Unveiling the Complexities: Exploring Mechanisms of Anthracyclineinduced Cardiotoxicity

Figures

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  Fig. (1). The schematic representation illustrating anthracycline-induced disruptions in the function of key signaling molecules, including PI3K/Akt, GSK-3β, FOXO, mTOR, TFEB, and autophagosome, ultimately leading to an increase in oxidative stress, autophagy, and apoptosis. In particular, Dox inhibits PI3K and Akt activity, which sets off a series of subsequent events marked by the dysregulation of TFEB, FOXO, and mTOR, as well as an increase in GSK-3β activity. This imbalance triggers increased oxidative stress, increased autophagic flux, and amplified apoptotic signaling pathways. Increased activity of GSK-3β promotes the opening of Mitochondrial Permeability Transition Pores (MPTP), which release cytochrome C into the cytoplasm and ultimately cause cell death. Furthermore, Dox directly inhibits AMPK activity, which also attenuates mTOR signaling and disrupts autophagic functions.

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  Fig. (2). The schematic depiction showing the mechanism underlying DIC, focusing on its impact on the Nrf2/Keap1/ARE and MAPK/ERK signaling pathways. Under normal conditions, Nrf2 and Keap1 are typically bound together, but separation occurs in response to stress stimuli. Dox impedes this separation process, leading to heightened oxidative stress as Nrf2 fails to activate the synthesis of ARE genes, including those encoding SOD, CAT, GSH, and GPx. This elevated oxidative stress activates the p38-MAPK and ERK pathways, resulting in the upregulation of NF-κβ and Bax proteins. Consequently, this cascade of events induces inflammation and apoptosis in cardiomyocytes, thereby contributing to cardiotoxicity.

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  Fig. (3). The depicted figure illustrates the inhibitory effect of Dox on the binding of NOTCH receptor to DLL-1 and Jag-1 ligands on sender cells, thereby resulting in decreased VEGFR levels and increased TGF-β1 expression in endothelial cells. This inhibition contributes to vascular senescence and cardiotoxicity. Additionally, Dox suppresses the transcription of β-catenin by the TCF/LEF transcription factor under stressful conditions, leading to diminished proliferation and migration of endothelial cells.

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  Fig. (4). The direct stimulation of TLR by Dox, leading to suppression of the Iĸĸ complex and the subsequent activation of NF-κβ, AP-1, and GATA. The activation of these proteins further stimulates the synthesis of interferons and cytokines, leading to an inflammatory response. Additionally, Dox activates Tweak binding with the Fn14 receptor, promoting inflammation through the upregulation of TRAF-2 and NIK components. The increase in cytokine levels activates the TNF Receptor (TNFR), initiating apoptosis via the extrinsic pathway. Furthermore, Dox inhibits cFLIP and XIAP, exacerbating apoptosis in cardiomyocytes and contributing to cardiotoxicity.