Disulfiram suppresses cancer stem-like properties and STAT3 signaling in triple-negative breast cancer cells

Kim, Yoon Jae; Kim, Ji Young; Lee, Nahyun; Oh, Eunhye; Sung, Daeil; Cho, Tae Min; Seo, Jae Hong

doi:10.1016/j.bbrc.2017.03.164

Cited by 46 publications

(34 citation statements)

References 25 publications

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“…FLU‐induced BCSC suppression is associated with the downregulation of STAT3 signaling in vitro and in vivo . We previously reported that STAT3 is preferentially activated in CD44 high /CD24 low stem‐like populations and its activity is significantly upregulated during mammosphere formation . Clinical and preclinical studies support the notion that a significant correlation exists between STAT3 activation and ALDH1 upregulation in human subjects .…”

Section: Discussionmentioning

confidence: 73%

“…We previously reported that STAT3 is preferentially activated in CD44 high /CD24 low stem-like populations and its activity is significantly upregulated during mammosphere formation. 40,41 Clinical and preclinical studies support the notion that a significant correlation exists between STAT3 activation and ALDH1 upregulation in human subjects. 42,43 STAT3 inhibition reduces CSC-load by disrupting the STAT3-Oct3/4 axis, cell migration, invasion, tumorigenic potential and metastasis in breast and pancreatic cancer in vitro and in vivo.…”

Section: Discussionmentioning

confidence: 81%

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Flubendazole elicits anti‐metastatic effects in triple‐negative breast cancer via STAT3 inhibition

Kim

et al. 2018

Intl Journal of Cancer

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Tumor metastasis remains the cause of 90% of cancer-related deaths. Cancer stem cells (CSC) are thought to be responsible for the aggressive and metastatic nature of triple-negative breast cancers (TNBC), and new therapeutic strategies are being devised to target them. Flubendazole (FLU) is a widely used anthelmintic agent that also exhibits anticancer activity in several cancer types. The aim of this study was to characterize the mechanism of action of FLU on breast cancer stem cell (BCSC)-like properties and metastasis in TNBC. FLU treatment caused a significant induction of apoptosis, accompanied by G2/M phase accumulation, caspase-3/-7 activation and the dysregulation of STAT3 activation in TNBC cells. The latter phenomenon was associated with impairment of cancer stem-like traits, concomitant with a reduction in the CD24 /CD44 , CD24 /CD49f subpopulation, ALDH1 activity and mammosphere formation. The BCSC-enriched populations exhibited enhanced metastasis with higher STAT3 activation, while FLU administration inhibited tumor growth, angiogenesis and lung and liver metastasis, coinciding with decreased MMP-2 and MMP-9 levels in circulating blood. FLU kills not only rapid proliferating tumor cells but also effectively eradicates BCSC-like cells in vitro and in vivo. Our findings warrant further investigation of FLU as a treatment for metastatic TNBC.

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Section: Discussionmentioning

confidence: 73%

Section: Discussionmentioning

confidence: 81%

Flubendazole elicits anti‐metastatic effects in triple‐negative breast cancer via STAT3 inhibition

Kim

et al. 2018

Intl Journal of Cancer

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“…Intriguingly, we demonstrate for the first time, to our knowledge, that DSF effectively represses the growth of bladder cancer PDX models. While DSF has been used as an alcohol‐aversive agent to treat alcoholism, DSF is the focus of renewed attention as an anticancer agent . In triple‐negative breast cancer cells, DSF/copper treatment induces apoptosis and impairs mammosphere formation by suppressing the STAT3 signaling pathway .…”

Section: Discussionmentioning

confidence: 99%

“…[30][31][32] In triple-negative breast cancer cells, DSF/copper treatment induces apoptosis and impairs mammosphere formation by suppressing the STAT3 signaling pathway. 30 DSF also represses proteasome activity in tumor tissue and the accumulation of the tumor suppressor proteins, p27 and Bax. 31 Moreover, DSF inhibits DNA methyltransferase 1, leading to a decrease in global 5-methyl cytosine content and an increase in unmethylated APC and RARB gene promoters.…”

Section: Discussionmentioning

confidence: 99%

ALDH1A1 in patient‐derived bladder cancer spheroids activates retinoic acid signaling leading to TUBB3 overexpression and tumor progression

