Low-Dose and Long-Term Olaparib Treatment Sensitizes MDA-MB-231 and SUM1315 Triple-Negative Breast Cancers Spheroids to Fractioned Radiotherapy

Dubois, Clémence; Martin, Fanny; Hassel, Chervin; Magnier, F; Daumar, Pierre; Aubel, C.E.; Guerder, Sylvie; Mounetou, Emmanuelle; Penault-Lorca, Frédérique; Bamdad, Mahchid

doi:10.3390/jcm9010064

Cited by 13 publications

(8 citation statements)

References 41 publications

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“…Several studies have examined the association between HORMAD1 expression and PARPi resistance ( 16 , 17 , 44 ). It was hypothesized that conventional chemotherapy combined with PARPi or sequential PARPi could be selected for tumors expressing high levels of HORMAD1 ( 45 ). The inhibition of PARP expression in cancer tissues may result in minimal side effects from tumor-specific treatment.…”

Section: Discussionmentioning

confidence: 99%

HORMAD1 promotes docetaxel resistance in triple negative breast cancer by enhancing DNA damage tolerance

et al. 2021

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HORMA domain-containing protein 1 (HORMAD1), is normally expressed only in the germline, but is frequently re-activated in human triple-negative breast cancer (TNBC); however, its function in TNBC is largely unknown. In the present study, the expression and biological significance of HORMAD1 in human TNBC was evaluated. Bioinformatics analysis and reverse transcription-quantitative PCR were used to evaluate HORMAD1 expression in datasets and cell lines. HORMAD1 protein expression was detected in TNBC samples using immunohistochemical assays, and the effect of HORMAD1 on cell proliferation was determined using Cell Counting Kit-8, plate colony formation and standard growth curve assays. Cell cycle, reactive oxygen species (ROS) and apoptosis analyses were conducted using flow cytometry. The activity of caspases was measured using caspase activity assay kit. The levels of key apoptosis regulators and autophagy markers were detected by western blot analysis. TNBC cell survival and apoptosis were not influenced by small interfering RNA targeting HORMAD1 alone; however, HORMAD1 knockdown enhanced autophagy and docetaxel (Doc)-induced apoptosis, compared with the control group. Furthermore, higher ROS levels and caspase-3, -8 and -9 activity were detected in MDA-MB-436 TNBC cells with HORMAD1 knockdown upon exposure to Doc. The levels of the induced DNA damage marker γH2AX were also higher, while those of the DNA repair protein RAD51 were lower in TNBC cells with HORMAD1 knockdown compared with the controls. Furthermore, the expression of the autophagy marker P62 was enhanced in MDA-MB-231 cells in response to HORMAD1 overexpression. Notably, Doc-induced apoptosis was similarly increased by both HORMAD1 overexpression and treatment with the autophagy inhibitor, 3-methyladenine (3MA); however, the Doc-induced increase in autophagy was not inhibited by 3MA. The present data indicated that HORMAD1 was involved in autophagy and that the inhibition of autophagy can partially enhance the induction of apoptosis by Doc. The role of HORMAD1 in the DNA damage tolerance of tumor cells may be the main reason for Doc resistance; hence, HORMAD1 could be an important therapeutic target in TNBC.

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Section: Discussionmentioning

confidence: 99%

HORMAD1 promotes docetaxel resistance in triple negative breast cancer by enhancing DNA damage tolerance

et al. 2021

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“…Cytotoxic and cytostatic effects of olaparib and IR were induced in a PTEN (phosphatase and tensin homolog) independent manner in the endometrial HEC-6 cells [ 39 ]. Cell survival variance of triple-negative breast cancers were impacted at 40% by the time of olaparib exposure, at 39% by radiotherapy, at 14% by the olaparib concentration, and at 9% by the type of cell line [ 40 ]. In our study, the cytostatic effect of olaparib may require prolonged dosing for therapeutic effect [ 41 ].…”

Section: Discussionmentioning

confidence: 99%

The Influence of PARP, ATR, CHK1 Inhibitors on Premature Mitotic Entry and Genomic Instability in High-Grade Serous BRCAMUT and BRCAWT Ovarian Cancer Cells

