Selective targeting of neuroblastoma tumour‐initiating cells by compounds identified in stem cell‐based small molecule screens

Smith, Kristen M.; Datti, Alessandro; Fujitani, Mayumi; Grinshtein, Natalie; Zhang, Libo; Morozova, Olena; Blakely, Kim M.; Rotenberg, Susan A.; Hansford, Loen M.; Miller, Freda D.; Yeger, Herman; Irwin, Meredith S.; Moffat, Jason; Marra, Marco A.; Baruchel, Sylvain; Wrana, Jeffrey L.; Kaplan, David R.

doi:10.1002/emmm.201000093

Cited by 60 publications

(63 citation statements)

References 45 publications

(55 reference statements)

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“…2, 3, 13). Compounds were identified that exhibited more that 50% growth inhibition at 1 mmol/L in all BTIC cultures using AlamarBlue reduction as we have previously described (30,31). Compounds that exhibited greater than 50% but lower than 74% cytotoxicity were considered "intermediate potency hits" and indicated in yellow while compounds demonstrating greater than 75% growth inhibition were defined as "strong hits" and indicated in green (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Disulfiram when Combined with Copper Enhances the Therapeutic Effects of Temozolomide for the Treatment of Glioblastoma

Lun

Wells

Grinshtein

et al. 2016

Clinical Cancer Research

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153

114

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Purpose: Glioblastoma is one of the most lethal cancers in humans, and with existing therapy, survival remains at 14.6 months. Current barriers to successful treatment include their infiltrative behavior, extensive tumor heterogeneity, and the presence of a stem-like population of cells, termed brain tumor-initiating cells (BTIC) that confer resistance to conventional therapies.Experimental Design: To develop therapeutic strategies that target BTICs, we focused on a repurposing approach that explored already-marketed (clinically approved) drugs for therapeutic potential against patient-derived BTICs that encompass the genetic and phenotypic heterogeneity of glioblastoma observed clinically.Results: Using a high-throughput in vitro drug screen, we found that montelukast, clioquinol, and disulfiram (DSF) were cytotoxic against a large panel of patient-derived BTICs. Of these compounds, disulfiram, an off-patent drug previously used to treat alcoholism, in the presence of a copper supplement, showed low nanomolar efficacy in BTICs including those resistant to temozolomide and the highly infiltrative quiescent stem-like population. Low dose DSF-Cu significantly augmented temozolomide activity in vitro, and importantly, prolonged in vivo survival in patient-derived BTIC models established from both newly diagnosed and recurrent tumors. Moreover, we found that in addition to acting as a potent proteasome inhibitor, DSF-Cu functionally impairs DNA repair pathways and enhances the effects of DNA alkylating agents and radiation. These observations suggest that DSF-Cu inhibits proteasome activity and augments the therapeutic effects of DNA-damaging agents (temozolomide and radiation).Conclusions: DSF-Cu should be considered as an adjuvant therapy for the treatment of patients with glioblastoma in both newly diagnosed and recurrent settings.

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Section: Resultsmentioning

confidence: 99%

“…High-throughput screening was performed at the SMART Facility of the Lunenfeld-Tanenbaum Research Institute (Toronto, Canada), as described previously (30,31). Drug "hits" were defined as compounds that caused a signal decrease of at least 75% at a screening dose of 1 mmol/L as compared with controls.…”

Section: High-throughput Screening and Secondary Validationmentioning

confidence: 99%

Disulfiram when Combined with Copper Enhances the Therapeutic Effects of Temozolomide for the Treatment of Glioblastoma

Lun

Wells

Grinshtein

et al. 2016

Clinical Cancer Research

Self Cite

153

114

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“…They found two compounds -dequalinium analogue (DECA-14) and rapamycin, that prevent NBL CSC self-renewal both in vitro and in vivo. This difference suggest that CSC in NBL play important role in metastases development [60].…”

mentioning

confidence: 91%

Neuroblastoma stem cells – mechanisms of chemoresistance and histonedeacetylase inhibitors

