The potential beneficial role of Ginkgetin in doxorubicin-induced hepatotoxicity: Elucidating the underlying claim

Abstract

Doxorubicin (DOX) is a widely used chemotherapeutic agent for various tumors treatment; apart from its chemotherapeutic activity, the traditional usage of DOX has been limited by its adverse effects on multiple organs, mainly hepatotoxicity. The molecular mechanisms underlying DOX hepatotoxicity are mainly due to the production of reactive oxygen species (ROS) inducing oxidative stress, diminishing antioxidant enzymes, apoptosis, inflammation, and mitochondrial dysfunction. Thus, there is an urgent need to develop a therapy that minimizes DOX hepatotoxicity and widens its use in various types of cancers without fear of its serious hepatotoxicity. Ginkgetin (GINK), a natural biflavonoid, exhibits diverse actions, including promising free radical scavenging, antioxidant, and anti-inflammatory activities. So, this study's objectives were to determine whether GINK could mitigate DOX's hepatotoxic effects and look into a putative hepatoprotective molecular pathway. Mice were divided into five groups: Normal control, control GINK 100, Untreated DOX group, and DOX groups treated with GINK (50 and 100 mg/kg) intraperitoneally daily for four days before DOX administration and an additional three days afterward. GINK 100 pretreatment showed marked protection from DOX hepatotoxicity and also attenuation of histopathological structural alterations. These outcomes were corroborated biochemically by a considerable decrease in alanine aminotransferases, aspartate aminotransferase, and alkaline phosphatase levels. GINK significantly augmented silent information regulator 1 and nuclear translocation of NF-E2-related factor 2 and repressed the expression and protein levels of forkhead box protein O1, inducible nitric oxide synthase, and P53 relative to DOX group. GINK alleviated oxidative stress and induced significant anti-inflammatory effects via suppression of interleukin-6, nuclear factor Kabba B, and iNOS respectively. This study is the first to investigate GINK's potentially beneficial effects in acute DOX hepatotoxicity, possibly exhibiting antioxidant, anti-inflammatory, and anti-apoptotic effects by modulation of Sirt1/FOXO-1/NF-κB Signal.

Keywords: Apoptosis; Doxorubicin; FOXO-1; Hepatotoxicity; NFĸB; Sirt1.