Gralewska

Gajek

Rybaczek

et al. 2022

Cells

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Olaparib is a poly (ADP-ribose) polymerase inhibitor (PARPi) that inhibits PARP1/2, leading to replication-induced DNA damage that requires homologous recombination repair. Olaparib is often insufficient to treat BRCA-mutated (BRCAMUT) and BRCA wild-type (BRCAWT) high-grade serous ovarian carcinomas (HGSOCs). We examined the short-term (up to 48 h) efficacy of PARPi treatment on a DNA damage response pathway mediated by ATR and CHK1 kinases in BRCAMUT (PEO-1) and BRCAWT (SKOV-3 and OV-90) cells. The combination of ATRi/CHK1i with PARPi was not more cytotoxic than ATR and CHK1 monotherapy. The combination of olaparib with inhibitors of the ATR/CHK1 pathway generated chromosomal abnormalities, independent on BRCAMUT status of cells and formed of micronuclei (MN). However, the beneficial effect of the PARPi:ATRi combination on MN was seen only in the PEO1 BRCAMUT line. Monotherapy with ATR/CHK1 inhibitors reduced BrdU incorporation due to a slower rate of DNA synthesis, which resulted from elevated levels of replication stress, while simultaneous blockade of PARP and ATR caused beneficial effects only in OV-90 cells. Inhibition of ATR/CHK1 increased the formation of double-strand breaks as measured by increased γH2AX expression at collapsed replication forks, resulting in increased levels of apoptosis. Our findings indicate that ATR and CHK1 inhibitors provoke premature mitotic entry, leading to genomic instability and ultimately cell death.

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“…In addition, PARPi has been validated to increase the sensitivity to radiotherapy in BRCAness phenotype. Co-treatment of PARPi and fractioned irradiation exhibited higher efficiency in 2D and 3D cell culture due to a cumulative induction of DNA doublestrand breaks (119).…”

Section: Parpi Plus Radiotherapymentioning

confidence: 98%

New Perspectives for Resistance to PARP Inhibitors in Triple-Negative Breast Cancer

Han

et al. 2020

Front. Oncol.

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Poly (ADP-ribose) polymerase (PARP) inhibitors are a therapeutic milestone exerting a synthetic lethal effect in the treatment of cancer involving BRCA1/2 mutation. Theoretically, PARP inhibitors (PARPi) eliminate tumor cells by disrupting DNA damage repair through either PARylation or the homologous recombination (HR) pathway. However, resistance to PARPi greatly hinders therapeutic effectiveness in triple-negative breast cancer (TNBC). Owing to the high heterogeneity and few genetic targets in TNBC, there has been limited therapeutic progress in the past decades. In view of this, there is a need to circumvent resistance to PARPi and develop potential treatment strategies for TNBC. We present, herein, a review of the scientific progress and explore the mechanisms underlying PARPi resistance in TNBC. The complicated mechanisms of PARPi resistance, including drug exporter formation, loss of poly (ADP-ribose) glycohydrolase (PARG), HR reactivation, and restoration of replication fork stability, are discussed in detail in this review. Additionally, we also discuss new combination therapies with PARPi that can improve the clinical response in TNBC. The new perspectives for PARPi bring novel challenges and opportunities to overcome PARPi resistance in breast cancer.

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Low-Dose and Long-Term Olaparib Treatment Sensitizes MDA-MB-231 and SUM1315 Triple-Negative Breast Cancers Spheroids to Fractioned Radiotherapy

Cited by 13 publications

References 41 publications

HORMAD1 promotes docetaxel resistance in triple negative breast cancer by enhancing DNA damage tolerance

HORMAD1 promotes docetaxel resistance in triple negative breast cancer by enhancing DNA damage tolerance

The Influence of PARP, ATR, CHK1 Inhibitors on Premature Mitotic Entry and Genomic Instability in High-Grade Serous BRCAMUT and BRCAWT Ovarian Cancer Cells

New Perspectives for Resistance to PARP Inhibitors in Triple-Negative Breast Cancer

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