Determinants of resistance to chemotherapy and ionizing radiation in breast cancer stem cells

Pavlopoulou, Athanasia; Oktay, Yavuz; Vougas, Konstantinos; Louka, Maria; Vorgias, Constantinos E.; Georgakilas, Alexandros G.

doi:10.1016/j.canlet.2016.07.018

Cited by 76 publications

(44 citation statements)

References 118 publications

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“…Our current work directs these prior findings to one of the most troublesome and deadly cancerstriple-negative breast cancer (TNBC)which is known to depend on the activity of the Wnt pathway [26,57]. We selected a panel of TNBC cell lines representing major clinically relevant subtypes (luminal-like, basal-like) as well as tumor-initiating cells ("cancer stem cells"), which are responsible for the resistance of this disease to chemotherapy [58]. We profiled the activity of clofazimine, both in terms of inhibition of the Wnt pathway and inhibition of cell proliferation, against this panel, revealing the strong promise of the drug against various TNBC lines including the tumor-initiating cells.…”

Section: Discussionmentioning

confidence: 90%

Towards the first targeted therapy for triple-negative breast cancer: Repositioning of clofazimine as a chemotherapy-compatible selective Wnt pathway inhibitor

Ahmed

Koval

et al. 2019

Cancer Letters

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Wnt signaling is overactivated in triple-negative breast cancer (TNBC) and several other cancers, and its suppression emerges as an effective anticancer treatment. However, no drugs targeting the Wnt pathway exist on the market nor in advanced clinical trials. Here we provide a comprehensive body of preclinical evidence that an anti-leprotic drug clofazimine is effective against TNBC. Clofazimine specifically inhibits canonical Wnt signaling in a panel of TNBC cells in vitro. In several mouse xenograft models of TNBC, clofazimine efficiently suppresses tumor growth, correlating with in vivo inhibition of the Wnt pathway in the tumors. Clofazimine is well compatible with doxorubicin, exerting additive effects on tumor growth suppression, producing no adverse effects. Its excellent and wellcharacterized pharmacokinetics profile, lack of serious adverse effects at moderate (yet therapeutically effective) doses, its combinability with cytotoxic therapeutics, and the novel mechanistic mode of action make clofazimine a prime candidate for the repositioning clinical trials. Our work may bring forward the anti-Wnt targeted therapy, desperately needed for thousands of patients currently lacking targeted treatments.

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Section: Discussionmentioning

confidence: 90%

Towards the first targeted therapy for triple-negative breast cancer: Repositioning of clofazimine as a chemotherapy-compatible selective Wnt pathway inhibitor

Ahmed

Koval

et al. 2019

Cancer Letters

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“…Although the detailed mechanisms for chemo‐radiotherapy resistance are unknown, several studies assessed the role of DNA injury repair response in the regulation of chemo‐radiotherapy resistance in solid cancers . In addition, the relationship between m 6 A and DNA injury repair response was also explored recently.…”

Section: Discussionmentioning

confidence: 99%

“…24,[34][35][36][37][38] Although the detailed mechanisms for chemo-radiotherapy resistance are unknown, several studies assessed the role of DNA injury repair response in the regulation of chemo-radiotherapy resistance in solid cancers. 5,39 In addition, the relationship between m 6 A and DNA injury repair response was also explored recently. Xiang et al 20 found that the methylation of m 6 A in RNA could be transiently induced after the ultraviolet irradiation exposure.…”

Section: Discussionmentioning

confidence: 99%

FTO regulates the chemo‐radiotherapy resistance of cervical squamous cell carcinoma (CSCC) by targeting β‐catenin through mRNA demethylation

Zhou

Bai

Xia

et al. 2018

Molecular Carcinogenesis

303

228

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The role of N -methyladenosine (m A) demethylase fat mass and obesity-associated protein (FTO) in the regulation of chemo-radiotherapy resistance remains largely unknown. Here, we show that the mRNA level of FTO is elevated in cervical squamous cell carcinoma (CSCC) tissues when compared with respective adjacent normal tissues. FTO enhances the chemo-radiotherapy resistance both in vitro and in vivo through regulating expression of β-catenin by reducing m A levels in its mRNA transcripts and in turn increases excision repair cross-complementation group 1 (ERCC1) activity. Clinically, the prognostic value of FTO for overall survival is found to be dependent on β-catenin expression in human CSCC samples. Taken together, these findings uncover a critical function for FTO and its substrate m A in the regulation of chemo-radiotherapy resistance, which may bear potential clinical implications for CSCC treatment.

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“…The role of germline genetic variations in the response to radiation has been studied extensively with the aim to establish predictive genetic markers for radiation toxicity 2-6 . Although the majority of these investigations have not found unambiguous associations, recent studies identified predictive genes in prostate and breast cancer patients 3, 7, 8 , indicating that optimizing RT through the identification of key genes related to the radioresistance/radiosensitivity phenotype might be possible in future 9 . Meanwhile, the development of a functional predictive assay based on cellular response to radiation remains an appealing proposition 10, 11 .…”

Section: Introductionmentioning

confidence: 99%

Compromized DNA repair as a basis for identification of cancer radiotherapy patients with extreme radiosensitivity

et al. 2016

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A small percentage of cancer radiotherapy patients develop abnormally severe side effects as a consequence of intrinsic radiosensitivity. We analysed the γ-H2AX response to ex-vivo irradiation of peripheral blood lymphocytes (PBL) and plucked eyebrow hair follicles from 16 patients who developed severe late radiation toxicity following radiotherapy, and 12 matched control patients. Longer retention of the γ-H2AX signal and lower colocalization efficiency of repair factors in over-responding patients confirmed that DNA repair in these individuals was compromised. Five of the radiosensitive patients harboured LoF mutations in DNA repair genes. An extensive range of quantitative parameters of the γ-H2AX response were studied with the objective to establish a predictor for radiosensitivity status. The most powerful predictor was the combination of the fraction of the unrepairable component of γ-H2AX foci and repair rate in PBL, both derived from non-linear regression analysis of foci repair kinetics. We introduce a visual representation of radiosenstivity status that allocates a position for each patient on a two-dimensional “radiosensitivity map”. This analytical approach provides the basis for larger prospective studies to further refine the algorithm, ultimately to triage capability.

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Determinants of resistance to chemotherapy and ionizing radiation in breast cancer stem cells

Cited by 76 publications

References 118 publications

Towards the first targeted therapy for triple-negative breast cancer: Repositioning of clofazimine as a chemotherapy-compatible selective Wnt pathway inhibitor

Towards the first targeted therapy for triple-negative breast cancer: Repositioning of clofazimine as a chemotherapy-compatible selective Wnt pathway inhibitor

FTO regulates the chemo‐radiotherapy resistance of cervical squamous cell carcinoma (CSCC) by targeting β‐catenin through mRNA demethylation

Compromized DNA repair as a basis for identification of cancer radiotherapy patients with extreme radiosensitivity

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