Khalil

Hraběta²,

Cipro³

et al. 2012

neo

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Cancer stem cells (CSCs) form a small proportion of tumor cells that have stem cell properties: self-renewal capacity, the ability to develop into different lineages and proliferative potential. The interest in CSCs emerged from their expected role in initiation, progression and recurrence of many tumors. They are generally resistant to conventional chemotherapy and radiotherapy. There are two hypotheses about their origin: The first assumes that CSCs may arise from normal stem cells, and the second supposes that differentiated cells acquire the properties of CSCs. Both hypotheses are not mutually exclusive, as it is possible that CSCs have a diverse origin in different tumors. CD133+ cells (CD133 is marker of CSC in some tumors) isolated from NBL, osteosarcoma and Ewing sarcoma cell lines are resistant to cisplatin, carboplatin, etoposide and doxorubicin than the CD133-ones. Being resistant to chemotherapy, there were many attempts to target CSCs epigenetically including the use of histone deacetylase inhibitors. The diverse influence of valproic acid (histone deacetylase inhibitor) on normal and cancer stem cells was proved in different experiments. We have found an increase percentage of CD133+ NBL cells after their incubation with VPA in a dose that does not induce apoptosis. Further researches on CSCs and clinical application for their detection are necessary: (i) to define the CSC function in carcinogenesis, cancer development and their role in metastasis; (ii) to find a specific marker for CSCs in different tumors; (iii) to explain the role of different pathways that determine their behavior and (iv) to explain mechanisms of chemoresistance of CSCs.

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“…However, some patients still suffered from failure of treatment including relapse and metastasis, which is thought to originate from cancer stem cells (CSC; refs. [3][4][5][6][7][8][9].…”

Section: Introductionmentioning

confidence: 99%

“…CSCs have the properties of self-renewal, differentiation, and resistance to chemotherapy or radiotherapy (7,10). Although the CSCs represent a small proportion of the tumor cells, they are key players in tumor initiation, recurrence, and metastasis (8)(9)(10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

Smac Mimetics in Combination with TRAIL Selectively Target Cancer Stem Cells in Nasopharyngeal Carcinoma

Wu¹,

Wang²,

Zhao³

et al. 2013

Molecular Cancer Therapeutics

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Nasopharyngeal carcinoma is a common malignancy in Southern China. After radiotherapy and chemotherapy, a considerable proportion of patients with nasopharyngeal carcinoma suffered tumor relapse and metastasis. Cancer stem cells (CSC) have been shown with resistance against therapies and thus considered as the initiator of recurrence and metastasis in tumors, where the antiapoptotic property of CSCs play an important role. Smac/DIABLO is an inverse regulator for the inhibitors of apoptosis protein family (IAP), which have been involved in apoptosis. Here, the effects of Smac mimetics on the CSCs of nasopharyngeal carcinoma were studied both in vitro and in vivo, using two clones of nasopharyngeal carcinoma cell line CNE2 as models. We found that one of the clones, S18, had CSC-like properties and IAPs were overexpressed. The combination of Smac mimetics and TNF-related apoptosis-inducing ligand (TRAIL) can reduce the percentage of SP cells and inhibit the colonyand sphere-forming abilities of S18 cells, indicating their ability to attenuate the CSCs. Moreover, in a nasopharyngeal carcinoma xenograft model, the administration of Smac mimetics in combination with TRAIL also led to the elimination of nasopharyngeal carcinoma stem cells. Furthermore, the Smac mimetics in combination with TRAIL induced the degradation of cIAP1 and XIAP and thus induced apoptosis in vitro and in vivo. Taken together, our data show that Smac mimetics exerted an antitumor effect on nasopharyngeal carcinoma cancer stem cells, and this combination treatment should be considered as a promising strategy for the treatment of nasopharyngeal carcinoma. Mol Cancer Ther; 12(9); 1728-37. Ó2013 AACR.

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Selective targeting of neuroblastoma tumour‐initiating cells by compounds identified in stem cell‐based small molecule screens

Cited by 60 publications

References 45 publications

Disulfiram when Combined with Copper Enhances the Therapeutic Effects of Temozolomide for the Treatment of Glioblastoma

Disulfiram when Combined with Copper Enhances the Therapeutic Effects of Temozolomide for the Treatment of Glioblastoma

Neuroblastoma stem cells – mechanisms of chemoresistance and histonedeacetylase inhibitors

Smac Mimetics in Combination with TRAIL Selectively Target Cancer Stem Cells in Nasopharyngeal Carcinoma

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