New molecular and biochemical insights of doxorubicin-induced hepatotoxicity

Prasanna, Pureti Lakshmi; Renu, Kaviyarasi; Gopalakrishnan, Abilash Valsala

doi:10.1016/j.lfs.2020.117599

Cited by 179 publications

(148 citation statements)

References 61 publications

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“…The anthracycline doxorubicin (Dox) has been the cornerstone of anticancer therapy over the past 50 years (Andreadis et al, 2007;Tarpey et al, 2019;Shen and Cheng, 2020). However, although Dox is widely used in the treatment of various cancers with promising efficacy, it is highly toxic and can cause dosedependent irreversible serious cardiotoxicity and liver damage with long-term use (Hartmann et al, 2020;Mitry et al, 2020;Prasanna et al, 2020;Qiao et al, 2020). As a result, the clinical use of many of such chemotherapeutic agents is limited (Takagi et al, 2014;Li et al, 2015;Shi et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Light-Responsive Micelles Loaded With Doxorubicin for Osteosarcoma Suppression

et al. 2021

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The enhancement of tumor targeting and cellular uptake of drugs are significant factors in maximizing anticancer therapy and minimizing the side effects of chemotherapeutic drugs. A key challenge remains to explore stimulus-responsive polymeric nanoparticles to achieve efficient drug delivery. In this study, doxorubicin conjugated polymer (Poly-Dox) with light-responsiveness was synthesized, which can self-assemble to form polymeric micelles (Poly-Dox-M) in water. As an inert structure, the polyethylene glycol (PEG) can shield the adsorption of protein and avoid becoming a protein crown in the blood circulation, improving the tumor targeting of drugs and reducing the cardiotoxicity of doxorubicin (Dox). Besides, after ultraviolet irradiation, the amide bond connecting Dox with PEG can be broken, which induced the responsive detachment of PEG and enhanced cellular uptake of Dox. Notably, the results of immunohistochemistry in vivo showed that Poly-Dox-M had no significant damage to normal organs. Meanwhile, they showed efficient tumor-suppressive effects. This nano-delivery system with the light-responsive feature might hold great promises for the targeted therapy for osteosarcoma.

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Section: Introductionmentioning

confidence: 99%

Light-Responsive Micelles Loaded With Doxorubicin for Osteosarcoma Suppression

et al. 2021

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“…Doxorubicin (DOX), also known as Adriamycin (a type of anthracycline), is a frontline cytotoxic drug used in numerous chemotherapeutic protocols for various cancer types, including breast cancer [1][2][3][4][5][6]. Despite its broad-spectrum cytotoxic effects [3,[7][8][9][10][11][12][13][14], DOX is associated with several severe side effects, including cardiotoxicity, hepatotoxicity, nephrotoxicity and fertility issues. In particular, DOX has been reported to cause lethal cardiomyopathy in cancer patients through free radical-induced oxidative stress and excessive production of reactive oxygen species [15,16].…”

Section: Introductionmentioning

confidence: 99%

“…Additionally, the development of drug resistance of the cytotoxic agents such as DOX poses a considerable challenge in cancer therapy [3,19,20]. Therefore, more efforts are being directed toward a combination therapy or the development of targeted drug delivery formulations to increase DOX therapeutic potential or alleviate adverse effects [11,[21][22][23][24][25][26][27][28][29][30].…”

Section: Introductionmentioning

confidence: 99%

Metabolomic Identification of Anticancer Metabolites of Australian Propolis and Proteomic Elucidation of Its Synergistic Mechanisms with Doxorubicin in the MCF7 Cells

