Cytotoxic mechanisms of doxorubicin at clinically relevant concentrations in breast cancer cells

Nicoletto, Rachel; Ofner, Clyde M.

doi:10.1007/s00280-022-04400-y

Cited by 90 publications

(51 citation statements)

References 119 publications

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“…Several mechanisms have been proposed for Dox-induced cardiotoxicity and heart failure: oxidative stress, free radical generation and apoptosis are the main mechanisms involved. Moreover, DNA damage, calcium homeostasis alteration, inflammatory response, mitochondrial dysfunction and autophagy have also been reported to play a pivotal role [ 6 , 8 , 9 , 10 , 11 ]. Therefore, the generation of reactive oxygen species (ROS) upon Dox treatment is believed to be the key event underlying the interconnected intracellular signaling pathways leading to cardiotoxicity.…”

Section: Introductionmentioning

confidence: 99%

Hydroxytyrosol Prevents Doxorubicin-Induced Oxidative Stress and Apoptosis in Cardiomyocytes

2022

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Doxorubicin (Dox) is a highly effective chemotherapeutic agent employed in the handling of hematological and solid tumors. The effective use of Dox in cancer therapy has been seriously limited due to its well-known cardiotoxic side effects, mainly mediated by oxidative damage. Therefore, the identification of an effective and safe antagonist against Dox-induced cardiotoxicity remains a challenge. In this respect, as plant polyphenols have attracted considerable interest due to their antioxidant properties and good safety profile, hydroxytyrosol (HT), the major phenolic compound in olive oil, could be a potential candidate due to its remarkable antioxidant and anticancer powers. In this study, the effect of HT was tested on Dox-induced cardiotoxicity by using a combination of biochemical and cellular biology techniques. Interestingly, HT was able to counteract Dox-induced cytotoxicity in cardiomyocytes by acting on the SOD2 level and the oxidative response, as well as on apoptotic mechanisms mediated by Bcl-2/Bax. At the same time, HT did not to interfere with the antitumorigenic properties of Dox in osteosarcoma cells. This study identifies new, beneficial properties for HT and suggests that it might be a promising molecule for the development of additional therapeutic approaches aimed at preventing anthracycline-related cardiotoxicity and improving long-term outcomes in antineoplastic treatments.

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Section: Introductionmentioning

confidence: 99%

Hydroxytyrosol Prevents Doxorubicin-Induced Oxidative Stress and Apoptosis in Cardiomyocytes

2022

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“…In the current study, we used the same protocol, namely one-day drug administration followed by several days of culture in fresh medium ( Figure S1a ). Of note, such a protocol, at least in the case of doxorubicin, is clinically relevant [ 24 ]. Previously, we have shown the increase in several markers of senescence in MCF-7 cells treated with 5 µM IRI: SA-β-gal activity, cell granularity, cell size, the p53/p21 signaling pathway, the IL-8 and VEGF signaling pathway and IL-8 and VEGF secretion [ 16 ].…”

Section: Resultsmentioning

confidence: 99%

Therapy-Induced Senescent/Polyploid Cancer Cells Undergo Atypical Divisions Associated with Altered Expression of Meiosis, Spermatogenesis and EMT Genes

Czarnecka‐Herok

Śliwińska

Herok

et al. 2022

IJMS

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Upon anticancer treatment, cancer cells can undergo cellular senescence, i.e., the temporal arrest of cell division, accompanied by polyploidization and subsequent amitotic divisions, giving rise to mitotically dividing progeny. In this study, we sought to further characterize the cells undergoing senescence/polyploidization and their propensity for atypical divisions. We used p53-wild type MCF-7 cells treated with irinotecan (IRI), which we have previously shown undergo senescence/polyploidization. The propensity of cells to divide was measured by a BrdU incorporation assay, Ki67 protein level (cell cycle marker) and a time-lapse technique. Advanced electron microscopy-based cell visualization and bioinformatics for gene transcription analysis were also used. We found that after IRI-treatment of MCF-7 cells, the DNA replication and Ki67 level decreased temporally. Eventually, polyploid cells divided by budding. With the use of transmission electron microscopy, we showed the presence of mononuclear small cells inside senescent/polyploid ones. A comparison of the transcriptome of senescent cells at day three with day eight (when cells just start to escape senescence) revealed an altered expression of gene sets related to meiotic cell cycles, spermatogenesis and epithelial–mesenchymal transition. Although chemotherapy (DNA damage)-induced senescence is indispensable for temporary proliferation arrest of cancer cells, this response can be followed by their polyploidization and reprogramming, leading to more fit offspring.

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“…Regarding the mechanism of action of compound 19, it is unlike that which is the same as doxorubicin. Indeed, the cytotoxicity of the latter involves miscellaneous ways such as DNA adduct formation, DNA intercalation, inhibition of topoisomerase II, oxidative stress by ROS formation, and lipid peroxidation [31]. Moreover, the comparison of the cytotoxic activities of analogues 12-18 shows that the longer the linear aliphatic chain, the lower their potencies.…”

Section: Resultsmentioning

confidence: 99%

On the Reaction of 2-Alkanoylnaphthohydroquinones with Hydroxylamine: Access to Cytotoxic 2-(Hydroxyamino)-1,4-naphthoquinone and Their 3-(Hydroxyimino)alkyl Analogous

Valderrama

Pérez-Herrera

Muccioli

et al. 2022

Journal of Chemistry

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Oximes are known for their anti-inflammatory, antimicrobial, antioxidant, and anticancer activities. Frequently, modification of biologically active carbonyl compounds into oximes leads to increased activity. The present study reports the reactivity of 2-alkanoylnaphthohydroquinones against hydroxylamine under aerial conditions. Results show that, depending on the structure of the hydroquinones, the reaction proceeds through two different chemical pathways to produce 2-(hydroxyamino)-1,4-naphthoquinone and their C-3 (hydroxyimino)alkyl derivatives. Both the formation of the quinoid compounds under aerial oxidation and C-C cleavage reactions of hemiaminal intermediates are discussed. In vitro screening of the substituted 1,4-naphthoquinones on a panel of cancer cells reveals moderate cytotoxic activities. Compound 19, 2-(hydroxyamino)-1,4-naphthoquinone, stands out by its anticancer potency against prostate cancer cells as shown by the lowest IC50 value (8.08 μM) and the best selectivity index (3.90).

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Cytotoxic mechanisms of doxorubicin at clinically relevant concentrations in breast cancer cells

Cited by 90 publications

References 119 publications

Hydroxytyrosol Prevents Doxorubicin-Induced Oxidative Stress and Apoptosis in Cardiomyocytes

Hydroxytyrosol Prevents Doxorubicin-Induced Oxidative Stress and Apoptosis in Cardiomyocytes

Therapy-Induced Senescent/Polyploid Cancer Cells Undergo Atypical Divisions Associated with Altered Expression of Meiosis, Spermatogenesis and EMT Genes

On the Reaction of 2-Alkanoylnaphthohydroquinones with Hydroxylamine: Access to Cytotoxic 2-(Hydroxyamino)-1,4-naphthoquinone and Their 3-(Hydroxyimino)alkyl Analogous

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