3D multicellular models reflect the efficiency of MSC-directed enzyme/prodrug treatment

Bohovic, Roman; Demkova, Lucia; Cihova, Marina; Skolekova, Svetlana; Durinikova, Erika; Toro, Lenka; Tyciakova, Silvia; Kozovská, Zuzana; Matúšková, Miroslava; Kučerová, Lucia

doi:10.4149/neo_2015_063

Cited by 7 publications

(6 citation statements)

References 15 publications

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“…More importantly, we observed no antitumorigenic action when dacarbazine was used. Our study further underlines the importance of drug testing in non-adherent spheroid cultures as these might better reflect the efficiency against tumor initiating cells [ 46 ].…”

Section: Discussionmentioning

confidence: 88%

Tyrosine kinase inhibitor SU11274 increased tumorigenicity and enriched for melanoma-initiating cells by bioenergetic modulation

et al. 2016

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BackgroundSmall molecule inhibitor of tyrosine kinase activity, compound SU11274, was reported to have antitumorigenic and antimetastatic effect in melanoma. In this study, we evaluated, whether similar effect could be achieved also in other melanoma cells including highly tumorigenic and hypermetastatic variant.MethodsThe effect of SU11274 was evaluated in adherent and non-adherent melanosphere cultures of human melanoma cells M14, M4Beu, A375 and EGFP-A375/Rel3. Tumorigenicity of SU11274-treated cells was tested by limiting dilution assay in xenograft model in vivo.ResultsHere we show that SU11274 enriched for melanoma-initiating cells in vivo. SU11274 substantially decreased number of cells in adherent and spheroid cultures, but increased their tumorigenic potential as determined by higher frequency of tumor-initiating cells in vivo. SU11274 treatment was not associated with any significant alteration in the expression of stem cell markers, but the inhibitor stimulated higher level of pluripotent markers. SU11274-treated melanoma cells exhibited higher ATP content and lactate release indicative of increased glycolysis. Our data suggest that the SU11274 altered bioenergetic state of the cells. Indeed, pharmacological intervention with a glycolytic inhibitor dichloroacetate significantly reduced SU11274-promoted increase in melanoma-initiating cells and decreased their tumorigenicity.ConclusionsOur data suggest critical role of glycolysis regulation in melanoma-initiating cells. Moreover, these data unravel substantial plasticity of melanoma cells and their adoptive mechanisms, which result in ambivalent response to therapeutic targeting.

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Section: Discussionmentioning

confidence: 88%

Tyrosine kinase inhibitor SU11274 increased tumorigenicity and enriched for melanoma-initiating cells by bioenergetic modulation

et al. 2016

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“…This strategy together with the gene therapy using genetically modified MSC, which are able to convert nontoxic prodrug to highly toxic chemotherapeutic at the site of the tumor seems to be the anticancer therapy of the near future. Combinations of traditional, targeted and stem cell-directed gene therapy could significantly advance the treatment of cancer [62][63][64][65][66].…”

Section: Discussionmentioning

confidence: 99%

Malignant melanoma: diagnosis, treatment and cancer stem cells

Kozovská¹,

Gabrisova²,

Kučerová³

2016

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Malignant melanoma represents a neoplasm stemming from melanocytes or the cells that develop from melanocytes. Melanocytes, pigment-producing cells, arise from the neural crest and migrate to their final destinations in the skin, uveal tract, meninges, and mucosa. Most melanocytes are found at the epidermal-dermal junction of the skin, and the vast majority of melanocytes arise from cutaneous sites. Cancerous growths develop when unrepaired DNA damage to skin cells (most often caused by ultraviolet radiation from sunshine or tanning beds) triggers mutations (genetic defects) that lead the skin cells to multiply rapidly and form malignant tumours. Malignant tumours consist of heterogeneous populations of tumour cells. Cancer stem cells (CSC) represent a population of cells within a tumour with highly tumorigenic and chemoresistant properties. These cells may be identified by the expression of CSC markers and also by functional assays as tumour-initiating properties in vivo, high aldehyde dehydrogenase activity tested by Aldefluor assay. There are several key stem cells markers specified for malignant melanoma: CD20, CD133, ABCB5, CD271 and ALDH1A. The review provides a detailed overview of risk factors, diagnosis, treatment possibilities and specific properties of cancer stem cells in malignant melanoma.

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“…In order to verify these findings, we examined the effect of CD::UPRT-MSC/5-FC in a 3D co-culture model, as it was previously described to be suitable for prediction of therapeutic outcome [16,22]. Significant decrease in the 3D aggregate volume of HT-29/EGFP and therapeutic MSC was observed when treated with 5-FC in concentration gradient ranging from 10 to 1000 µg/ml.…”

Section: High-performance Liquid Chromatography-mass Spectrometry Anamentioning

confidence: 90%

Cytotoxic response of 5-fluorouracil-resistant cells to gene- and cell-directed enzyme/prodrug treatment

et al. 2018

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Gene-directed enzyme/prodrug therapy (GDEPT) mediated by mesenchymal stromal cells (MSC) was already approved for clinical study on a progressive disease refractory to standard therapy. In this work, we examined the effect of several GDEPT approaches on chemoresistant cells. First, we derived 5-fluorouracil (5-FU)-resistant variant of human colorectal adenocarcinoma cells HT-29 designated HT-29/EGFP/FUR. Our data show that the upregulation of thymidylate synthase (TS) and downregulation of thymidine phosphorylase (TP), orotate phosphoribosyl transferase (OPRT) and dihydropyrimidine dehydrogenase (DPD) contributed to the 5-FU resistance in cancer cells. Next, we combined the MSC expressing either yeast cytosine deaminase (CD-MSC) or fusion yeast CD::uracil phosphoribosyl transferase (CD::UPRT-MSC) and prodrug 5-fluorocytosine (5-FC) in a cell-mediated GDEPT approach. Bystander cytotoxic effect in the direct co-cultures of the tumor and therapeutic cells mixed in a 5:1 ratio resulted in 55% and 70% inhibition of proliferation, respectively. However, the acquired chemoresistance to 5-FU can be overcome by introducing the prodrug-converting transgene into the tumor cells. When the transgene CD::UPRT was expressed in the chemoresistant cells (CD::UPRT-FUR), substantial suicide effect and a 90% decrease in viability was observed using non-toxic concentration of 62.5 µg/ml 5-FC. In summary, we demonstrate here that the transgene introduction circumvented 5-FU resistance in the tumor cells.

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3D multicellular models reflect the efficiency of MSC-directed enzyme/prodrug treatment

Cited by 7 publications

References 15 publications

Tyrosine kinase inhibitor SU11274 increased tumorigenicity and enriched for melanoma-initiating cells by bioenergetic modulation

Tyrosine kinase inhibitor SU11274 increased tumorigenicity and enriched for melanoma-initiating cells by bioenergetic modulation

Malignant melanoma: diagnosis, treatment and cancer stem cells

Cytotoxic response of 5-fluorouracil-resistant cells to gene- and cell-directed enzyme/prodrug treatment

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