β‐LAPachone ameliorates doxorubicin‐induced cardiotoxicity via regulating autophagy and Nrf2 signalling pathways in mice

Abstract

β‐LAPachone (B‐LAP) is a naphthoquinone that possesses antioxidant properties. In the present investigation, the protective effect of B‐LAP against doxorubicin (DOX)‐induced cardiotoxicity was examined in mice. Thirty‐five mice were divided into 5 groups: control group, B‐LAP (5 mg/kg) group, DOX (15 mg/kg) group, DOX+B‐LAP (2.5 mg/kg) group and DOX+B‐LAP (5 mg/kg) group. B‐LAP was administered orally for 14 days of experimental period. A single dose of DOX (15 mg/kg) was injected intraperitoneally on day 3. Cardiac function, histoarchitecture, indices of oxidative stress and circulating markers of cardiac injury were examined. B‐LAP (5 mg/kg) decreased serum levels of lactate dehydrogenase (LDH), creatine kinase MB (CK‐MB) and cardiac troponin I (cTnI), and ameliorated cardiac histopathological alterations. In addition to increasing cellular NAD+/NADH ratio, B‐LAP up‐regulated the cardiac levels of SIRT1, beclin‐1, p‐LKB1 and p‐AMPK, and reduced the cardiac levels of p‐mTOR, interleukin (IL)‐1β, TNF (tumour necrosis factor)‐α and caspase‐3. B‐LAP also elevated the nuclear accumulation of Nrf2 and simultaneously up‐regulated the protein levels of haem oxygenase (HO‐1) and glutathione S‐transferase (GST) in the hearts of DOX mice. While B‐LAP reduced malondialdehyde concentrations in heart of DOX‐treated mice, it further promoted the activities of cardiac superoxide dismutase (SOD), glutathione peroxidase (GPX) and catalase (CAT).In accordance with increased cell survival, B‐LAP significantly improved the cardiac function of DOX mice. Collectively, these findings underline the protective potential of B‐LAP against DOX‐induced cardiotoxicity by regulating autophagy and AMPK/Nrf2 signalling pathway in mice.

Nrf2 Signaling Pathway in Chemoprotection and Doxorubicin Resistance: Potential Application in Drug Discovery

“…-LAPachone (B-LAP) as a protective agent, targets AMPK/Nrf2 signaling in reducing DOX-mediated cardiotoxicity. B-LAP promotes expression of AMPK to induce Nrf2 signaling for elevating expression levels of SOX, CAT and GPX, leading to amelioration of DOX-mediated cardiotoxicity [101]. Following Nrf2 activation by phytochemicals, ROS levels decrease, preventing mitochondrial dysfunction and subsequent induction of apoptosis in cells exposed to DOX [102].…”

Natural compounds against doxorubicin‐induced cardiotoxicity: A review on the involvement of Nrf2/ARE signaling pathway

“…β‐lapachone is a natural quinone that is isolated from the bark of the Lapacho tree ( Tabebuia avellanedae ) (Nazari Soltan Ahmad et al, 2020). B‐LAP was shown to induce anti‐inflammatory and antioxidant activities via repressing NF‐kB protein complex and activating Nrf2 transcription factor, respectively (Moon, Choi, Kim, Park, & Kim, 2007; J.‐S.…”

“…Also, anti‐tumor activities of B‐LAP were reported against breast cancer (Lamberti, Vittar, da Silva, Ferreira, & Rivarola, 2013). Nazari Soltan Ahmad et al examined the protective effect of B‐LAP in a mouse model of DOX‐induced cardiotoxicity; results showed that B‐LAP protective effects were mediated through regulation of the Nrf2 signaling pathway as it induced nuclear accumulation of Nrf2 and up‐regulated protein levels of HO‐1 and GST in heart samples (Figure 1) (Nazari Soltan Ahmad et al, 2020).…”

Heparin and Heparin-Based Drug Delivery Systems: Pleiotropic Molecular Effects at Multiple Drug Resistance of Osteosarcoma and Immune Cells

“…Activation of Nrf2 protects healthy cells from death. However, data from numerous studies indicate a link between Nrf2 overexpression and MDR1-associated chemoresistance in tumor cells [ 54 , 189 , 190 ].…”