Induction of immunogenic cell death in radiation-resistant breast cancer stem cells by repurposing anti-alcoholism drug disulfiram

Sun, Ting; Yang, Wei; Toprani, Sneh M.; Guo, Wei; He, Lizhi; DeLeo, Albert B.; Ferrone, Soldano; Zhang, Gong; Wang, Enwen; Lin, Zunwen; Hu, Pan; Wang, Xinhui

doi:10.1186/s12964-019-0507-3

Cited by 61 publications

(67 citation statements)

References 47 publications

(64 reference statements)

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“…DES exposure appeared in an adjusted RR of 1.42, and gestational diabetes and soy formula had a similar RR of 1.28 and 1.25, sequentially. Although there is an inconsistency in this study: when dividing women who reported to have 'definitely' or 'probably' been exposed to DES, women exposed showed no increased risk, while those who classified as being exposed had a RR of 2.07, this study also described that experiencing menarche under the age of 10 or 11 resulted in RR of 1.54 and 1.32, respectively, and being poor had a RR of 1.24 55,82 . Another study from 85 UF cases reported an association between prenatal DES and UF risk 83 .…”

Section: (I) Prenatal Des Exposure (Ii)gestational Diabetes (Iii)pregnancy Diabetes (Mothers Who Had Diabetes Before Pregnancy) (Iv) Soy mentioning

confidence: 64%

Endocrine-Disrupting Chemicals and Vitamin D Deficiency in the Pathogenesis of Uterine Fibroids

Elkafas

Badary

Elmorsy

et al. 2021

Journal of Advanced Pharmacy Research

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Uterine fibroids (UFs) are the most prevalent gynecologic neoplasm, affecting 70-80% of women over their lifespan. Although UFs are benign they can become life-threatening and require invasive surgeries such as myomectomy and hysterectomy. Notwithstanding the significant negative influence UFs have on female reproductive health, very little is known about early events that initiate tumor development. Several risk factors for UFs have been identified including vitamin D deficiency, inflammation, DNA repair deficiency, and environmental exposures to endocrine-disrupting chemicals (EDCs). EDCs have come under scrutiny recently due to their role in UF development. Epidemiologic studies have found an association between increased risk for early UF diagnosis and in utero EDC exposure. Environmental exposure to EDCs during uterine development increases UF incidence in a UF animal model. Notably, several studies demonstrated that abnormal myometrial stem cells (MMSCs) are the cell origin for UFs development. Our recent studies demonstrated that early-life EDC exposure reprogrammed the MMSCs toward a pro-fibroid landscape and altered the DNA repair and inflammation pathways. Notably, Vitamin D3 (VITD3) as a natural compound shrank the UF growth concomitantly with the reversion of several abnormal biological pathways and ameliorated the developmental exposureinduced DNA damage and pro-inflammation pathway in primed MMSCs. This review highlights and emphasizes the importance of multiple pathway interactions in the context of hypovitaminosis D at the MMSCs level and provides proofof-concept information that can help develop a safe, long-term, durable, and non-surgical therapeutic option for UFs.

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Section: (I) Prenatal Des Exposure (Ii)gestational Diabetes (Iii)pregnancy Diabetes (Mothers Who Had Diabetes Before Pregnancy) (Iv) Soy mentioning

confidence: 64%

Endocrine-Disrupting Chemicals and Vitamin D Deficiency in the Pathogenesis of Uterine Fibroids

Elkafas

Badary

Elmorsy

et al. 2021

Journal of Advanced Pharmacy Research

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“…In radiation-resistant breast cancer cell lines, the efficacy of radiotherapy was enhanced by DSF in a Cu-dependent manner; moreover, radiotherapy alone only triggered a low level of immunogenic cell death, DSF/Cu complex was able to increase radiotherapy-induced immunogenic cell death; further investigation revealed reactive oxygen species (ROS) generation and IRE1α/XBP1 signal pathway were partially responsible for improving radiotherapy-induced immunogenic cell death. 23 These findings suggested DSF as a novel radiosensitizer in the existence of Cu for breast cancer.…”

Section: Dsf Binds To Metal Ionsmentioning

confidence: 92%

<p>The Evolving Role of Disulfiram in Radiobiology and the Treatment of Breast Cancer</p>

