Umbelliferone attenuates doxorubicin-induced hepatorenal toxicity while enhancing its in vitro anticancer activity: Insight into hepatic apoptosis-, autophagy-, and FOXO3a-associated signaling

This is the authors' abstract. We don't add key points for this paper.

Doxorubicin (DOX) causes severe hepatorenal toxicity through oxidative stress, inflammation, apoptosis, and dysregulated autophagy. This study investigated whether umbelliferone (UMB) protects against DOX toxicity while simultaneously enhancing its anticancer efficacy. In DOX-treated Wistar rat models, UMB significantly attenuated hepatorenal injury by improving serum biochemistry, tissue histopathology, and key markers of oxidative stress and inflammation. Mechanistically, UMB inhibited hepatic apoptosis by downregulating pro-apoptotic Bax and cleaved caspase-3 while upregulating anti-apoptotic Bcl-2. Additionally, UMB treatment was associated with decreased p62 and FOXO3a expression while elevating LC3-II levels and p-AMPK phosphorylation. Complementary in vitro experiments using MCF-7 and SW-620 cancer cell lines revealed that UMB synergistically enhanced DOX-induced cytotoxicity and effectively suppressed cancer cell migration and colony formation. Ultimately, UMB protects against DOX-induced hepatorenal toxicity in vivo and enhances DOX-induced anticancer activity in vitro. These findings suggest that UMB may have potential as a chemotherapeutic adjunct; however, further studies using tumor-bearing animal models are required to confirm whether UMB can simultaneously protect normal organs and enhance antitumor efficacy in a single biological system.