Synergistic interaction between lipid-loading and doxorubicin exposure in Huh7 hepatoma cells results in enhanced cytotoxicity and cellular oxidative stress: implications for acute and chronic care of obese cancer patients

AlGhamdi, Shareefa A.; Leoncikas, Vytautas; Plant, Kathryn E.; Plant, Nick

doi:10.1039/c5tx00173k

Cited by 10 publications

(9 citation statements)

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“…[29][30][31] In particular, ROS generation could trigger a wide range of transcriptional changes as the second messengers in a signaling cascade, and it might be recovered after leading to apoptosis or cell death. [32][33][34][35][36] In this study, the level of ROS production was detected after treatment of NCI-H460 cells with CDA14 and CDO14 liposomes for 24 h. The results showed that the intracellular ROS level was dose-dependent and increased significantly compared with the control in NCI-H460 cells. The ROS production of CDA14 was higher than that of CDO14 at the same concentrations; in particular, the ROS production of CDA14 increased remarkably at 120 μg Fig.…”

Section: Effects On the Mmpmentioning

confidence: 75%

Correlation of the cytotoxic effects of cationic lipids with their headgroups

et al. 2018

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As effective non-viral vectors of gene therapy, cationic lipids still have the problem of toxicity, which has become one of the main bottlenecks for their applications. The toxicity of cationic lipids is strongly connected to the headgroup structures. In this article, we studied the cytotoxicity of two cationic lipids with a quaternary ammonium headgroup (CDA14) and a tri-peptide headgroup (CDO14), respectively, and with the same linker bond and hydrophobic domain. The IC values of CDA14 and CDO14 against NCI-H460 cells were 109.4 μg mL and 340.5 μg mL, respectively. To determine the effects of headgroup structures of cationic lipids on cytotoxicity, apoptosis related pathways were investigated. As the lipids with a quaternary ammonium headgroup could induce more apoptotic cells than the ones with a peptide headgroup, the enzymatic activity of caspase-9 and caspase-3 increased obviously, whereas the mitochondrial membrane potential (MMP) decreased. At the same time, the reactive oxygen species (ROS) levels also increased and the cell cycle was arrested at the S phase. The results showed that the toxicity of the cationic lipid had a close relationship with its headgroup structures, and the cytotoxic mechanism was mainly the caspase activation dependent signaling pathway and mitochondrial dysfunction. Through this study, we hope to provide the scientific basis for exploiting safer and more efficient cationic lipids for gene delivery.

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Section: Effects On the Mmpmentioning

confidence: 75%

Correlation of the cytotoxic effects of cationic lipids with their headgroups

et al. 2018

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“…Doxorubicin (DOX) is a first-line anthracycline quinone and an effective anticancer drug extensively used in clinical practice [1]. However, the clinical use of DOX is limited due to its dose-dependent and cumulative cardiotoxicity, which may cause dilated cardiomyopathy and heart failure [2, 3]. Multiple mechanisms are involved in DOX-induced cardiotoxicity, including an increase in reactive oxygen species (ROS) and lipid peroxidation, calcium overloading, and deterioration of mitochondrial function, leading to impaired DNA and cardiomyocyte apoptosis [4, 5].…”

Section: Introductionmentioning

confidence: 99%

Berberine Ameliorates Doxorubicin-Induced Cardiotoxicity via a SIRT1/p66Shc-Mediated Pathway

Zhang

et al. 2019

Oxidative Medicine and Cellular Longevity

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Doxorubicin- (DOX-) induced cardiotoxicity is associated with oxidative stress and cardiomyocyte apoptosis. The adaptor protein p66Shc regulates the cellular redox status and determines cell susceptibility to apoptosis. This study is aimed at investigating the involvement of sirtuin 1- (SIRT1-) mediated p66Shc inhibition in DOX-induced redox signalling and exploring the possible protective mechanisms of berberine (Ber) against DOX-triggered cardiac injury in rats and a cultured H9c2 cell line. Our results showed that the Ber pretreatment markedly increased CAT, SOD, and GSH-PX activities, decreased the levels of MDA, and improved the electrocardiogram and histopathological changes in the myocardium in DOX-treated rats (in vivo). Furthermore, Ber significantly ameliorated the DOX-induced oxidative insult and mitochondrial damage by adjusting the levels of intracellular ROS, ΔΨm, and [Ca2+]m in H9c2 cells (in vitro). Importantly, the Ber pretreatment increased SIRT1 expression following DOX exposure but downregulated p66Shc. Consistent with the results demonstrating the SIRT1-mediated inhibition of p66Shc expression, the Ber pretreatment inhibited DOX-triggered cardiomyocyte apoptosis and mitochondrial dysfunction. After exposing H9c2 cells to DOX, the increased SIRT1 expression induced by Ber was abrogated by a SIRT1-specific inhibitor (EX527) or the use of siRNA against SIRT1. Accordingly, SIRT1 inhibition significantly abrogated the suppression of p66Shc expression and protection of Ber against DOX-induced oxidative stress and apoptosis. These results suggest that Ber protects the heart from DOX injury through SIRT1-mediated p66Shc suppression, offering a novel mechanism responsible for the protection of Ber against DOX-induced cardiomyopathy.

