Doxorubicin induces cardiotoxicity through upregulation of death receptors mediated apoptosis in cardiomyocytes

Zhao, Li‐Xia; Zhang, Baolin

doi:10.1038/srep44735

Cited by 261 publications

(169 citation statements)

References 57 publications

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“…Despite strong anticancer effects, DOX and CP have cardiotoxic and nephrotoxic effects [25][26][27], respectively, that decrease their therapeutic efficiencies. DOX causes cumulative and dose-dependent cardiotoxicity, including abnormal changes to the structure and function of myocardium, severe cardiomyopathy, and congestive heart failure, resulting in cardiac transplants and death in many patients [25,26]. CP is finally cleared by the kidneys through glomerular filtration and tubular secretion; therefore, the drug molecules are filtered out when the concentration in the kidney exceeds the concentration in the blood.…”

Section: Discussionmentioning

confidence: 99%

Doxorubicin·Hydrochloride/Cisplatin-Loaded Hydrogel/Nanosized (2-Hydroxypropyl)-Beta-Cyclodextrin Local Drug-Delivery System for Osteosarcoma Treatment In Vivo

et al. 2019

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Osteosarcoma (OSA) is a difficult cancer to treat due to its tendency for relapse and metastasis; advanced methods are therefore required for OSA treatment. In this study, we prepared a local drug-delivery system for OSA treatment based on doxorubicin·hydrochloride (DOX·HCl)/cisplatin (CP)-loaded visible light-cured glycol chitosan (GC) hydrogel/(2-hydroxypropyl)-beta-cyclodextrin (GDHCP), and compared its therapeutic efficiency with that of DOX·HCl-and CP-loaded GC hydrogels (GD and GHCP). Because of diffusion driven by concentration gradients in the swollen matrix, the three hydrogels showed sustained releases of DOX·HCl and CP over 7 days, along with initial 3-h bursts. Results of in vitro cell viability and in vivo animal testing revealed that GDHCP had a stronger anticancer effect than GD and GHCP even though there were no significant differences. Body weight measurement and histological evaluations demonstrated that the drug-loaded GC hydrogels had biocompatibility without cardiotoxicity or nephrotoxicity. These results suggested that GDHCP could be a good platform as a local drug-delivery system for clinical use in OSA treatment.

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Section: Discussionmentioning

confidence: 99%

Doxorubicin·Hydrochloride/Cisplatin-Loaded Hydrogel/Nanosized (2-Hydroxypropyl)-Beta-Cyclodextrin Local Drug-Delivery System for Osteosarcoma Treatment In Vivo

et al. 2019

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“…Cluster 4 had high number of G-protein coupled receptor signaling pathway members (60%, p = 0.01). Apoptotic process, believed to play an important role in drug-induced hepatotoxicity [44] and cardiotoxicity [45], was the largest enriched category in Cluster 7 (63.62%, p=0.01). No significant GO term enrichment for any functions was identified in Cluster 8.…”

Section: Model Interpretationmentioning

confidence: 99%

An integrative machine learning approach for prediction of toxicity-related drug safety

Lysenko

Sharma

Boroevich

et al. 2018

Preprint

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blurb: Prediction of toxicity-related drug clinical trial failures, withdrawals from market and idiosyncratic toxicity risk by combining biological network analysis with machine learning. AbstractRecent trends in drug development have been marked by diminishing returns of escalating costs and falling rate of new drug approval. Unacceptable drug toxicity is a substantial cause of drug failure during clinical trials as well as the leading cause of drug withdraws after release to market. Computational methods capable of predicting these failures can reduce waste of resources and time devoted to the investigation of compounds that ultimately fail. We propose an original machine learning method that leverages identity of drug targets and off-targets, functional impact score computed from Gene Ontology annotations, and biological network data to predict drug toxicity. We demonstrate that our method (TargeTox) can distinguish potentially idiosyncratically toxic drugs from safe drugs and is also suitable for speculative evaluation of different target sets to support the design of optimal low-toxicity combinations.A recent evaluation of current methods was performed by [10]. Their work has shown that chemistrybased scoring and rule-based systems have only very modest power to predict clinical trial failures. These methods could not accurately predict clinical trial failure due to drug toxicity if taken in isolation and not combined with additional features. One possible explanation is that these schemes, like Lipinski's Rule of 5 [11], are now routinely used to screen drugs [12] and compounds at clinical trial stage likely to have already passed such screening. Another part of the explanation could be that these rules do not strongly apply to a very large subset (estimated at 50-80% of all drugs) of "metabolite-like" compounds that can mimic naturally-occurring metabolites and behave in a similar way [13]. And lastly, toxicity-related responses are mostly mediated by drug-protein interactions [14], which may not necessarily have a clear correspondence to molecular structure features.