Wang¹,

Shen²,

Yan³

et al. 2020

OTT

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Disulfiram (DSF), also known as "Antabuse", has been widely used in clinical practice to treat alcoholism. In the past decades, both in vivo and in vitro experiments showed that DSF has strong anti-cancer activity, there were some clinical studies indicated the administration of this drug was associated with favorable survival in breast cancer. It is also evident that DSF has a radioprotective effect on normal cells and could be utilized during the course of radiation therapy. Moreover, increasing evidences demonstrated the role of DSF in enhancing the radiosensitivity of tumor cells in number of alternative mechanisms. Recent studies have also elaborated the anticancer mechanism of DSF in tumor cells. This review summarizes the anticancer activity of DSF both in preclinical studies and clinical trials, focuses on the advances of this drug in radiobiology and the treatment of breast cancer, and reveals the promising of repurposing DSF as a novel radiosensitizer and radioprotector in further clinical trials.

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“…G44-26; Miltenyi Biotec Inc.). The ALDH þ CD44 þ PCSCs were detected by flow cytometry using a BD Accuri C6 flow cytometer (BD Biosciences) and sorted using a FACS Aria II Cell Sorter Flow Cytometer (BD Biosciences) (32).…”

Section: Fir or Single-dose Irradiationmentioning

confidence: 99%

“…FIR-treated cells were collected, washed, resuspended at a cell density of 10 6 cells/500 mL of 1X binding buffer, and stained with 5 mL of Annexin V-FITC and 5 mL of 7AAD at RT for 15 minutes in the dark. A minimum of 10,000 cells within the properly gated region was analyzed for apoptosis by flow cytometry (32).…”

Section: Apoptosis Assaymentioning

confidence: 99%

Targeting Radiation-Resistant Prostate Cancer Stem Cells by B7-H3 CAR T Cells

Zhang

Sadagopan

et al. 2021

Molecular Cancer Therapeutics

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Radiotherapy (RT) is a key treatment for prostate cancer. However, RT resistance can contribute to treatment failure. Prostate cancer stem cells (PCSCs) are radioresistant. We recently found that fractionated irradiation (FIR) upregulates expression of the immune checkpoint B7-H3 (CD276) on PCSCs and bulk cells in each prostate cancer cell line tested. These findings prompted us to investigate whether B7-H3 targeting chimeric antigen receptor (CAR) T cells, which may abrogate function of an immune checkpoint and mediate lysis of targeted cells, can target RT-resistant PCSCs in vitro and in vivo. B7-H3 expression is naturally higher on PCSCs than bulk prostate cancer cells and cytotoxicity of B7-H3 CAR T cells to PCSCs is more potent than to bulk prostate cancer cells. Furthermore, FIR significantly upregulates B7-H3 expression on PCSCs and bulk prostate cancer cells. The duration of FIR or single-dose irradiation-induced further upregulation of B7-H3 on bulk prostate cancer cells and PCSCs lasts for up to 3 days. B7-H3 CAR T-cell cytotoxicity against FIR-resistant PCSCs at a low effector to target ratio of 1:1 was assessed by flow cytometry and sphere formation assays. Further upregulation of B7-H3 expression by FIR made PCSCs even more sensitive to B7-H3 CAR T-cellmediated killing. Consequently, the FIR and B7-H3 CAR T-cell therapy combination is much more effective than FIR or CAR T cells alone in growth inhibition of hormone-insensitive prostate cancer xenografts in immunodeficient mice. Our work provides a sound basis for further development of this unique combinatorial model of RT and B7-H3 CAR T-cell therapy for prostate cancer.Significance: We demonstrate that FIR significantly upregulates B7-H3 expression by RT-resistant PCSCs and bulk cells; cytotoxicity of B7-H3 CAR T cells to FIR-treated PCSCs is potent and results in significantly improved antitumor efficacy in mice.

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Induction of immunogenic cell death in radiation-resistant breast cancer stem cells by repurposing anti-alcoholism drug disulfiram

Cited by 61 publications

References 47 publications

Endocrine-Disrupting Chemicals and Vitamin D Deficiency in the Pathogenesis of Uterine Fibroids

Endocrine-Disrupting Chemicals and Vitamin D Deficiency in the Pathogenesis of Uterine Fibroids

<p>The Evolving Role of Disulfiram in Radiobiology and the Treatment of Breast Cancer</p>

Targeting Radiation-Resistant Prostate Cancer Stem Cells by B7-H3 CAR T Cells

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