Impact of Wnt/β-Catenin Inhibition on Cell Proliferation through CDC25A Downregulation in Soft Tissue Sarcomas

Martinez-Font, Esther; Pérez-Capó, Marina; Ramos, Rafael; Felipe-Abrio, Irene; Garcías, Carmen; Luna, Pablo; Terrasa, Josefa; Martin‐Broto, Javier; Vögler, Oliver; Alemany, Regina; Obrador‐Hevia, Antònia

doi:10.3390/cancers12092556

Cited by 17 publications

(18 citation statements)

References 53 publications

(85 reference statements)

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“…Preclinical studies showed that PRI-724, the second-generation of CBP/catenin antagonist, inhibited cell proliferation and reduced cell growth in a variety of cancer types, including neuroendocrine tumors [ 48 ], osteosarcoma [ 54 ], head and neck carcinoma [ 55 ], hepatocellular carcinoma [ 56 ] and also in soft tissue sarcomas [ 57 ]. Similarly to LGK974, we showed that GCT cell lines were sensitive to PRI-724 in a dose-dependent manner.…”

Section: Discussionmentioning

confidence: 99%

“…Due to the significant efficacy of PRI-724 treatment in NTERA-2 CisR cells, we tried to further sensitize these cells using a combined treatment approach with cisplatin. Previous studies of combined treatments with PRI-724 showed its ability to enhance the cytotoxic effect of chemotherapeutic drugs in platinum-resistant ovarian cancer cells [ 65 ] as well as in soft tissue sarcomas [ 57 ]. Our in vitro data showed synergistic effect only when higher PRI-724 concentrations were used.…”

Section: Discussionmentioning

confidence: 99%

“…PRI-724 treatment led to decreased protein levels of the Wnt target cyclin D1 in human osteosarcoma cells [ 54 ]. Downregulation of CCND1 and CDC25A genes was also observed in soft tissue sarcoma cell lines [ 57 ]. After treatment of clear cell renal cell carcinoma cells with LGK974, the expression levels of β-catenin, cyclin D1, c-Myc, MMP9 , and MMP2 were significantly decreased [ 49 ].…”

Section: Discussionmentioning

confidence: 99%

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Targeting of Deregulated Wnt/β-Catenin Signaling by PRI-724 and LGK974 Inhibitors in Germ Cell Tumor Cell Lines

Schmidtova

Kalavska

Lišková

et al. 2021

IJMS

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The majority of patients with testicular germ cell tumors (GCTs) can be cured with cisplatin-based chemotherapy. However, for a subset of patients present with cisplatin-refractory disease, which confers a poor prognosis, the treatment options are limited. Novel therapies are therefore urgently needed to improve outcomes in this challenging patient population. It has previously been shown that Wnt/β-catenin signaling is active in GCTs suggesting that its inhibitors LGK974 and PRI-724 may show promise in the management of cisplatin-refractory GCTs. We herein investigated whether LGK-974 and PRI-724 provide a treatment effect in cisplatin-resistant GCT cell lines. Taking a genoproteomic approach and utilizing xenograft models we found the increased level of β-catenin in 2 of 4 cisplatin-resistant (CisR) cell lines (TCam-2 CisR and NCCIT CisR) and the decreased level of β-catenin and cyclin D1 in cisplatin-resistant NTERA-2 CisR cell line. While the effect of treatment with LGK974 was limited or none, the NTERA-2 CisR exhibited the increased sensitivity to PRI-724 in comparison with parental cell line. Furthermore, the pro-apoptotic effect of PRI-724 was documented in all cell lines. Our data strongly suggests that a Wnt/β-catenin signaling is altered in cisplatin-resistant GCT cell lines and the inhibition with PRI-724 is effective in NTERA-2 CisR cells. Further evaluation of Wnt/β-catenin pathway inhibition in GCTs is therefore warranted.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Targeting of Deregulated Wnt/β-Catenin Signaling by PRI-724 and LGK974 Inhibitors in Germ Cell Tumor Cell Lines

Schmidtova

Kalavska

Lišková

et al. 2021

IJMS

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“…ICG‐001 and C‐82 are CBP inhibitors. They are also metabolites of PRI‐724, which is under clinical trials for its antitumor activity, 227 they inhibited fibrosis via Wnt/β‐Catenin signaling, with ICG‐001 showing great efficacy in upregulating apoptosis and inhibiting migration as well as C‐82 showing potent inhibition of proliferation and cell viability 106 …”

Section: Potential New Pharmaceuticals and Their Target‐signaling Pathwaysmentioning

confidence: 99%

Pharmaceuticals targeting signaling pathways of endometriosis as potential new medical treatment: A review