Namekawa

Ikeda

Horie‐Inoue

et al. 2019

Intl Journal of Cancer

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Acquired chemoresistance is a critical issue for advanced bladder cancer patients during long‐term treatment. Recent studies reveal that a fraction of tumor cells with enhanced tumor‐initiating potential, or cancer stem‐like cells (CSCs), may particularly contribute to acquired chemoresistance and recurrence. Thus, CSC characterization will be the first step towards understanding the mechanisms underlying advanced disease. Here we generated long‐term patient‐derived cancer cells (PDCs) from bladder cancer patient specimens in spheroid culture, which is favorable for CSC enrichment. Pathological features of bladder cancer PDCs and PDC‐dependent patient‐derived xenografts (PDXs) were basically similar to those of their corresponding patients’ specimens. Notably, CSC marker aldehyde dehydrogenase 1A1 (ALDH1A1), a critical enzyme that synthesizes retinoic acid (RA), was abundantly expressed in PDCs. ALDH1A1 inhibitors and shRNAs repressed both PDC proliferation and spheroid formation, whereas all‐trans RA could rescue ALDH1A1 shRNA‐suppressed spheroid formation. ALDH inhibitor also reduced the in vivo growth of PDC‐derived xenografts. ALDH1A1 knockdown study showed that tubulin beta III (TUBB3) was one of the downregulated genes in PDCs. We identified functional RA response elements in TUBB3 promoter, whose transcriptional activities were substantially activated by RA. Clinical survival database reveals that TUBB3 expression may associate with poor prognosis in bladder cancer patients. Moreover, TUBB3 knockdown was sufficient to suppress PDC proliferation and spheroid formation. Taken together, our results indicate that ALDH1A1 and its putative downstream target TUBB3 are overexpressed in bladder cancer, and those molecules could be applied to alternative diagnostic and therapeutic options for advanced disease.

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“…A few therapeutic agents have been shown to be cytotoxic to CSCs including salinomycin [13], curcumin [14], disulfiram [15] and chloroquine [16]. However, poor drug solubility and stability, system side effects, a short systemic half-life, poor biodistribution and low therapeutic index limit the efficacy of these drugs in vivo [17].…”

Section: Introductionmentioning

confidence: 99%

Cockle Shell-Derived Aragonite CaCO3 Nanoparticles for Co-Delivery of Doxorubicin and Thymoquinone Eliminates Cancer Stem Cells

Ibiyeye

Zuki

2020

IJMS

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Cancer stem cells CSCs (tumour-initiating cells) are responsible for cancer metastasis and recurrence associated with resistance to conventional chemotherapy. This study generated MBA MD231 3D cancer stem cells enriched spheroids in serum-free conditions and evaluated the influence of combined doxorubicin/thymoquinone-loaded cockle-shell-derived aragonite calcium carbonate nanoparticles. Single loaded drugs and free drugs were also evaluated. WST assay, sphere forming assay, ALDH activity analysis, Surface marker of CD44 and CD24 expression, apoptosis with Annexin V-PI kit, cell cycle analysis, morphological changes using a phase contrast light microscope, scanning electron microscopy, invasion assay and migration assay were carried out; The combination therapy showed enhanced apoptosis, reduction in ALDH activity and expression of CD44 and CD24 surface maker, reduction in cellular migration and invasion, inhibition of 3D sphere formation when compared to the free drugs and the single drug-loaded nanoparticle. Scanning electron microscopy showed poor spheroid formation, cell membrane blebbing, presence of cell shrinkage, distortion in the spheroid architecture; and the results from this study showed that combined drug-loaded cockle-shell-derived aragonite calcium carbonate nanoparticles can efficiently destroy the breast CSCs compared to single drug-loaded nanoparticle and a simple mixture of doxorubicin and thymoquinone.

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Disulfiram suppresses cancer stem-like properties and STAT3 signaling in triple-negative breast cancer cells

Cited by 46 publications

References 25 publications

Flubendazole elicits anti‐metastatic effects in triple‐negative breast cancer via STAT3 inhibition

Flubendazole elicits anti‐metastatic effects in triple‐negative breast cancer via STAT3 inhibition

ALDH1A1 in patient‐derived bladder cancer spheroids activates retinoic acid signaling leading to TUBB3 overexpression and tumor progression

Cockle Shell-Derived Aragonite CaCO3 Nanoparticles for Co-Delivery of Doxorubicin and Thymoquinone Eliminates Cancer Stem Cells

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