the lung
of CP-intoxicated rats. Oral administration of AV prevented CP-induced lung injury
and oxidative stress and enhanced antioxidant defenses. AV downregulated Keap1
and upregulated Nrf2, GCLC, HO-1, and SOD3 mRNA. In addition, AV boosted the
expression of PI3K, Akt, mTOR, and cytoglobin. In vitro, AV showed a synergistic
anticancer effect when combined with CP. In conclusion, AV protected against CPinduced
ALI by attenuating oxidative stress and boosting Nrf2/HO-1 and PI3K/Akt/
mTOR signaling. Therefore, AV might represent a promising adjuvant to prevent lung
injury in patients receiving CP.