Prevention of doxorubicin (DOX)-induced genotoxicity and cardiotoxicity: Effect of plant derived small molecule indole-3-carbinol (I3C) on oxidative stress and inflammation

Hajra, Subhadip; Patra, Arup Ranjan; Basu, Aninda; Bhattacharya, Sudin

doi:10.1016/j.biopha.2018.02.088

Cited by 80 publications

(57 citation statements)

References 57 publications

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“…The pathophysiological mechanisms of DOX-induced cardiotoxicity remain incompletely understood. Accumulating evidence implicates genotoxic stress associated with DOX-mediated induction of double-strand DNA breaks through inhibition of topoisomerase 2 (48,50), oxidative stress due to increased generation of reactive oxygen species (ROS) and antioxidant depletion (12,13), inflammation (11,45), as well as mitochondrial and autophagy dysregulation (8,15,21), in DOX-induced cardiac injury, leading to cardiomyocyte dysfunction and cell death.…”

Section: Introductionmentioning

confidence: 99%

p38δ genetic ablation protects female mice from anthracycline cardiotoxicity

George

Kiss

Obaid

et al. 2020

Preprint

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BACKGROUND: The efficacy of an anthracycline antibiotic doxorubicin (DOX) as a chemotherapeutic agent is limited by dose-dependent cardiotoxicity. DOX is associated with activation of intracellular stress signaling pathways including p38 MAPKs. While previous studies have implicated p38 MAPK signaling in DOX-induced cardiac injury, the roles of the individual p38 isoforms, specifically, of the alternative isoforms p38 and p38, remain uncharacterized. OBJECTIVES: To determine the potential cardioprotective effects of p38 and p38 genetic deletion in mice subjected to acute DOX treatment. METHODS: Male and female wild-type (WT), p38 -/-, p38 -/-and p38 -/- -/-mice were injected with 30 mg/kg DOX and their survival was tracked for ten days. During this period cardiac function was assessed by echocardiography and electrocardiography and fibrosis by PicroSirius Red staining.Immunoblotting was performed to assess the expression of signaling proteins and markers linked to autophagy. RESULTS: Significantly improved survival was observed in p38 -/-female mice post-DOX relative to WT females, but not in p38 -/-or p38 -/- -/-male or female mice. The improved survival in DOX-treated p38 -/-females was associated with decreased fibrosis, increased cardiac output and LV diameter relative to DOX-treated WT females, and similar to saline-treated controls. Structural and echocardiographic parameters were either unchanged or worsened in all other groups. Increased autophagy, as evidenced by increased LC3-II level, and decreased mTOR activation was also observed in DOX-treated p38 -/-females. CONCLUSIONS: p38 plays a crucial role in promoting DOX-induced cardiotoxicity in female mice by inhibiting autophagy. Therefore, p38 targeting could be a potential cardioprotective strategy in anthracycline chemotherapy. NEW AND NOTEWORTHY:This study for the first time identifies the roles of the alternative p38 and p38 MAPK isoforms in promoting DOX-cardiotoxicity in a sex-specific manner. While p38 systemic deletion did not affect DOX-cardiotoxicity, p38 systemic deletion was cardioprotective in female but not in male mice. Cardiac structure and function were preserved in DOX-treated p38-/-females and autophagy was increased.

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Section: Introductionmentioning

confidence: 99%

p38δ genetic ablation protects female mice from anthracycline cardiotoxicity

George

Kiss

Obaid

et al. 2020

Preprint

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“…Doxorubicin (DOX) is effective in the treatment of hematological malignancies, solid tumors, soft tissue sarcomas and breast cancer (1,2). However, adverse reactions such as neutropenia, heart arrhythmias, irreversible cardiomyopathy, congestive heart failure and neurotoxicity significantly limit its clinical use (3).…”

Section: Introductionmentioning

confidence: 99%

Involvement of neurotrophic signaling in doxorubicin‑induced cardiotoxicity

Liao

Zhang

et al. 2019

Exp Ther Med

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Dose dependent cardiotoxicity is the primary side effect of doxorubicin (DOX), but the underlying molecular mechanisms remain unclear. An increasing amount of evidence has demonstrated that neurotrophic signaling plays a pivotal role in both neurons and the heart, but the biological association between neurotrophic signaling and DOX-induced cardiotoxicity remains unknown. The present study determined the level of neurotrophins and their receptors in the heart of rats following DOX administration. DOX was administered 7 times at a dose of 2.5 mg/kg once every 2 days via intraperitoneal injection. The present study revealed that cardiac injury parameters, such as creatine kinase (CK), creatine kinase-myocardial bound, lactate dehydrogenase, troponin T and aspartate transaminase in serum were significantly increased in the DOX group. Both the gene and protein expression of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in the heart were markedly decreased following DOX treatment. Notably, the protein level of BDNF in the serum was inhibited in DOX-treated rats, whereas DOX induced a significant increase in the protein level of NGF in the serum. DOX induced a significant decrease in the level of tropomyosin-associated kinase A (TrkA) and the ratio of pTrkA/TrkA and pTrkB/TrkB. Furthermore, the administration of DOX suppressed downstream protein kinase B and extracellular signal regulated kinase phosphorylation. The present study first demonstrated that BDNF/TrkB signaling and NGF/TrkA signaling were altered by DOX, which indicated that neurotrophic signaling was involved in DOX-induced cardiotoxicity.

