High Density Lipoprotein and Its Precursor Protein Apolipoprotein A1 as Potential Therapeutics to Prevent Anthracycline Associated Cardiotoxicity

Figure 1. Direct cardiotoxic effects of anti-cancer therapies in cardiomyocytes. Doxorubicin cardiomyocyte cytotoxicity through diverse pathways including DNA damage, accumulation of ROS and RNS, mitochondrial dysfunction, apoptosis and impaired autophagy. Inhibition of ErbB2/4 receptor complex with trastuzumab impacts several signaling pathways resulting in impaired protein synthesis and myocardial structure via the Src/Fak pathway (6). Trastuzumab mediated supression of ErbB2/4 stimulated PI3K-Akt signaling impacts cell survival via mTOR pathway as well as increases apoptosis via BAD/BcL-xL pathway (7). Chemotherapy with fluoropyrimidines, such as 5-fluorouracil (5-FU) cause increase in formation of ROS and RNS leading to mitochondrial dysfunction and activation of caspase-3 and apoptosis (8). Radiotherapy leads to ROS and RNS formation, mitochondrial dysfunction and single-stranded DNA breaks leading to apoptosis activation (9).

Figure 2. Mechanisms of DOX-induced cardiotoxicity. DOX enters the cell by passive diffusion, and within the cytoplasm undergoes redox cycling resulting in the generation of ROS and RNS (47). Oxidative and nitrosative stress are known to contribute to activation of cell death pathways, such as autophagy, necrosis, and apoptosis. DOX can promote Ca2+ overload by inhibiting SERCA2a and transiently enhancing the activity of RyR2. DOX can bind cardiolipin, a major inner mitochondrial membrane lipid. At the mitochondria DOX promotes damage to mitochondrial DNA (mtDNA) through interactions with Top-2β, and Top-1mt. In the nucleus, DOX interacts with Top-2β and DNA to form the Top-2β–DOX—DNA cleavage complex (48). By binding to Top-2β, DOX disrupts the rejoining of DNA leading to the accumulation of double stranded DNA breaks thereby triggering apoptosis (49). Damage to mitochondrial DNA affects mitochondrial biogenesis and contributes to mitochondrial dysfunction and therefore reduced ATP production (50).

Figure 3. Effects of HDL on DOX-induced cytotoxicity of cardiomyocytes. HDL binds to SR-B1 leading to activation of the PI3K/Akt pathway (137). In addition, HDL is able to activate ERK1/2-JAK-STAT3 signaling via a pathway involving HDL mediated delivery of the bioactive lipid, S1P acting via the S1P2 receptor (136). Together these pathways prevent DOX-induced apoptosis and atrophy.

Figure 4. Emerging roles of high density lipoprotein (HDL) in cancer and cancer therapy associated cardiotoxicity from preclinical studies. HDL induces cardioprotective effects in cardiomyocytes via SR-B1 receptor and activation of PI3K-Akt pathway as well as via S1P2 receptor leading activation of STAT3-JAK-ERK1/2 pathway (136, 137). rHDL used as a drug delivery system may allow for targeted delivery to at least some types of tumors, sparing cardiomyocytes (45, 152). Furthermore, the major apoliprotein of HDL (ApoA1) directly attenuates tumor growth and metastasis in preclinical models (167). These pathways are not necessarily muatually exclusive.