scholarly journals Doxorubicin-Induced Cognitive Impairment: The Mechanistic Insights

2021 ◽  
Vol 11 ◽  
Author(s):  
Jiajia Du ◽  
Aoxue Zhang ◽  
Jing Li ◽  
Xin Liu ◽  
Shuai Wu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Oxidative Stress ◽  
Dna Damage ◽  
Cognitive Impairment ◽  
Adjuvant Chemotherapy ◽  
Cognitive Deficits ◽  
Attention And Memory ◽  
Epigenetic Factors ◽  
Glial Cell Interactions ◽  
Chemo Brain

Chemotherapy can significantly prolong the survival of patients with breast cancer; Nevertheless, the majority of patients receiving chemotherapy such as doxorubicin may have cognitive deficits that manifest as impairments in learning, reasoning, attention, and memory. The phenomenon of chemotherapy-induced cognitive decline is termed as chemotherapy-related cognitive impairment (CRCI) or chemo-brain. Doxorubicin (DOX), a commonly used drug in adjuvant chemotherapy for patients with breast cancer, has been reported to induce chemo-brain through a variety of mechanisms including DNA damage, oxidative stress, inflammation, dysregulation of apoptosis and autophagy, changes in neurotransmitter levels, mitochondrial dysfunction, glial cell interactions, neurogenesis inhibition, and epigenetic factors. These mechanisms do not operate independently but are inter-related, coordinately contributing to the development of chemo-brain. Here we review the relationships of these mechanisms and pathways in attempt to provide mechanistic insights into the doxorubicin-induced cognitive impairment.

scholarly journals Patient-Reported Cognitive Impairment Among Women With Early Breast Cancer Randomly Assigned to Endocrine Therapy Alone Versus Chemoendocrine Therapy: Results From TAILORx

2020 ◽  
Vol 38 (17) ◽  
pp. 1875-1886 ◽  
Author(s):  
Lynne I. Wagner ◽  
Robert J. Gray ◽  
Joseph A. Sparano ◽  
Timothy J. Whelan ◽  
Sofia F. Garcia ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cognitive Impairment ◽  
Adjuvant Chemotherapy ◽  
Endocrine Therapy ◽  
Early Breast Cancer ◽  
Menopausal Status ◽  
Unique Contribution ◽  
End Point ◽  
Patient Reported ◽  
Chemoendocrine Therapy

PURPOSE Cancer-related cognitive impairment (CRCI) is common during adjuvant chemotherapy and may persist. TAILORx provided a novel opportunity to prospectively assess patient-reported cognitive impairment among women with early breast cancer who were randomly assigned to chemoendocrine therapy (CT+E) versus endocrine therapy alone (E), allowing us to quantify the unique contribution of chemotherapy to CRCI. METHODS Women with a 21-gene recurrence score of 11 to 25 enrolled in TAILORX were randomly assigned to CT+E or E. Cognitive impairment was assessed among a subgroup of 552 evaluable women using the 37-item Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog) questionnaire, administered at baseline, 3, 6, 12, 24, and 36 months. The FACT-Cog included the 20-item Perceived Cognitive Impairment (PCI) scale, our primary end point. Clinically meaningful changes were defined a priori and linear regression was used to model PCI scores on baseline PCI, treatment, and other factors. RESULTS FACT-Cog PCI scores were significantly lower, indicating more impairment, at 3, 6, 12, 24, and 36 months compared with baseline for both groups. The magnitude of PCI change scores was greater for CT+E than E at 3 months, the prespecified primary trial end point, and at 6 months, but not at 12, 24, and 36 months. Tests of an interaction between menopausal status and treatment were nonsignificant. CONCLUSION Adjuvant CT+E is associated with significantly greater CRCI compared with E at 3 and 6 months. These differences abated over time, with no significant differences observed at 12 months and beyond. These findings indicate that chemotherapy produces early, but not sustained, cognitive impairment relative to E, providing reassurance to patients and clinicians in whom adjuvant chemotherapy is indicated to reduce recurrence risk.