Alsherbiny

Bhuyan

Radwan

et al. 2021

IJMS

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The combination of natural products with standard chemotherapeutic agents offers a promising strategy to enhance the efficacy or reduce the side effects of standard chemotherapy. Doxorubicin (DOX), a standard drug for breast cancer, has several disadvantages, including severe side effects and the development of drug resistance. Recently, we reported the potential bioactive markers of Australian propolis extract (AP−1) and their broad spectrum of pharmacological activities. In the present study, we explored the synergistic interactions between AP−1 and DOX in the MCF7 breast adenocarcinoma cells using different synergy quantitation models. Biochemometric and metabolomics-driven analysis was performed to identify the potential anticancer metabolites in AP−1. The molecular mechanisms of synergy were studied by analysing the apoptotic profile via flow cytometry, apoptotic proteome array and measuring the oxidative status of the MCF7 cells treated with the most synergistic combination. Furthermore, label-free quantification proteomics analysis was performed to decipher the underlying synergistic mechanisms. Five prenylated stilbenes were identified as the key metabolites in the most active AP−1 fraction. Strong synergy was observed when AP−1 was combined with DOX in the ratio of 100:0.29 (w/w) as validated by different synergy quantitation models implemented. AP−1 significantly enhanced the inhibitory effect of DOX against MCF7 cell proliferation in a dose-dependent manner with significant inhibition of the reactive oxygen species (p < 0.0001) compared to DOX alone. AP−1 enabled the reversal of DOX-mediated necrosis to programmed cell death, which may be advantageous to decline DOX-related side effects. AP−1 also significantly enhanced the apoptotic effect of DOX after 24 h of treatment with significant upregulation of catalase, HTRA2/Omi, FADD together with DR5 and DR4 TRAIL-mediated apoptosis (p < 0.05), contributing to the antiproliferative activity of AP−1. Significant upregulation of pro-apoptotic p27, PON2 and catalase with downregulated anti-apoptotic XIAP, HSP60 and HIF-1α, and increased antioxidant proteins (catalase and PON2) may be associated with the improved apoptosis and oxidative status of the synergistic combination-treated MCF7 cells compared to the mono treatments. Shotgun proteomics identified 21 significantly dysregulated proteins in the synergistic combination-treated cells versus the mono treatments. These proteins were involved in the TP53/ATM-regulated non-homologous end-joining pathway and double-strand breaks repairs, recruiting the overexpressed BRCA1 and suppressed RIF1 encoded proteins. The overexpression of UPF2 was noticed in the synergistic combination treatment, which could assist in overcoming doxorubicin resistance-associated long non-coding RNA and metastasis of the MCF7 cells. In conclusion, we identified the significant synergy and highlighted the key molecular pathways in the interaction between AP−1 and DOX in the MCF7 cells together with the AP−1 anticancer metabolites. Further in vivo and clinical studies are warranted on this synergistic combination.

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“…Doxorubicin (DOX, Adriamycin) is the classiest of anthracycline chemotherapeutic agents 1 . However, the clinical application of DOX is still limited due to its reversible cardiotoxicity, nephrotoxicity and hepatotoxicity 2‐4 . Indeed, acute kidney injury (AKI) is a common complication of DOX in both cancer patients and animal models which compromises their renal function 5‐13 .…”

Section: Introductionmentioning

confidence: 99%

“…1 However, the clinical application of DOX is still limited due to its reversible cardiotoxicity, nephrotoxicity and hepatotoxicity. [2][3][4] Indeed, acute kidney injury (AKI) is a common complication of DOX in both cancer patients and animal models which compromises their renal function. [5][6][7][8][9][10][11][12][13] Clinical manifestations after DOX treatment include polyuria, macroalbuminuria, interstitial tubular fibrosis and renal cell apoptosis.…”

mentioning

confidence: 99%

Acylated ghrelin protects against doxorubicin‐induced nephropathy by activating silent information regulator 1

Shati

El‐kott

2021

Basic Clin Pharma Tox

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This study investigated the nephroprotective role of acylated ghrelin (AG) against DOX‐induced nephropathy and examined whether the protection involves silent information regulator 1 (SIRT1). Rats were divided into control, control + AG, DOX, DOX + AG, DOX + AG + [D‐Lys3]‐GHRP‐6 (a ghrelin receptor antagonist), and DOX + AG + EX‐527 (a sirt1 inhibitor). DOX was given over the first 2 weeks. AG (10 ng/kg) and both inhibitors were given as 3 doses/wk for 5 weeks. AG improved the structure and the function of the kidneys; down‐regulated the renal expression of TGF‐β1, collagen 1A1 and α‐SMA; and inhibited the renal collagen deposition in the kidneys of DOX‐treated rats. Concomitantly, it reduced the renal levels of ROS, MDA, TNF‐α, and IL‐6 and protein levels of cytochrome‐c, TGF‐β1, Smad3 and α‐SMA in these rats. In both the control and DOX‐treated rats, AG significantly increased the renal levels of SOD and GSH, decreased the expression of cleaved caspase‐3 and Bax, increased the total levels and the nuclear activity of SIRT1 and reduced the deacetylation of p53, NF‐κB and FOXO‐31. All the effects were abolished by the concurrent administration of EX‐527 and [D‐Lys3]‐GHRP‐6. In conclusion, AG prevents DOX‐induced nephropathy in SIRT1 and GSHRa1‐dependent mechanism.

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New molecular and biochemical insights of doxorubicin-induced hepatotoxicity

Cited by 179 publications

References 61 publications

Light-Responsive Micelles Loaded With Doxorubicin for Osteosarcoma Suppression

Light-Responsive Micelles Loaded With Doxorubicin for Osteosarcoma Suppression

Metabolomic Identification of Anticancer Metabolites of Australian Propolis and Proteomic Elucidation of Its Synergistic Mechanisms with Doxorubicin in the MCF7 Cells

Acylated ghrelin protects against doxorubicin‐induced nephropathy by activating silent information regulator 1

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