Enhancement of adriamycin toxicity by iron chelates is not a free radical mechanism

The possible involvement of metal ions and free radicals in the cytotoxic mechanism of Adriamycin (ADR) was investigated, using a model system ofEscherichia coli cells. It is shown thatE. coli mediated the production of free radicals under anaerobic (ADR-semiquinone) and aerobic (superoxide) conditions. ADR-induced loss of colony-forming ability was enhanced by the addition of iron (Fe) chelates. These observations suggested that a Fenton-type free radical mechanism was responsible for ADR toxicity. However, the mortality rate was essentially unchanged by the exclusion of oxygen. It was also unaffected by the addition of H₂O₂, catalase, or chelating agents. Cu(II), Zn(II) or Mg(II) had no effect on ADR toxicity. ADR and iron chelates did not induce measurable amounts of DNA strand-breaks. These observations suggest a mechanism of ADR-induced cell killing that is enhanced by Fe chelates, but does not directly involve oxygen-derived free radicals.     

Apelin-13 attenuates cisplatin-induced cardiotoxicity through inhibition of ROS-mediated DNA damage and regulation of MAPKs and AKT pathways

Platinum-based chemotherapy represents one of the most effective ways in combating human cancers. However, the cardiotoxicity subsequent severely limited its clinical application. Increased evidences indicate that oxidative stress plays a crucial role in the pathological process of platinum-induced cardiotoxicity. It is reported that apelin-13 a bioactive peptide has the scavenging capacity of free radical, and it has the potential to regulate the cardiovascular system. Hence, the potential of apelin-13 to antagonize cisplatin-induced cardiotoxicity was evaluated in H9c2 rat myocardial cells in vitro and in C57 mice in vivo. The results showed that cisplatin indeed caused DNA damage in H9c2 cells by promoting the accumulation of intracellular reactive oxygen species (ROS) and superoxide anion, which led to cell apoptosis and resulted in overt cardiotoxicity. However, apelin-13 pre-treatment effectively attenuated the cisplatin-induced ROS and superoxide anion generation, inhibited DNA damage, and suppressed the PARP cleavage and caspases activation. Further investigation revealed that apelin-13 blocked cisplatin-induced H9c2 cells apoptosis involving the regulation of MAPKs and PI3K/Akt signaling pathway. Importantly, apelin-13 co-treatment also significantly attenuated cisplatin-induced cardiotoxicity in vivo by inhibiting myocardial cells apoptosis and improving angiogenesis in mice heart. Taken together, our results suggest that the use of apelin-13 may be an effective strategy for antagonizing the cardiotoxicity-induced by platinum-based chemotherapy.     

Adriamycin-induced oxidative mitochondrial cardiotoxicity

The anticancer agent Adriamycin (ADR) has long been recognized to induce a dose-limiting cardiotoxicity. Numerous studies have attempted to characterize and elucidate the mechanism(s) behind its cardiotoxic effect. Despite a wealth of data covering a wide-range of effects mediated by the drug, the definitive mechanism remains a matter of debate. However, there is consensus that this toxicity is related to the induction of reactive oxygen species (ROS). Induction of ROS in the heart by ADR occurs via redox cycling of the drug at complex I of the electron transport chain. Many studies support the theory that mitochondria are a primary target of ADR-induced oxidative stress, both acutely and long-term. This review focuses on the effects of ADR redox cycling on the mitochondrion, which support the hypothesis that these organelles are indeed a major factor in ADR cardiotoxicity. This review has been constructed with particular emphasis on studies utilizing cardiac models with clinically relevant doses or concentrations of ADR in the hope of advancing our understanding of the mechanisms of ADR toxicity. This compilation of current data may reveal valuable insights for the development of therapeutic strategies better tailored to minimizing the dose-limiting effect of ADR.     