Hung

Zhang

Tan

et al. 2021

Medicinal Research Reviews

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Endometriosis (EM) is defined as endometrial tissues found outside the uterus. Growth and development of endometriotic cells in ectopic sites can be promoted via multiple pathways, including MAPK/MEK/ERK, PI3K/Akt/mTOR, NF‐κB, Rho/ROCK, reactive oxidative stress, tumor necrosis factor, transforming growth factor‐β, Wnt/β‐catenin, vascular endothelial growth factor, estrogen, and cytokines. The underlying pathophysiological mechanisms include proliferation, apoptosis, autophagy, migration, invasion, fibrosis, angiogenesis, oxidative stress, inflammation, and immune escape. Current medical treatments for EM are mainly hormonal and symptomatic, and thus the development of new, effective, and safe pharmaceuticals targeting specific molecular and signaling pathways is needed. Here, we systematically reviewed the literature focused on pharmaceuticals that specifically target the molecular and signaling pathways involved in the pathophysiology of EM. Potential drug targets, their upstream and downstream molecules with key aberrant signaling, and the regulatory mechanisms promoting the growth and development of endometriotic cells and tissues were discussed. Hormonal pharmaceuticals, including melatonin, exerts proapoptotic via regulating matrix metallopeptidase activity while nonhormonal pharmaceutical sorafenib exerts antiproliferative effect via MAPK/ERK pathway and antiangiogenesis activity via VEGF/VEGFR pathway. N‐acetyl cysteine, curcumin, and ginsenoside exert antioxidant and anti‐inflammatory effects via radical scavenging activity. Natural products have high efficacy with minimal side effects; for example, resveratrol and epigallocatechin gallate have multiple targets and provide synergistic efficacy to resolve the complexity of the pathophysiology of EM, showing promising efficacy in treating EM. Although new medical treatments are currently being developed, more detailed pharmacological studies and large sample size clinical trials are needed to confirm the efficacy and safety of these treatments in the near future.

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“…The study demonstrated that PRI-724 significantly reduces cell proliferation of different subtypes of STS cell lines in vitro by downregulating the expression of the WNT target gene CDC25A , which is highly expressed in STS patient samples, thereby inducing cell death or cycle arrest. Most importantly, combination of PRI-724 with standard STS chemotherapeutic drugs, DXR or trabectedin, enhanced their antitumor activity in a synergistic manner, suggesting that this new strategy with PRI-724 could also have a beneficial clinical effect on patients with STS [ 196 ]. These results are a basis for future clinical trials evaluating inhibitors of β-catenin–co-activator interactions in STS patients with an activated Wnt signaling pathway, the latter being a novel selection criterion that could be included when recruiting patients.…”

Section: Targeting Wnt Signaling Pathway In Stsmentioning

confidence: 99%

WNT/β-Catenin Pathway in Soft Tissue Sarcomas: New Therapeutic Opportunities?

Martinez-Font

Pérez-Capó

Vögler

et al. 2021

Cancers

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Soft tissue sarcomas (STS) are a very heterogeneous group of rare tumors, comprising more than 50 different histological subtypes that originate from mesenchymal tissue. Despite their heterogeneity, chemotherapy based on doxorubicin (DXR) has been in use for forty years now and remains the standard first-line treatment for locally advanced unresectable or metastatic STS, although overall survival could not be improved by combination with other chemotherapeutics. In this sense, the development of new therapeutic approaches continues to be a largely unmatched goal. The WNT/β-catenin signaling pathway is involved in various fundamental processes for embryogenic development, including the proliferation and differentiation of mesenchymal stem cells. Although the role of this pathway has been widely researched in neoplasms of epithelial origin, little is known about its relevance for mesenchymal neoplasms. This review covers the most important molecular alterations of the WNT signaling pathway in STS. The detection of these alterations and the understanding of their functional consequences for those pathways controlling sarcomagenesis development and progression are crucial to broaden the current knowledge about STS as well as to identify novel drug targets. In this regard, the current therapeutic options and drug candidates to modulate WNT signaling, which are usually classified by their interaction site upstream or downstream of β-catenin, and their presumable clinical impact on STS are also discussed.

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Impact of Wnt/β-Catenin Inhibition on Cell Proliferation through CDC25A Downregulation in Soft Tissue Sarcomas

Cited by 17 publications

References 53 publications

Targeting of Deregulated Wnt/β-Catenin Signaling by PRI-724 and LGK974 Inhibitors in Germ Cell Tumor Cell Lines

Targeting of Deregulated Wnt/β-Catenin Signaling by PRI-724 and LGK974 Inhibitors in Germ Cell Tumor Cell Lines

Pharmaceuticals targeting signaling pathways of endometriosis as potential new medical treatment: A review

WNT/β-Catenin Pathway in Soft Tissue Sarcomas: New Therapeutic Opportunities?

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