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“…Pengurangan dosis dengan tetap mempertahankan efektiivitas doxorubicin menjadi salah satu cara untuk menurunkan efek kardiotoksik. 28 Hasil penelitian ini menunjukkan ko-administrasi GM 40 µg/mL dapat meningkatkan efek sitotoksik doxorubicin 3 nM hingga 51%. Perlakuan tunggal doxorubicin membutuhkan konsentrasi 6 nM untuk menghasilkan efek sitotoksik 50% (IC50).…”

Section: Pembahasanunclassified

Efek Sinergis Kombinasi Ekstrak Air Akar Batu (Gerrardanthus Macrorhizus) dengan Doxorubicin pada Sel Kanker Payudara T47D

Haryanti¹

2018

bpk

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Doxorubicin is one of the most widely used chemotherapy agents in cancer therapy. The clinical results of doxorubicin are limited by cardiotoxic side effects which relate to their doses. This study was conducted to investigate cytotoxic activity of caudex Gerrardanthus macrorhizus aqueous extract and its combination with doxorubicin on T47D cells. Dried caudex powder was extracted by infusion method, evaporated in oven 40 0 C to get dried extract (GM). The MTT assay was performed triplo to determine cytotoxic effect, either alone or in combination. Flow cytometry was used to observe cell cycle profile and apoptotic induction. Based on the observation under inverted microscope, GM alone did not exhibit cytotoxic effects but showed morphological alteration becoming rounded and shrinkaged cells compared to untreated cells. Nevertheless, GM 40 μg/mL was able to improve cytotoxic effect of doxorubicin to 51%. Combination treatment of doxorubicin 3 nM and 40 μg/mL GM inhibited T47D cell cycle in G2/M phase. This combination also resulted apoptotic induction, compared to untreated cell and each single treatment. Based on the results, caudex G. macrorhizus is potential to be further investigated as a cochemotherapy agent with doxorubicin. AbstrakDoxorubicin adalah salah satu agen kemoterapi yang digunakan secara luas dalam terapi kanker. Hasil klinis doxorubicin dibatasi oleh kardiotoksisitas yang berkorelasi dengan besaran dosis. Penelitian ini dilakukan untuk mengkaji aktivitas sitotoksik ekstrak air caudex Gerrardanthus macrorhizus dan kombinasinya dengan doxorubicin pada sel T47D. Serbuk caudex G. macrorhizus (GM) kering diekstraksi dengan metode infusa, kemudian diuapkan dalam oven 40 0 C. Uji MTT dilakukan untuk menguji efek sitotoksik ekstrak dengan tiga ulangan, baik tunggal maupun kombinasi dengan doxorubicin. Flow cytometry digunakan untuk mengetahui profil siklus sel dan induksi apoptosis. Hasil pengamatan di bawah mikroskop inverted menunjukkan ekstrak tunggal GM tidak memberikan efek sitotoksik namun mengakibatkan perubahan morfologi pada sel T47D menjadi membulat dan mengkerut dibandingkan kontrol sel. Ekstrak GM 40 μg/mL mampu meningkatkan efek sitotoksik doxorubicin 3 nM hingga 51%. Kombinasi doxorubicin 3 nM dan ekstrak 40 μg/mL menghambat siklus sel pada fase G2/M dan meningkatkan induksi apoptosis, dibandingkan kontrol sel dan masing-masing perlakuan tunggalnya. Berdasarkan hasil penelitian ini, caudex G. macrorhizus berpotensi untuk diteliti lebih lanjut sebagai agen ko-kemoterapi dengan doxorubicin.

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Doxorubicin induces cardiotoxicity through upregulation of death receptors mediated apoptosis in cardiomyocytes

Cited by 261 publications

References 57 publications

Doxorubicin·Hydrochloride/Cisplatin-Loaded Hydrogel/Nanosized (2-Hydroxypropyl)-Beta-Cyclodextrin Local Drug-Delivery System for Osteosarcoma Treatment In Vivo

Doxorubicin·Hydrochloride/Cisplatin-Loaded Hydrogel/Nanosized (2-Hydroxypropyl)-Beta-Cyclodextrin Local Drug-Delivery System for Osteosarcoma Treatment In Vivo

An integrative machine learning approach for prediction of toxicity-related drug safety

Efek Sinergis Kombinasi Ekstrak Air Akar Batu (Gerrardanthus Macrorhizus) dengan Doxorubicin pada Sel Kanker Payudara T47D

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