Pathway-centric analysis of the DNA damage response to chemotherapeutic agents in two breast cell lines

Antberg, Linn; Cifani, Paolo; Levander, Fredrik; James, Peter

doi:10.1016/j.euprot.2015.05.002

Cited by 4 publications

(3 citation statements)

References 28 publications

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“…In agreement, other authors also reported cytotoxicity in the MDA-MB-231 cell line at the same Dox concentration [ 56 ]. Dox cytotoxicity seems to be correlated to the increase of DNA damages and consequently induction of cell death in MDA-MB-231 cells, concordantly with other reports with the same cell line [ 57 , 58 ]. Dox is known for causing DNA damage through several different mechanisms (e.g., DNA intercalation, topoisomerase II inhibition, ROS induction), which can trigger cell cycle arrest, impairment of mitochondrial function and cell death [ 59 , 60 ].…”

Section: Discussionsupporting

confidence: 90%

Fucoxanthin Holds Potential to Become a Drug Adjuvant in Breast Cancer Treatment: Evidence from 2D and 3D Cell Cultures

et al. 2021

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Fucoxanthin (Fx) is a carotenoid derived from marine organisms that exhibits anticancer activities. However, its role as a potential drug adjuvant in breast cancer (BC) treatment is still poorly explored. Firstly, this study investigated the cytotoxic effects of Fx alone and combined with doxorubicin (Dox) and cisplatin (Cis) on a panel of 2D-cultured BC cell lines (MCF7, SKBR3 and MDA-MB-231) and one non-tumoral cell line (MCF12A). Fucoxanthin induced cytotoxicity against all the cell lines and potentiated Dox cytotoxic effects towards the SKBR3 and MDA-MB-231 cells. The combination triggering the highest cytotoxicity (Fx 10 µM + Dox 1 µM in MDA-MB-231) additionally showed significant induction of cell death and genotoxic effects, relative to control. In sequence, the same combination was tested on 3D cultures using a multi-endpoint approach involving bioactivity assays and microscopy techniques. Similar to 2D cultures, the combination of Fx and Dox showed higher cytotoxic effects on 3D cultures compared to the isolated compounds. Furthermore, this combination increased the number of apoptotic cells, decreased cell proliferation, and caused structural and ultrastructural damages on the 3D models. Overall, our findings suggest Fx has potential to become an adjuvant for Dox chemotherapy regimens in BC treatment.

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Section: Discussionsupporting

confidence: 90%

Fucoxanthin Holds Potential to Become a Drug Adjuvant in Breast Cancer Treatment: Evidence from 2D and 3D Cell Cultures

et al. 2021

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“…The different mechanisms of these three DDR inhibitors may explain their varying radiosensitizing capabilities. Differences in repair capacity of these cell lines due to variations in other DNA repair genes have been explored in detail elsewhere [ 29 , 30 ].…”

Section: Discussionmentioning

confidence: 99%

DNA Repair Inhibitors Potentiate Fractionated Radiotherapy More Than Single-Dose Radiotherapy in Breast Cancer Cells

Wong

Liberal

McMahon

2022

Cancers

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Pharmacological inhibitors of DNA damage response (DDR) proteins, such as the ataxia-telangiectasia mutated (ATM) and ataxia-telangiectasia and Rad3-related (ATR) kinases and poly (ADP-ribose) polymerase (PARP), have been developed to overcome tumor radioresistance. Despite demonstrating radiosensitization preclinically, they have performed suboptimally in clinical trials, possibly due to an incomplete understanding of the influence of DDR inhibition on ionizing radiation (IR) dose fractionation and sublethal damage repair. Hence, this study aimed to evaluate the radiosensitizing ability under fractionation of ATM inhibitor AZD0156, ATR inhibitor AZD6738 and PARP inhibitor AZD2281 (olaparib), utilizing MDA-MB-231 and MCF-7 human breast cancer cells. Clonogenic assays were performed to assess cell survival and sublethal damage repair after treatment with DDR inhibitors and either single-dose or fractionated IR. Immunofluorescence microscopy was utilized to evaluate DNA double-strand break repair kinetics. Cell cycle distributions were investigated using flow cytometry. All inhibitors showed significant radiosensitization, which was significantly greater following fractionated IR than single-dose IR. They also led to more unrepaired DNA double-strand breaks at 24 h post-IR. This study provides preclinical evidence for the role of AZD0156, AZD6738 and olaparib as radiosensitizing agents. Still, it highlights the need to evaluate these drugs in fractionated settings mirroring clinical practice to optimize the trial design.

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“…Among them, MCF‐7 cells were found to be more sensitive to catechol than MDA‐MB‐231 cells. Higher DNA repairing efficacies, mutant p53 genotype, condensed chromatin structure, and interactions between extracellular matrix (ECM) to the tumor microenvironment in the MDA‐MB‐231 cells could be among the factors contributing to its chemoresistance (Antberg, Cifani, Levander, & James, 2015; Ramadan et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Natural compound catechol induces DNA damage, apoptosis, and G1 cell cycle arrest in breast cancer cells

Vazhappilly

Hodeify

Siddiqui

et al. 2020

Phytotherapy Research

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Targeting cell cycle and inducing DNA damage by activating cell death pathways are considered as effective therapeutic strategy for combating breast cancer progression. Many of the naturally known small molecules target these signaling pathways and are effective against resistant and/or aggressive types of breast cancers. Here, we investigated the effect of catechol, a naturally occurring plant compound, for its specificity and chemotherapeutic efficacies in breast cancer (MCF‐7 and MDA‐MB‐231) cells. Catechol treatment showed concentration‐dependent cytotoxicity and antiproliferative growth in both MCF‐7 and MDA‐MB‐231 cells while sparing minimal effects on noncancerous (F‐180 and HK2) cells. Catechol modulated differential DNA damage effects by activating ATM/ATR pathways and showed enhanced γ–H2AX expression, as an indicator for DNA double‐stranded breaks. MCF‐7 cells showed G1 cell cycle arrest by regulating p21‐mediated cyclin E/Cdk2 inhibition. Furthermore, activation of p53 triggered a caspase‐mediated cell death mechanism by inhibiting regulatory proteins such as DNMT1, p‐BRCA1, MCL‐1, and PDCD6 with an increased Bax/Bcl‐2 ratio. Overall, our results showed that catechol possesses favorable safety profile for noncancerous cells while specifically targeting multiple signaling cascades to inhibit proliferation in breast cancer cells.

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Pathway-centric analysis of the DNA damage response to chemotherapeutic agents in two breast cell lines

Cited by 4 publications

References 28 publications

Fucoxanthin Holds Potential to Become a Drug Adjuvant in Breast Cancer Treatment: Evidence from 2D and 3D Cell Cultures

Fucoxanthin Holds Potential to Become a Drug Adjuvant in Breast Cancer Treatment: Evidence from 2D and 3D Cell Cultures

DNA Repair Inhibitors Potentiate Fractionated Radiotherapy More Than Single-Dose Radiotherapy in Breast Cancer Cells

Natural compound catechol induces DNA damage, apoptosis, and G1 cell cycle arrest in breast cancer cells

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