Theranostic magnetic nanoparticles enhance DNA damage and mitigate doxorubicin-induced cardio-toxicity for effective multi-modal tumor therapy.

The chemo-therapeutic efficacy of Doxorubicin (Dox), a potent anti-cancer drug used in the treatment of several solid tumors, is severely compromised by its cardio-toxicity. To overcome this shortcoming and exploit the utmost theranostic potential of nano-formulations, magnetic nanoparticles co-encapsulated with Dox and indocyanine green (ICG) in a liposomal carrier and tagged with cyclic RGD peptide were rationally designed and synthesized. These magneto-liposomes (T-LMD) showed αvß3-integrin receptor targeting and higher cyto-toxicity in several cancer cell lines (i.e. lung, breast, skin, brain and liver cancer) in combination with or without gamma radiation or magnetic hyperthermia therapy as compared to clinical liposomal nano-formulation of Dox (Lippod™). Mechanism of chemo-radio-sensitization was found to involve activation of JNK mediated pro-apoptotic signaling axis and delayed repair of DNA double strand breaks. Real time imaging of ICG labeled T-LMD suggested ~6-18 fold higher tumor accumulation of T-LMD as compared to off-target organs (kidney, liver, spleen, intestine, lungs and heart) and resulted in its higher combinatorial (chemo-radio-hyperthermia) tumor therapy efficacy as compared to Lippod™. Moreover, T-LMD showed insignificant toxicity to the heart tissue as suggested by serum levels of CK-MB, histo-pathological analysis, anti-oxidant enzyme activities (Catalase and GST) and markers of cardiac fibrosis, suggesting its potential for targeted multi-modal therapy of cancer.

Protective role of black seed oil in doxorubicin-induced cardiac toxicity in children with acute lymphoblastic leukemia.

BACKGROUND: Leukemia is the most common pediatric malignancy. It affects bone marrow cells especially lymphoid cell precursor. Leukemia is treated mainly by chemotherapy. Doxorubicin is a well-established chemotherapeutic agent included in treatment protocols of acute lymphoblastic leukemia. Its efficacy is often limited by its cardiotoxic side effects. Many studies are directed to overcome this problem. Black seed oil was found to have a potent cardioprotective effect.Aim of the study: To assess the protective role of black seed oil against doxorubicin-induced cardiotoxicity in children with acute lymphoblastic leukemia. SUBJECTS AND METHODS: This study was carried out on 40 children with acute lymphoblastic leukemia including 20 patients under doxorubicin therapy and black seed oil 80 mg/kg/dose divided into 3 doses starting at the same moment of beginning of doxorubicin infusion therapy and continued for 1 week after each doxorubicin dose [group I] and 20 patients under doxorubicin and placebo for 1 week after each doxorubicin dose [group II]. They underwent conventional echo-Doppler measures of left ventricular systolic and diastolic functions and pulsed wave tissue Doppler of lateral mitral annulus. RESULTS: No significant differences were found in parameters of electrocardiograph including S-T segment and Q-T interval either before or after doxorubicin therapy. No significant differences in echocardiographic parameters were found between group I and group II before therapy. Non-significant changes in parameters of diastolic function [E/A ratio or e/a ratio] were found after doxorubicin therapy in group I and II, but there were significant reduction in parameters of systolic function [EF, FS and s wave] after doxorubicin therapy more in group II than group I.Conclusion and recommendation: From this study, we concluded that: Black seed oil improves some cardiac side effects of doxorubicin as shown by better systolic functions in children with acute lymphoblastic leukemia who were treated with Doxorubicin and black seed (group I) than in children with acute lymphoblastic leukemia who were treated with doxorubicin alone with no black seeds (group II), and therefore multi center studies is recommended to be done before we can recommend the use of black seed oil as an adjuvant therapy in patients with acute lymphoblastic leukemia under doxorubicin-based treatment protocol.

Inhibition of the cardiac myocyte mineralocorticoid receptor ameliorates doxorubicin-induced cardiotoxicity.

Aim: Anthracyclines such as doxorubicin are widely used in cancer therapy but their use is limited by cardiotoxicity. Up to date there is no established strategy for the prevention of anthracyclin-induced heart failure. In this study, we evaluated the role of the cardiac myocyte mineralocorticoid receptor (MR) during doxorubicin-induced cardiotoxicity. Methods and results: A single high-dose or repetitive low-dose doxorubicin administration lead to markedly reduced left ventricular function in mice. Treatment with the MR antagonist eplerenone prevented doxorubicin-induced left ventricular dysfunction. In order to identify the cell types and molecular mechanisms involved in this beneficial effect we used a mouse model with cell type-specific MR deletion in cardiac myocytes. Cardiac myocyte MR deletion largely reproduced the effect of pharmacological MR inhibition on doxorubicin-induced cardiotoxicity. RNAseq from isolated cardiac myocytes revealed a repressive effect of doxorubicin on gene expression which was prevented by MR deletion. Conclusions: We show here that (i) eplerenone prevents doxorubicin-induced left ventricular dysfunction in mice, and (ii) this beneficial effect is related to inhibition of MR in cardiac myocytes. Together with present clinical trial data our findings suggest that MR antagonism may be appropriate for the prevention of doxorubicin-induced cardiotoxicity.

Cardioprotective effect of cannabidiol in rats exposed to doxorubicin toxicity.

The potential protective effect of cannabidiol, the major non-psychotropic Cannabis constituent, was investigated against doxorubicin cardiotoxicity in rats. Cardiotoxicity was induced by six equal doses of doxorubicin (2.5mgkg(-1) i.p., each) given at 48h intervals over two weeks to achieve a total dose of 15mgkg(-1). Cannabidiol treatment (5mgkg(-1)/day, i.p.) was started on the same day of doxorubicin administration and continued for four weeks. Cannabidiol significantly reduced the elevations of serum creatine kinase-MB and troponin T, and cardiac malondialdehyde, tumor necrosis factor-α, nitric oxide and calcium ion levels, and attenuated the decreases in cardiac reduced glutathione, selenium and zinc ions. Histopathological examination showed that cannabidiol ameliorated doxorubicin-induced cardiac injury. Immunohistochemical analysis revealed that cannabidiol significantly reduced the expression of inducible nitric oxide synthase, nuclear factor-κB, Fas ligand and caspase-3, and increased the expression of survivin in cardiac tissue of doxorubicin-treated rats. These results indicate that cannabidiol represents a potential protective agent against doxorubicin cardiac injury.