Adjuvant Chemotherapy for Breast Cancer and Cognitive Impairment

2009 ◽  
Vol 102 (9) ◽  
pp. 929-934 ◽  
Author(s):  
Álvaro Pinto Marín ◽  
Andrés Redondo Sánchez ◽  
Enrique Espinosa Arranz ◽  
Pilar Zamora Auñón ◽  
Manuel González Barón
Keyword(s):  
Breast Cancer ◽  
Cognitive Impairment ◽  
Adjuvant Chemotherapy

scholarly journals Aryl Hydrocarbon Receptor Ligand 5F 203 Induces Oxidative Stress That Triggers DNA Damage in Human Breast Cancer Cells

2015 ◽  
Vol 28 (5) ◽  
pp. 855-871 ◽  
Author(s):  
Lancelot S. McLean ◽  
Cheri N. Watkins ◽  
Petreena Campbell ◽  
Dain Zylstra ◽  
Leah Rowland ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Oxidative Stress ◽  
Dna Damage ◽  
Human Breast Cancer ◽  
Breast Cancer Cells ◽  
Human Breast Cancer Cells ◽  
Human Breast ◽  
Receptor Ligand ◽  
Aryl Hydrocarbon Receptor Ligand ◽  
Aryl Hydrocarbon

scholarly journals Influence of breast cancer risk factors on proliferation and DNA damage in human breast glandular tissues: role of intracellular estrogen levels, oxidative stress and estrogen biotransformation

2021 ◽  
Author(s):  
Juliane Wunder ◽  
Daniela Pemp ◽  
Alexander Cecil ◽  
Maryam Mahdiani ◽  
René Hauptstein ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Oxidative Stress ◽  
Risk Factors ◽  
Dna Damage ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Linear Regression Models ◽  
Cancer Etiology ◽  
Cancer Risk Factors ◽  
Breast Cancer Risk Factors

AbstractBreast cancer etiology is associated with both proliferation and DNA damage induced by estrogens. Breast cancer risk factors (BCRF) such as body mass index (BMI), smoking, and intake of estrogen-active drugs were recently shown to influence intratissue estrogen levels. Thus, the aim of the present study was to investigate the influence of BCRF on estrogen-induced proliferation and DNA damage in 41 well-characterized breast glandular tissues derived from women without breast cancer. Influence of intramammary estrogen levels and BCRF on estrogen receptor (ESR) activation, ESR-related proliferation (indicated by levels of marker transcripts), oxidative stress (indicated by levels of GCLC transcript and oxidative derivatives of cholesterol), and levels of transcripts encoding enzymes involved in estrogen biotransformation was identified by multiple linear regression models. Metabolic fluxes to adducts of estrogens with DNA (E-DNA) were assessed by a metabolic network model (MNM) which was validated by comparison of calculated fluxes with data on methoxylated and glucuronidated estrogens determined by GC– and UHPLC–MS/MS. Intratissue estrogen levels significantly influenced ESR activation and fluxes to E-DNA within the MNM. Likewise, all BCRF directly and/or indirectly influenced ESR activation, proliferation, and key flux constraints influencing E-DNA (i.e., levels of estrogens, CYP1B1, SULT1A1, SULT1A2, and GSTP1). However, no unambiguous total effect of BCRF on proliferation became apparent. Furthermore, BMI was the only BCRF to indeed influence fluxes to E-DNA (via congruent adverse influence on levels of estrogens, CYP1B1 and SULT1A2).