Potential cytotoxicity of silver nanoparticles: Stimulation of autophagy and mitochondrial dysfunction in cardiac cells

In the present study, we elucidated the potential cytotoxicity of AgNPs in H9c2 rat cardiomyoblasts and assessed the underlying toxicological manifestations responsible for their toxicity thereof. The results indicated that the exposure of AgNPs to H9c2 cardiac cells decreased cell viability in a dose-dependent manner and caused cell cycle arrest followed by induction of apoptosis. The AgNPs treated cardiac cells showed a generation of reactive oxygen species (ROS) and mitochondrial dysfunction where mitochondrial ATP was reduced and the expression of AMPK1α increased. AgNPs also induced ROS-mediated autophagy in H9c2 cells. There was a significant time-dependent increase in intracellular levels of Atg5, Beclin1, and LC3BII after exposure to AgNPs, signifying the autophagic response in H9c2 cells. More importantly, the addition of N-acetyl-L-cysteine (NAC) inhibited autophagy and significantly reduced the cytotoxicity of AgNPs in H9c2 cells. The study highlights the prospective toxicity of AgNPs on cardiac cells, collectively signifying a potential health risk.     

α-Lipoic acid increases tolerance of cardiomyoblasts to glucose/glucose oxidase-induced injury via ROS-dependent ERK1/2 activation

α-Lipoic acid (LA) has been shown to improve the diabetic cardiac symptoms. However, the underlying mechanisms have not been elucidated precisely. We have reported recently that LA potentially protected neurons from substance-induced apoptosis. We hypothesized that LA could attenuate cardiac cells death induced by oxidative stress derived from high glucose. To test this possibility, we examined the effects of LA on d-glucose/glucose oxidase (DG/GO, 30mM/5mU)-induced injury in rat cardiomyoblast H9c2 cells. We observed that LA pretreatment significantly increased cell viability in DG/GO-challenged cells. LA pretreatment also attenuated DG/GO-induced apoptosis as evidenced by decreases in both nuclear condensation and loss of mitochondrial potential. In addition, LA activated ERK1/2 and moderately increased ROS production. Blockade of ERK1/2 activation by PD98059 completely abolished LA-induced protection against DG/GO challenge. Inhibition of ROS by N-acetylcysteine abrogated LA-induced ERK1/2 activation and cytoprotection. Furthermore, we observed that the ROS production induced by LA was significantly slower and milder than that by DG/GO. Our results suggest that pretreatment with LA moderately increased ROS production to induce a preconditioning-like effect by ERK1/2 activation thereby increased tolerance of H9c2 cells to DG/GO challenge.     

A novel agent attenuates cardiotoxicity and improves antitumor activity of doxorubicin in breast cancer cells

Doxorubicin (Dox) is a well-known chemotherapeutic agent used in the treatment of various cancers. However, Dox-induced cardiotoxicity limits its further clinical use. We have previously reported a small molecular named biotin-conjugated ADTM analog (BAA) that exhibits cytoprotective effects against oxidative stress–induced cell injury in cardiomyoblast H9c2 cells. Here, the protective effects of BAA, indexed by attenuation of the cardiotoxicity induced by Dox as well as synergistic antitumor activity that increases the chemotherapeutic efficacy of Dox were investigated. Our results demonstrated that BAA significantly ameliorated Dox-induced toxicity in the H9c2 cells and zebrafish models. In addition, BAA attenuated Dox-induced endoplasmic reticulum (ER) stress in H9c2 cells. An ER stress inhibitor, 4-phenylbutyric acid, reversed the protective effect of BAA in H9c2 cells. In contrast, in human breast tumor MDA-MB-231 cells, BAA significantly enhanced Dox-induced cytotoxicity through upregulating Dox-induced ER stress response. Taken together, our findings indicate that Dox combined with BAA can significantly enhance its antitumor activity in breast cancer cells and reduce its cardiotoxicity, at least in part, by mediating ER stress activation.     

Insulin-like growth factor-1 protects H9c2 cardiac myoblasts from oxidative stress-induced apoptosis via phosphatidylinositol 3-kinase and extracellular signal-regulated kinase pathways

