Salinomycin exerts anticancer effects on human breast carcinoma MCF-7 cancer stem cells via modulation of Hedgehog signaling

Lü, Ying; Ma, Wei; Murata, Jun; Yu, Xiaotang; Hou, Zhengxin; Fan, Shujun; Song, Bo; Wang, Huan; Li, Jiazhi; Kang, Le; Liu, Pixu; Liu, Quentin; Li, Lianhong

doi:10.1016/j.cbi.2014.12.002

Cited by 53 publications

(33 citation statements)

References 48 publications

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“…As an anticancer drug, SAL induces cell apoptosis and prevents cell proliferation have been reported in breast, head and neck squamous cell, pancreatic and colorectal cancer [27–29]. More importantly, the cancer stem cells (CSCs) inhibiting activity of SAL has previously been demonstrated in a variety of tumors [30].…”

Section: Discussionmentioning

confidence: 99%

Synergistic induction of apoptosis by salinomycin and gefitinib through lysosomal and mitochondrial dependent pathway overcomes gefitinib resistance in colorectal cancer

Zou

Nie

et al. 2015

Oncotarget

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Here, we showed the antibiotic salinomycin (SAL) combined with GEF exerted synergistic cytotoxicity effects in colorectal cancer cells irrespective of their EGFR and KRAS status, with a relatively low toxicity to normal cells. Additionally, combination of the two drugs overcame Ras-induced resistance and the acquired resistance to GEF. Further, we identified a new potential mechanism of this cooperative interaction by showing that GEF and SAL acted together to enhance production of reactive oxygen species (ROS), loss of mitochondrial membrane potential (MMP) and lysosomal membrane potential (LMP). And the ROS contributed the loss of MMP and LMP. We also found that GEF and SAL acted in concert to induce apoptosis via a mitochondrial-lysosomal cross-talk and caspase-independent pathway triggered by cathepsin B and D. Lastly, SAL in combination with GEF sensitized GEF-resistant cells to GEF in a nude mouse xenograft model. This novel combination treatment might provide a potential clinical application to overcome GEF resistance in colorectal cancer.

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Section: Discussionmentioning

confidence: 99%

Synergistic induction of apoptosis by salinomycin and gefitinib through lysosomal and mitochondrial dependent pathway overcomes gefitinib resistance in colorectal cancer

Zou

Nie

et al. 2015

Oncotarget

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“…Inhibition of Hh signaling also suppresses EMT by inhibiting Snail, Slug and ZEB2 [292]. It is recently found that salinomycin that shows selective toxicity in BCSCs, inhibits Shh-mediated Hh activation through down-regulating the expression of Ptch1, Smo, Gli1, and Gli2 as well as stemness markers Snail, Nanog, Oct4 and Sox2 [291,293,294]. Therefore, Hh signaling induces self-renewal and EMT of BC cells [292,295,296].…”

Section: Her2 Promotes Stemness Signaling Pathwaysmentioning

confidence: 99%

HER2 in Breast Cancer Stemness: A Negative Feedback Loop towards Trastuzumab Resistance

Nami

Wang

2017

Cancers

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HER2 receptor tyrosine kinase that is overexpressed in approximately 20% of all breast cancers (BCs) is a poor prognosis factor and a precious target for BC therapy. Trastuzumab is approved by FDA to specifically target HER2 for treating HER2+ BC. However, about 60% of patients with HER2+ breast tumor develop de novo resistance to trastuzumab, partially due to the loss of expression of HER2 extracellular domain on their tumor cells. This is due to shedding/cleavage of HER2 by metalloproteinases (ADAMs and MMPs). HER2 shedding results in the accumulation of intracellular carboxyl-terminal HER2 (p95HER2), which is a common phenomenon in trastuzumab-resistant tumors and is suggested as a predictive marker for trastuzumab resistance. Up-regulation of the metalloproteinases is a poor prognosis factor and is commonly seen in mesenchymal-like cancer stem cells that are risen during epithelial to mesenchymal transition (EMT) of tumor cells. HER2 cleavage during EMT can explain why secondary metastatic tumors with high percentage of mesenchymal-like cancer stem cells are mostly resistant to trastuzumab but still sensitive to lapatinib. Importantly, many studies report HER2 interaction with oncogenic/stemness signaling pathways including TGF-β/Smad, Wnt/β-catenin, Notch, JAK/STAT and Hedgehog. HER2 overexpression promotes EMT and the emergence of cancer stem cell properties in BC. Increased expression and activation of metalloproteinases during EMT leads to proteolytic cleavage and shedding of HER2 receptor, which downregulates HER2 extracellular domain and eventually increases trastuzumab resistance. Here, we review the hypothesis that a negative feedback loop between HER2 and stemness signaling drives resistance of BC to trastuzumab.

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“…Tumorspere cultures were made in ultralow attachment six-well plate (Corning, Lowell, MA, USA) in suspension (500 cells/mL) in serum-free DMEM/F12 media, supplemented with B27 (1:50, Invitrogen, Carlsbad, CA, USA), 20 ng/mL human recombinant epidermal growth factor (Sigma-Aldrich), 20 ng/mL basic fibroblast growth factor (Sigma-Aldrich), 4 μg/mL heparin (SigmaAldrich), 5 μg/mL insulin (Sigma-Aldrich) and 1 % of penicillin-streptomycin in a humidified incubator at 37 o C in 5 % CO 2 [12,13]. Tumorsphere formation was tested by culturing MCF-7 cells in the presence or absence of pectolinarigenin under the conditions mentioned above.…”

Section: Tumorsphere Culturementioning

confidence: 99%

“…Tumor spheres of MCF-7 were cultured as described elsewhere [12]. Tumor spheres with a tight appearance were observed in serum free medium (Fig 1B).…”

Section: Pectolinarigenin Inhibited Bcscs Selfrenewal Propertiesmentioning

confidence: 99%

Evaluation of Anti-tumor and Chemoresistance-lowering Effects of Pectolinarigenin from <i>Cirsium japonicum</i> Fisch ex DC in Breast Cancer

Lu¹,

Xu²,

Lu³

et al. 2016

Trop. J. Pharm Res

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Salinomycin exerts anticancer effects on human breast carcinoma MCF-7 cancer stem cells via modulation of Hedgehog signaling

Cited by 53 publications

References 48 publications

Synergistic induction of apoptosis by salinomycin and gefitinib through lysosomal and mitochondrial dependent pathway overcomes gefitinib resistance in colorectal cancer

Synergistic induction of apoptosis by salinomycin and gefitinib through lysosomal and mitochondrial dependent pathway overcomes gefitinib resistance in colorectal cancer

HER2 in Breast Cancer Stemness: A Negative Feedback Loop towards Trastuzumab Resistance

Evaluation of Anti-tumor and Chemoresistance-lowering Effects of Pectolinarigenin from <i>Cirsium japonicum</i> Fisch ex DC in Breast Cancer

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