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“…Non-alcoholic fatty liver disease (NAFLD), a co-morbidity associated with obesity is characterized by macrovesicular steatosis, triglyceride accumulation in hepatocytes, increased hepatic oxidative stress and increased sensitivity to drug induced liver injury (Li et al, 2019). A study done by Alghamdi et al (2015) showed that DXR in the presence of palmitate and oleate (lipid loading) caused a signi cant accumulation of lipids within the human hepatoma cell line (Huh7 cells) and enhanced acute toxicity in lipid-loaded hepatocytes, which is mediated through increased oxidative stress and ROS (Alghamdi et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Obese mammary tumour-bearing mice are highly sensitive to doxorubicin-induced hepatotoxicity

Sedeman

Christowitz

Jager

et al. 2022

Preprint

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Background: Breast cancer is a major health burden for women, worldwide. Lifestyle-related risk factors, such as obesity and being overweight, have reached epidemic proportions and contributes to the development of breast cancer. Doxorubicin (DXR) is a chemotherapeutic drug commonly used to treat breast cancer, and although effective, may cause toxicity to other organs. The mechanisms and effects of DXR on hepatic tissue, and the contributing role of obesity, in breast cancer patients are poorly understood. The aim of this study was therefore to investigate the effects of doxorubicin on hepatic tissue in an obese tumour-bearing mouse model. Methods: A diet-induced obesity (DIO) mouse model was established, where seventy-four three-week-old female C57BL/6 mice were divided into two main groups, namely the high fat diet (containing 60% kcal fat) and standard diet (containing 10% kcal fat) groups. After eight weeks on their respective diets, the DIO phenotype was established, and the mice were further divided into tumour and non-tumour groups. Mice were subcutaneously inoculated with E0771 triple negative breast cancer cells in the fourth mammary gland and received three doses of 4 mg/kg DXR (cumulative dosage of 12 mg/kg) or vehicle treatments via intraperitoneal injection. The expression levels of markers involved in apoptosis and alanine aminotransferase (ALT) were compared by means of western blotting. To assess the pathology and morphology of hepatic tissue, haematoxylin and eosin staining was performed. The presence of fibrosis and lipid accumulation in hepatic tissues were assessed with Masson’s trichrome and Oil Red O staining, respectively. Results: Our western blot results indicated that a significant increase in the ratio of cleaved caspase-8 and caspase-8 protein expression was observed in the standard diet tumour-bearing mice treated with DXR compared to the high fat diet tumour-bearing mice treated with DXR. Microscopic examination of liver tissue showed significant changes in the high fat diet tumour-bearing mice treated with DXR, consisting of macrovesicular steatosis, hepatocyte ballooning and lobular inflammation, compared to the standard diet tumour-bearing mice treated with DXR and the control group (standard diet mice). These changes are the hallmarks of non-alcoholic fatty liver disease, associated with obesity.Conclusion: Our results suggest that DXR activated the extrinsic apoptotic pathway in tumour-bearing mice on the standard diet. The histopathological findings indicated that DXR caused significant hepatic parenchymal injury in the obese tumour-bearing mouse model. Hepatotoxicity is aggravated in obesity as an underlying co-morbidity. It has been shown that obesity is associated with poor clinical outcomes in patients receiving neo-adjuvant chemotherapy treatment regimens.

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Synergistic interaction between lipid-loading and doxorubicin exposure in Huh7 hepatoma cells results in enhanced cytotoxicity and cellular oxidative stress: implications for acute and chronic care of obese cancer patients

Abstract: Doxorubicin and lipid-loading (steatosis) interact synergistically in Huh7 hepatoma cells. This results in enhanced cytotoxicity and pro-inflammatory ROS accumulation.

Cited by 10 publications

References 50 publications

Correlation of the cytotoxic effects of cationic lipids with their headgroups

Correlation of the cytotoxic effects of cationic lipids with their headgroups

Berberine Ameliorates Doxorubicin-Induced Cardiotoxicity via a SIRT1/p66Shc-Mediated Pathway

Obese mammary tumour-bearing mice are highly sensitive to doxorubicin-induced hepatotoxicity

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