Oxidative stress plays a critical role in cardiac injuries during ischemia/reperfusion. Insulin-like growth factor-1 (IGF-1) promotes cell survival in a number of cell types, but the effect of IGF-1 on the oxidative stress has not been elucidated in cardiac muscle cells. Therefore, we examined the role of IGF-1 signaling pathway in cell survival against H2O2-induced apoptosis in H9c2 cardiac myoblasts. H2O2 treatment induced apoptosis in H9c2 cells, and pretreatment of cells with IGF-1 suppressed apoptotic cell death. The antiapoptotic effect of IGF-1 was blocked by LY294002 (an inhibitor of phosphatidylinositol 3-kinase) and by PD98059 (an inhibitor of extracellular signal-regulated kinase (ERK)). The protective effect of IGF-1 was also blocked by rapamycin (an inhibitor of p70 S6 kinase). Furthermore, H9c2 cells stably transfected with constitutively active PI 3-kinase (H9c2-p110*) and Akt (H9c2-Gag-Akt) constructs were more resistant to H2O2 cytotoxicity than control cells. Although H2O2 activates both p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK), IGF-1 inhibited only JNK activation. Activated PI 3-kinase (H9c2-p110*) and pretreatment of cells with IGF-1 down-regulated Bax protein levels compared to control cells. Taken together, our results suggest that IGF-1 transmits a survival signal against oxidative stress-induced apoptosis in H9c2 cells via PI 3-kinase and ERK-dependent pathways and the protective effect of IGF-1 is associated with the inhibition of JNK activation and Bax expression.     

Attenuation of the acute adriamycin-induced cardiac and hepatic oxidative toxicity by N-(2-mercaptopropionyl) glycine in rats

The protective effect of the synthetic aminothiol, N-(2-mercaptopropionyl) glycine (MPG) on adriamycin (ADR) induced acute cardiac and hepatic oxidative toxicity was evaluated in rats. ADR toxicity, induced by a single intraperitoneal injection (15 mg/kg), was indicated by an elevation in the level of serum glutamic pyruvic transaminase (GPT), glutamic oxaloacetic transaminase (GOT), creatine kinase isoenzyme (CK-MB), and lactic dehydrogenase (LDH). ADR produced significant elevation in thiobarbituric acid reactive substances (TBARS), indicating lipid peroxidation, and significantly inhibited the activity of superoxide dismutase (SOD) in heart and liver tissues. In contrast, a single injection of ADR did not affect the cardiac or hepatic glutathione (GSH) content and cardiac catalase (CAT) activity but elevated hepatic CAT. Pretreatment with MPG, (2.5 mg/kg) intragastrically, significantly reduced TBARS concentration in both heart and liver and ameliorated the inhibition of cardiac and hepatic SOD activity. In addition, MPG significantly decreased the serum level of GOT, GPT, CK-MB, and LDH of ADR treated rats. These results suggest that MPG exhibited antioxidative potentials that may protect heart and liver against ADR-induced acute oxidative toxicity. This protective effect might be mediated, at least in part, by the high redox potential of sulfhydryl groups that limit the activity of free radicals generated by ADR.     

Attenuation of the acute adriamycin-induced cardiac and hepatic oxidative toxicity by N-(2-mercaptopropionyl) glycine in rats

The protective effect of the synthetic aminothiol, N-(2-mercaptopropionyl) glycine (MPG) on adriamycin (ADR) induced acute cardiac and hepatic oxidative toxicity was evaluated in rats. ADR toxicity, induced by a single intraperitoneal injection (15 mg/kg), was indicated by an elevation in the level of serum glutamic pyruvic transaminase (GPT), glutamic oxaloacetic transaminase (GOT), creatine kinase isoenzyme (CK-MB), and lactic dehydrogenase (LDH). ADR produced significant elevation in thiobarbituric acid reactive substances (TBARS), indicating lipid peroxidation, and significantly inhibited the activity of superoxide dismutase (SOD) in heart and liver tissues. In contrast, a single injection of ADR did not affect the cardiac or hepatic glutathione (GSH) content and cardiac catalase (CAT) activity but elevated hepatic CAT. Pretreatment with MPG, (2.5 mg/kg) intragastrically, significantly reduced TBARS concentration in both heart and liver and ameliorated the inhibition of cardiac and hepatic SOD activity. In addition, MPG significantly decreased the serum level of GOT, GPT, CK-MB, and LDH of ADR treated rats. These results suggest that MPG exhibited antioxidative potentials that may protect heart and liver against ADR-induced acute oxidative toxicity. This protective effect might be mediated, at least in part, by the high redox potential of sulfhydryl groups that limit the activity of free radicals generated by ADR.