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“…All chemicals were administered intraperitoneally at a dose of 50 mg/kg body weight for 14 consecutive days. In previous studies [9,12,[20][21][22]24,25], the dose of 50 mg/kg of several phytochemicals (SFN, indole-3-carbinol, quercetin, and curcumin) was effective in inducing several important antioxidant enzymes expression (including HO-1). Therefore, the phytochemical dose of 50 mg/kg was chosen in this current study because we wanted to observe which phytochemical is the most potent in inducing HO-1 at that particular dose.…”

Section: Animals Used and Their Treatmentsmentioning

confidence: 99%

“…Moreover, the end products of HO-1 catabolism exhibit antioxidative, anti-inflammatory, and antiapoptotic properties [7]. Sulforaphane (SFN), indole-3-carbinol, curcumin, and quercetin have been known to induce HO-1 activation and expression in various conditions [8][9][10][11][12][13]. However, no one has ever compared which phytochemical is the most potent in inducing the expression of HO-1 in mice liver where the liver is healthy and not subject to any disease and toxicity.…”

Section: Introductionmentioning

confidence: 99%

The Effect of Administration of an Equal Dose of Different Classes of Phytochemicals on Heme Oxygenase-1 Gene and Protein Expression in Mice Liver

Abdullah¹,

Alrawaiq²,

Atia³

2019

Asian J Pharm Clin Res

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Objective: Heme oxygenase-1 (HO-1) is enzyme that possesses antioxidant, anti-inflammatory, and cytoprotective functions. Induction of HO-1 occurs as an adaptive and beneficial response to various injurious stimuli such as oxidative stress. This study is aimed at monitoring the effects of administration of equal doses (50 mg/kg) of sulforaphane (SFN), curcumin, quercetin, indole-3-carbinol, and butylated hydroxyanisole (BHA) for 14 days on the levels of liver HO-1 gene and protein expression in mice. Method: A total of 48 adult male ICR white mice (25–30 g) were divided into eight groups: Normal control group (n=6), SFN-treated group (n=6), quercetin-treated group (n=6), curcumin-treated group (n=6), BHA-treated group (n=6), indole-3-carbinol treated group (n=6), vehicle 1 control group (n=6), and vehicle 2 control group (n=6). All chemicals were administered intraperitoneally at a dose of 50 mg/kg for 14 days. Vehicle 1 (dimethyl sulfoxide, TweenTM 20, and normal saline at a ratio of 0.05:0.1:0.85) was used to dissolve SFN, quercetin, and curcumin. Vehicle 2 (corn oil) was used to dissolve indole-3-carbinol and BHA. At day 15, the animals were sacrificed and their livers were isolated. From the liver, total RNA was extracted, reverse transcribed and subjected to quantitative real‐time polymerase chain reaction to detect HO-1 gene expression. Agarose gel electrophoresis was also performed to verify the specificity of the amplification. HO-1 protein expression was determined by Western blotting. Results: HO-1 gene expression showed significant increase of 4.6±0.3, 3.6±0.2, 3.6±0.4, 3.3±0.3, and 3.0±0.4-fold and HO-1 protein expression showed significant increase of 2.3±0.2, 2.2±0.2, 2.2±0.1, 1.8±0.1, and 1.7±0.2-fold following treatment with 50 mg/kg of SFN, indole-3-carbinol, BHA, curcumin, and quercetin, respectively, compared to controls (p<0.05). Conclusion: At a dose of 50 mg/kg, SFN administration for 14 days resulted in the highest induction of HO-1 gene and protein expression level in mice liver, and quercetin the lowest.

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Prevention of doxorubicin (DOX)-induced genotoxicity and cardiotoxicity: Effect of plant derived small molecule indole-3-carbinol (I3C) on oxidative stress and inflammation

Cited by 80 publications

References 57 publications

p38δ genetic ablation protects female mice from anthracycline cardiotoxicity

p38δ genetic ablation protects female mice from anthracycline cardiotoxicity

Involvement of neurotrophic signaling in doxorubicin‑induced cardiotoxicity

The Effect of Administration of an Equal Dose of Different Classes of Phytochemicals on Heme Oxygenase-1 Gene and Protein Expression in Mice Liver

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