Arsenic: a potentially useful poison for Hedgehog-driven cancers

Abstract. Rhabdomyosarcomas (RMS) are soft tissue tumours treated with a combination of surgery and chemotherapy. However, mortality rates remain high in case of recurrences and metastatic disease due to drug resistance and failure to undergo apoptosis. Therefore, innovative approaches targeting specific signalling pathways are urgently needed. We analysed the impact of different hedgehog (Hh) pathway inhibitors on growth and survival of six RMS cell lines using MTS assay, colony formation assay, 3D spheroid cultures, flow cytometry and western blotting. Especially the glioma-associated oncogene family (GLI) inhibitor arsenic trioxide (ATO) effectively reduced viability as well as clonal growth and induced cell death in RMS cell lines of embryonal, alveolar and sclerosing, spindle cell subtype, whereas normal skeletal muscle cells were hardly compromised by ATO. Combination of ATO with itraconazole potentiated the reduction of colony formation and spheroid size. These results show that ATO is a promising substance for treatment of relapsed and refractory RMS by directly targeting GLI transcription factors. The combination with itraconazole or other chemotherapeutic drugs has the opportunity to enforce the treatment efficiency of resistant and recurrent RMS. IntroductionRhabdomyosarcomas (RMS) are the most common paediatric soft tissue tumours, accounting for ~5% of all cancers at that age. Several histologic RMS variants can be differentiated with two thirds of RMS belonging to the embryonal subtype (ERMS) usually diagnosed in younger children below the age of 6 years. The more aggressive alveolar subtype (ARMS), which is more common in adolescents and young adults, makes up ~20% of new cases. ARMS are characterised by the reciprocal translocations t(2;13)(p35;q14) or t(1;13)(p36;q14) leading to the expression of fusion proteins consisting of the DNA-binding domains of PAX3 or PAX7 and the transactivation domain of FOXO1 (1,2). ERMS often exhibit loss of heterozygosity (LOH) at the chromosomal band 11p15.5 affecting the expression of the tumour suppressor genes H19 and CDKN1C (2). There are additional subtypes as the high grade pleomorphic RMS with a very unfavourable prognosis (3) and the sclerosing, spindle cell variant. In children this subtype often has a favourable outcome, whereas in adults it is highly aggressive (4,5).The standard therapy of RMS is surgery combined with a first line chemotherapy composed of vincristine, actinomycin D and cyclophosphamide (6). However, mortality rates remain high in case of recurrences and metastatic disease. Chemotherapy resistance and the failure of RMS cells to undergo apoptosis often occurs during disease progression (7). Therefore, new innovative approaches targeting specific signalling pathways are urgently needed.The hedgehog (Hh) pathway is involved in development, tissue regeneration but also several kinds of cancer including basal cell carcinoma, medulloblastoma, osteosarcoma, Ewing sarcoma and RMS (8-11). Ligand-dependent activation of Hh signalling occurs via ...

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“…ATO directly binds to GLI1 and GLI2, inhibiting their transcriptional activation capacity (34). Moreover, aTO promotes GLi2 degradation (35).…”

Section: Discussionmentioning

confidence: 99%

Targeting hedgehog signalling by arsenic trioxide reduces cell growth and induces apoptosis in rhabdomyosarcoma

Boehme

Zaborski

Riester

et al. 2015

International Journal of Oncology

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“…It is also associated with liver, lung, skin and bladder cancers [9]. Paradoxically, arsenic compounds have a history of over 2000 years of use as medicine [10]. In particular, it is used in the treatment of diseases caused by protozoan parasites [11].…”

Section: Introductionmentioning

confidence: 99%

“…Arsenic trioxide also shows high cytotoxic effect in small cell lung carcinoma, which otherwise responds very poorly to treatments [16]. Similarly, it has recently been shown that arsenic can be a choice of therapy for treating other forms of cancer [10] [17]. However, the efficiency of response to arsenic-based drugs depends partly on the levels of cellular arsenic uptake [18].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of MAPK Hog1 Results in Increased Hsp104 Aggregate Formation Probably through Elevated Arsenite Influx into the Cells, an Approach with Numerous Potential Applications