Persistent cognitive deficits in breast cancer survivors treated with adjuvant chemotherapy: Neuropsychological and neurophysiological evidence

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 8556-8556
Author(s):  
S. B. Schagen ◽  
B. Kreukels ◽  
F. Van Dam
Keyword(s):  
Breast Cancer ◽  
Information Processing ◽  
Adjuvant Chemotherapy ◽  
Cancer Patients ◽  
Neuropsychological Assessment ◽  
Cognitive Deficits ◽  
Healthy Controls ◽  
Breast Cancer Patients ◽  
Neurophysiological Assessment ◽  
One Year

8556 Background: Cognitive deficits are reported in several studies in women with breast cancer treated with adjuvant chemotherapy. The current aim was to investigate whether breast cancer patients that had deviant cognitive performance on neuropsychological tests one year after treatment, differed from patients with intact performance on neurophysiological parameters and self-reported complaints, this time examined five years post treatment. Methods: 63 breast cancer patients treated with CMF chemotherapy underwent neuropsychological testing one year post therapy. Their performance was compared to that of healthy controls (n=60). 26 of these patients were examined neurophysiologically 4 years after the initial neuropsychological assessment. Neurophysiological assessment included quantitative EEG, auditory oddball task and a visual information processing task with concurrent EEG registration. Patients were also interviewed regarding cognitive complaints experienced in daily life. Results: At the initial neuropsychological assessment 33.3% of breast cancer patients treated with CMF chemotherapy were classified as cognitively impaired compared to 10% of healthy controls (p=.01). At the neurophysiological assessment four years later, patients that scored in the impaired range on the initial neuropsychological examination had significantly longer P3 latencies and reduced P3 amplitudes in an information processing task. The impaired patients also made more errors, had longer reaction times, and reported more cognitive complaints. Conclusion: The results of this study show converging neuropsychological and neurophysiological evidence for the persistence of cognitive problems in breast cancer patients up to five years after completion of CMF chemotherapy. [Table: see text] No significant financial relationships to disclose.

Activation of and dependence on ataxia telangiectasia mutated kinase in PTEN-deficient tumor cells.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 10553-10553
Author(s):  
Nuala McCabe ◽  
Steven M. Walker ◽  
Nicolas Goffard ◽  
Katarina Wikstrom ◽  
Caroline Greenan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Oxidative Stress ◽  
Ovarian Cancer ◽  
Dna Damage ◽  
Ataxia Telangiectasia ◽  
Clustering Analysis ◽  
Gene List ◽  
Hierarchical Clustering Analysis ◽  
Wild Type ◽  
Ataxia Telangiectasia Mutated

10553 Background: Loss of PTEN function has been widely reported to cause up-regulation of the PI3K/AKT signalling pathway resulting in increased cell growth, proliferation and survival. More recently it has been reported that PTEN null cells demonstrate genomic instability and have increased production of reactive oxygen species (ROS) and oxidative stress induced DNA damage. Ataxia Telangiectasia Mutated (ATM) is the primary response kinase, which responds to stalled DNA replication and DNA double strand breaks due to oxidative DNA damage. Methods: A metagene representing ATM activation was generated from cell line data and used to perform hierarchical clustering analysis of public DNA microarray profiling datasets of breast cancer, ovarian cancer and glioblastoma with known PTEN IHC/mutation status. Furthermore, we ask if ATM activation may be therapeutically exploited in PTEN null tumours using ATM specific siRNA and compounds in 2 PTEN isogenic cell line model systems. Results: We show that PTEN null cells have elevated levels of ROS, DNA damage and have endogenous activation of ATM, an enzyme important in responding to DNA damage resulting from oxidative stress. We hypothesised that PTEN deficient tumours may rely on ATM enzyme for survival. To investigate this we generated a 189-gene list representing ATM activation and used this to perform hierarchical clustering analysis of a breast cancer DNA microarray dataset. This list was able to significantly cluster tumours with known loss of PTEN expression (p=0.004). Furthermore, this gene list was able to segregate PTEN null/mutant tumours from PTEN wild-type tumours in 2 independent datasets of glioblastoma and ovarian cancer (p=0.015 and p=0.012). In addition, we found that inhibition of ATM using the selective inhibitor KU-55933 caused DNA damage, cell cycle arrest and apoptosis specifically in PTEN deficient cells when compared to PTEN wild-type cells. Conclusions: These observations suggest that ATM may represent a therapeutic target in PTEN deficient tumours and furthermore ATM activation may be the basis of a biomarker of PTEN status in human cancers.

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