Objectives Doxorubicin (Dox) belongs to the anthracycline drug classification and is a widely administered chemotherapeutic. However, Dox use in therapy is limited by its cardiotoxicity, representing a significant drawback of Dox treatment applicability. A large amount of current research is on reducing Dox-induced cardiotoxicity by developing targeted delivery systems and investigating cardiotoxicity mechanisms. Recently, discrepancies have challenged the traditional understanding of Dox metabolism, mechanisms of action and cardiotoxicity drivers. This review summarises the current knowledge around Dox’s metabolism, mechanisms of anticancer activity, and delivery systems and offers a unique perspective on the relationships between several proposed mechanisms of Dox-induced cardiotoxicity. Key findings While there is a strong understanding of Dox’s pharmacokinetic properties, it is unclear which enzymes contribute to Dox metabolism and how Dox induces its cytotoxic effect in neoplastic and non-neoplastic cells. Evidence suggests that there are several potentially synergistic mechanisms involved in Dox-induced cardiotoxicity. Summary It has become clear that Dox operates in a multifactorial fashion dependent on cellular context. Accumulation of oxidative stress appears to be a common factor in cardiotoxicity mechanisms, highlighting the importance of novel delivery systems and antioxidant therapies.

Objectives: Pigment epithelium-derived factor (PEDF) has been recently linked to insulin resistance and is capable of differentiating myocytes to bone. We examined in more detail the intricate signalling of the insulin pathway influenced by PEDF in skeletal myocytes. We tested whether this serpin is also capable of generating de novo bone from adipocytes in vitro and in vivo, and how the anticancer drug doxorubicin links with PEDF and cellular metabolism. Methods and key findings: We demonstrate that PEDF can inhibit phosphorylation of insulin receptor (IR) and insulin receptor substrate (IRS) in skeletal myocytes. PEDF constitutively activates p42/44 MAPK/Erk, but paradoxically does not affect mitogenic signalling. PEDF did not perturb either mitochondrial activity or proliferation in cells representing mesenchymal stem cells, cardiomyocytes, and skeletal myocytes and adipocytes. PEDF induced transdifferentiation of adipocytes to osteoblasts, promoting bone formation in cultured adipocytes in vitro and gelfoam fatpad implants in vivo. Bone formation in white adipose tissue (WAT) was better than in brown adipose tissue (BAT). The frontline anticancer drug doxorubicin increased levels of PEDF in a human breast cancer cell line, mirroring the in vivo finding where cardiac muscle tissue was stained increasingly for PEDF as the dose of doxorubicin increased in mice. PEDF also increased levels of reactive oxygen species (ROS) and glutathione (GSH) in the breast cancer cell line. Conclusions: PEDF may be used to regenerate bone from adipose tissue in cases of trauma such as fractures or bone cancers. The increased presence of PEDF in doxorubicin-treated tumour cells need further exploration, and could be useful therapeutically in future. The safety of PEDF administration in vivo was further demonstrated in this study.

Objectives Cardiovascular diseases are the leading cause of death worldwide, with patients having limited options for treatment. Pigment epithelium-derived factor (PEDF) is an endogenous multifunctional protein with several mechanisms of action. Recently, PEDF has emerged as a potential cardioprotective agent in response to myocardial infarction. However, PEDF is also associated with pro-apoptotic effects, complicating its role in cardioprotection. This review summarises and compares knowledge of PEDF’s activity in cardiomyocytes with other cell types and draws links between them. Following this, the review offers a novel perspective of PEDF’s therapeutic potential and recommends future directions to understand the clinical potential of PEDF better. Key findings PEDF’s mechanisms as a pro-apoptotic and pro-survival protein are not well understood, despite PEDF’s implication in several physiological and pathological activities. However, recent evidence suggests that PEDF may have significant cardioprotective properties mediated by key regulators dependent on cell type and context. Conclusions While PEDF’s cardioprotective activity shares some key regulators with its apoptotic activity, cellular context and molecular features likely allow manipulation of PEDF’s cellular activity, highlighting the importance of further investigation into its activities and its potential to be applied as a therapeutic to mitigate damage from a range of cardiac pathologies.