Ahmadpour¹,

Banaeiyan²,

Grötli³

et al. 2014

AJMB

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Arsenic is a highly toxic and carcinogenic metalloid widely dispersed in the environment, contaminating water and soil and accumulating in crops. Paradoxically, arsenic is also part of modern therapy and employed in treating numerous ailments and diseases. Hence, inventing strategies to tune cellular arsenic uptake based on purpose is striking. Here, we describe an approach in which the arsenite uptake can be increased using a MAPK inhibitor. Employing microfluidic flow chambers in combination with optical tweezers and fluorescent microscopy, we elevated the influx of arsenite into the yeast Saccharomyces cerevisiae cells following short-term treatment with a Hog1 kinase inhibitor. The increase in arsenite uptake was followed on arsenite triggered redistribution of a reporter protein, Hsp104-GFP, which was imaged over time. The effect was even more pronounced when the yeast mother and daughter cells were analyzed disjointedly, an opportunity provided owing to single-cell analysis. Our data firstly provide a strategy to increase arsenite uptake and secondly show that arsenite triggered aggregates, previously shown to be sites of damaged proteins, are distributed asymmetrically and less accumulated in daughter cells. Inventing approaches to tune arsenite uptake has a great value for its use in environmental as well as medical applications.

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“…It has been used to treat a variety of conditions including cancer [9,10]. As 2 O 3 has been proven efficacious in the treatment of acute promyelocytic leukemia (APL) with limited adverse effects [11][12][13].…”

Section: Introductionmentioning

confidence: 99%

Radiosensitization of cervical cancer xenografts by arsenic trioxide and the role of VEGF and Ku70

Ren

Tey

et al. 2012

J Radiat Oncol

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Objective The aim of this study is to explore the effect of arsenic trioxide (As 2 O 3 ) on radiosensitivity in cervical carcinoma xenografts and the possible underlying mechanisms of vascular endothelial growth factor (VEGF) and Ku autoantigen protein p70 (Ku70). Methods The tumor-bearing C57BL/6mouse model was established by injecting U14 cervical carcinoma cells into the right infra-axillary dermis of 40 mice. The mice were randomized into four groups: (1) control group (peritoneal injection, 0.2 ml of 0.9% normal saline); (2) As 2 O 3 only group (peritoneal injection, 2.0 mg/kg, 0.2 ml As 2 O 3 ); (3) irradiation only group (peritoneal injection 0.9%NS, 0.2 ml+6 MeV electron beam, 10 Gy); and (4) As 2 O 3 + irradiation group (peritoneal injection, 2.0 mg/kg, 0.2 ml As 2 O 3 +6 MeV electron beam, 10 Gy). The mice were sacrificed 25 days after randomisation. U14 cervical tumors from the mice were harvested and weighed. Response to treatment using radiation and/or As 2 O 3 was evaluated by extent of inhibition (i.e., growth inhibition rate) of tumor growth. VEGF and Ku70 mRNA expression and protein levels were evaluated by RT-PCR and immunohistochemistry, respectively. Results As 2 O 3 + irradiation was found to significantly increase the inhibition of tumor growth. The growth inhibition rates in As 2 O 3 only, irradiation only, and As 2 O 3 + irradiated groups were 10.48%, 30.30%, and 73.15%, respectively (p <0.05). The combination also significantly downregulated the expression of VEGF and Ku70 in irradiated cervical carcinoma xenografts as compared to the control group, As 2 O 3 only group, or irradiation only group (p <0.05). Conclusions Arsenic trioxide effectively sensitizes the cervical carcinoma xenografts to ionizing irradiation. Downregulation of the expression of VEGF and Ku70 is likely to play an important role.

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Arsenic: a potentially useful poison for Hedgehog-driven cancers

Cited by 26 publications

References 20 publications

Targeting hedgehog signalling by arsenic trioxide reduces cell growth and induces apoptosis in rhabdomyosarcoma

Targeting hedgehog signalling by arsenic trioxide reduces cell growth and induces apoptosis in rhabdomyosarcoma

Inhibition of MAPK Hog1 Results in Increased Hsp104 Aggregate Formation Probably through Elevated Arsenite Influx into the Cells, an Approach with Numerous Potential Applications

Radiosensitization of cervical cancer xenografts by arsenic trioxide and the role of VEGF and Ku70

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