Pancreatic cancer tumorspheres are cancer stem-like cells with increased chemoresistance and reduced metabolic potential

Domenichini, Alice; Edmands, Jeanne S; Adamska, Aleksandra; Begicevic, Romana-Rea; Paternoster, Silvano; Falasca, Marco

doi:10.1016/j.jbior.2019.02.001

“…We also veri ed the e cacy of JVG045 in a population of pancreatic cancer tumorspheres enriched in cancer stem-like cells (26). Cancer stem-like cells are slow-cycling cells with a capacity for self-renewal that can elude most therapeutic treatments and are thus responsible for chemoresistance, tumour relapse and metastatic spread to distant sites (45).…”

Section: Re-nhc Complexes Show Anticancer Activity In Neuroblastoma Cmentioning

confidence: 94%

“…Cancer stem-like cells are slow-cycling cells with a capacity for self-renewal that can elude most therapeutic treatments and are thus responsible for chemoresistance, tumour relapse and metastatic spread to distant sites (45). We previously showed that pancreatic cancer tumorspheres are highly resistant to the main therapeutic drugs Gemcitabine and Carboplatin (26). To test its potential as a therapeutic agent, we tested JVG045 on tumorspheres isolated from the human pancreatic cancer cell line AsPC-1.…”

Section: Re-nhc Complexes Show Anticancer Activity In Neuroblastoma Cmentioning

confidence: 99%

Rhenium N-heterocyclic Carbene Complexes Block Growth of Aggressive Cancers by Inhibiting FGFR- and SRC-Mediated Signalling

Domenichini

¹

,

Casari

²

,

Simpson

³

et al. 2020

Preprint

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0

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Background: Platinum-based anticancer drugs have been at the frontline of cancer therapy for the last 40 years, and are used in more than half of all treatments for different cancer types. However, they are not universally effective, and patients often suffer severe side effects because of their lack of cellular selectivity. There is therefore a compelling need to investigate the anticancer activity of alternative metal complexes. Here we describe the potential anticancer activity of rhenium-based complexes with preclinical efficacy in different types of solid malignancies.Methods: Kinase profile assay of rhenium complexes. Toxicology studies using zebrafish. Analysis of the growth of pancreatic cancer cell line-derived xenografts generated in zebrafish and in mice upon exposure to rhenium compounds.Results: We describe rhenium complexes which block cancer proliferation in vitro by inhibiting the signalling cascade induced by FGFR and Src. Initially, we tested the toxicity of rhenium complexes in vivo using a zebrafish model and identified one compound that displays anticancer activity with low toxicity even in the high micromolar range. Notably, the rhenium complex has anticancer activity in very aggressive cancers such as pancreatic ductal adenocarcinoma and neuroblastoma. We demonstrate the potential efficacy of this complex via a significant reduction in cancer growth in mouse xenografts.Conclusions: Our findings provide a basis for the development of rhenium-based chemotherapy agents with enhanced selectivity and limited side effects compared to standard platinum-based drugs.

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“…All cell lines were cultured less than 3 months after resuscitation and regularly tested for Mycoplasma . Primary cell line (KPC) was established from pancreatic tumours of KRAS WT/G12D , P53 WT/R172H , PDX-1CRE +/+ (KPC) transgenic mouse model as described elsewhere [6–8].…”

Section: Methodsmentioning

confidence: 99%

“…To validate the effect of MCI-715 on tumorigenic potential of cancer cells and their ability to form colonies in anchorage-independent conditions, soft agar colony formation assay was performed as previously described [8, 9]. Colonies were visualized with ChemiDoc XRS+ System (Bio-Rad) and quantified with ImageJ software.…”

Section: Methodsmentioning

confidence: 99%

Pharmacological inhibition of ABCC3 slows tumour progression in animal models of pancreatic cancer

Adamska

¹

,

Domenichini

²

,

Capone

³

et al. 2019

J Exp Clin Cancer Res

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Background Pancreatic Ductal Adenocarcinoma (PDAC) is an aggressive and lethal disease, lacking effective therapeutic approaches. Available therapies only marginally prolong patient survival and are frequently coupled with severe adverse events. It is therefore pivotal to investigate novel and safe pharmacological approaches. We have recently identified the ABC transporter, ABCC3, whose expression is dependent on mutation of TP53, as a novel target in PDAC. ABCC3-mediated regulation of PDAC cell proliferation and tumour growth in vivo was demonstrated and was shown to be conferred by upregulation of STAT3 signalling and regulation of apoptosis. Methods To verify the potential of ABCC3 as a pharmacological target, a small molecule inhibitor of ABCC3, referred to here as MCI-715, was designed. In vitro assays were performed to assess the effects of ABCC3 inhibition on anchorage-dependent and anchorage-independent PDAC cell growth. The impact of ABCC3 inhibition on specific signalling pathways was verified by Western blotting. The potential of targeting ABCC3 with MCI-715 to counteract PDAC progression was additionally tested in several animal models of PDAC, including xenograft mouse models and transgenic mouse model of PDAC. Results Using both mouse models and human cell lines of PDAC, we show that the pharmacological inhibition of ABCC3 significantly decreased PDAC cell proliferation and clonal expansion in vitro and in vivo , remarkably slowing tumour growth in mice xenografts and patient-derived xenografts and increasing the survival rate in a transgenic mouse model. Furthermore, we show that stromal cells in pancreatic tumours, which actively participate in PDAC progression, are enriched for ABCC3, and that its inhibition may contribute to stroma reprogramming. Conclusions Our results indicate that ABCC3 inhibition with MCI-715 demonstrated strong antitumor activity and is well tolerated, which leads us to conclude that ABCC3 inhibition is a novel and promising therapeutic strategy for a considerable cohort of patients with pancreatic cancer. Electronic supplementary material The online version of this article (10.1186/s13046-019-1308-7) contains supplementary material, which is available to authorized users.

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“…Pancreatic cancer tumorspheres enriched in cancer stem cells were cultured according to the protocol previously described by Domenichini et al (26). Primary mouse pancreatic cancer cells KPC were used according to the protocol previously described (26). The KPC (KrasLSL.G12D/+; p53R172H/+; PdxCretg/+) mouse model is a clinically relevant genetically engineered mouse model (GEMM) for PDAC.…”

Section: Cell Culturementioning

confidence: 99%

Rhenium N-heterocyclic carbene complexes block growth of aggressive cancers by inhibiting FGFR- and SRC-mediated signalling

Domenichini

¹

,

Casari

²

,

Simpson

³

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

Background: Platinum-based anticancer drugs have been at the frontline of cancer therapy for the last 40 years, and are used in more than half of all treatments for different cancer types. However, they are not universally effective, and patients often suffer severe side effects because of their lack of cellular selectivity. There is therefore a compelling need to investigate the anticancer activity of alternative metal complexes. Here we describe the potential anticancer activity of rhenium-based complexes with preclinical efficacy in different types of solid malignancies.Methods: Kinase profile assay of rhenium complexes. Toxicology studies using zebrafish. Analysis of the growth of pancreatic cancer cell line-derived xenografts generated in zebrafish and in mice upon exposure to rhenium compounds.Results: We describe rhenium complexes which block cancer proliferation in vitro by inhibiting the signalling cascade induced by FGFR and Src. Initially, we tested the toxicity of rhenium complexes in vivo using a zebrafish model and identified one compound that displays anticancer activity with low toxicity even in the high micromolar range. Notably, the rhenium complex has anticancer activity in very aggressive cancers such as pancreatic ductal adenocarcinoma and neuroblastoma. We demonstrate the potential efficacy of this complex via a significant reduction in cancer growth in mouse xenografts.Conclusions: Our findings provide a basis for the development of rhenium-based chemotherapy agents with enhanced selectivity and limited side effects compared to standard platinum-based drugs.

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Pancreatic cancer tumorspheres are cancer stem-like cells with increased chemoresistance and reduced metabolic potential

Cited by 23 publications

References 56 publications

Rhenium N-heterocyclic Carbene Complexes Block Growth of Aggressive Cancers by Inhibiting FGFR- and SRC-Mediated Signalling

Rhenium N-heterocyclic Carbene Complexes Block Growth of Aggressive Cancers by Inhibiting FGFR- and SRC-Mediated Signalling

Pharmacological inhibition of ABCC3 slows tumour progression in animal models of pancreatic cancer

Rhenium N-heterocyclic carbene complexes block growth of aggressive cancers by inhibiting FGFR- and SRC-mediated signalling

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