Coupling to a cancer-selective heparan-sulfate-targeted branched peptide can by-pass breast cancer cell resistance to methotrexate

Depau, Lorenzo; Brunetti, Jlenia; Falciani, Chiara; Scali, Silvia; Riolo, Giulia; Mandarini, Elisabetta; Pini, Alessandro; Bracci, Luisa

doi:10.18632/oncotarget.19056

Cited by 22 publications

(20 citation statements)

References 39 publications

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“…Osteosarcoma resistance to methotrexate can be originated by different adaptive molecular mechanisms, including modifications of drug targets, metabolic pathways, drug influx / efflux, and activation of savage pathways. Multi-drug resistance (MDR) is normally a consequence of overexpression of membrane-active transporters responsible for drug extrusion out of the cell[ 35 ]. Methotrexate is not able to passively cross cell membranes, needing specific transporters for cell internalization.…”

Section: Discussionmentioning

confidence: 99%

Patient-derived osteosarcoma cells are resistant to methotrexate

et al. 2017

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Osteosarcoma is the most common primary bone tumor in children and young adults. The median survival of osteosarcoma patients has not significantly improved since 1990, despite administration of different classes of chemotherapy agents, such as methotrexate, cisplatin and doxorubicin. Cancer stem cells (CSCs) are responsible for the resistance of osteosarcoma to chemotherapy and OCT4, SOX2 and SSEA4 have been used to identify CSCs in osteosarcoma. Here, we used low-passage patient-derived osteosarcoma cells and osteosarcoma cells directly isolated from patients before and after chemotherapy treatments to evaluate the effects of chemotherapy on stem cell markers expression. We demonstrate that primary osteosarcoma cells are resistant to methotrexate treatment and sensitive to cisplatin and doxorubicin in vitro. We also verified that cisplatin and doxorubicin reduce the expression of SOX2 and OCT4 in primary osteosarcoma cells whereas methotrexate does not alter SOX2 and OCT4 expression, however it increases SSEA4 expression in primary osteosarcoma cells. Finally, we found that, although the combination treatment cisplatin plus doxorubicin inhibited the in vivo growth of osteosarcoma cells in NOD-SCID gamma mice subcutaneously injected with SaOs2, the combination treatment cisplatin plus doxorubicin plus methotrexate did not inhibit the in vivo growth of these cells. These observations may provide an explanation for the poor response of osteosarcomas to chemotherapy and point to the need of reevaluating the therapeutic strategies for human osteosarcomas.

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Section: Discussionmentioning

confidence: 99%

Patient-derived osteosarcoma cells are resistant to methotrexate

et al. 2017

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“…These peptides’ chemical structure allows coupling with various functional units utilized in cancer therapy. Noteworthy, peptides bearing methotrexate were found to by-pass the obtained, by breast cancer cells, resistance to the drug ( 75 ). The HSPG glypican-2 was recently shown to be highly expressed in neuroblastoma but not detectable in normal childhood tissues.…”

Section: Pgs As Therapeutic Targets In Cancermentioning

confidence: 99%

Proteoglycans—Biomarkers and Targets in Cancer Therapy

et al. 2018

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Proteoglycans (PGs), important constituents of the extracellular matrix, have been associated with cancer pathogenesis. Their unique structure consisting of a protein core and glycosaminoglycan chains endowed with fine modifications constitutes these molecules as capable cellular effectors important for homeostasis and contributing to disease progression. Indeed, differential expression of PGs and their interacting proteins has been characterized as specific for disease evolvement in various cancer types. Importantly, PGs to a large extent regulate the bioavailability of hormones, growth factors, and cytokines as well as the activation of their respective receptors which regulate phenotypic diversibility, gene expression and rates of recurrence in specific tumor types. Defining and targeting these effectors on an individual patient basis offers ground for the development of newer therapeutic approaches which may act as either supportive or a substitute treatment to the standard therapy protocols. This review discusses the roles of PGs in cancer progression, developing technologies utilized for the defining of the PG “signature” in disease, and how this may facilitate the generation of tailor-made cancer strategies.

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“…Blocked FH4 causes restricted transfer of one-carbon group during the synthesis of glycosides pyrimidine nucleotide and purine nucleon, and inhibits the synthesis of DNA (7). Single-agent MTX, as a chemotherapeutic drug, easily leads to the development of acquired drug resistance, so it is often used in combination with other drugs such as cell cycle inhibitor (8). Pralatrexate (PTX), an upgraded product of methotrexate, is a new anti-folic acid and anti-tumor drug that can effectively inhibit DHFR.…”

Section: Introductionmentioning

confidence: 99%

Clinical efficacy and mechanism of Pralatrexate combined with Palbociclib Isethionate in treatment of bladder cancer patients

Wang

Song

2018

Oncol Lett

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The clinical efficacy and mechanism of Pralatrexate (PTX) combined with Palbociclib Isethionate (PAL) in the treatment of bladder cancer patients was investigated. A retrospective analysis of medical records of 82 bladder cancer patients admitted to Shengjing Hospital of China Medical University from February 2015 to February 2018 was performed. Patients treated with PTX combined with PAL served as study group (42 cases) and patients with conventional GC (gemcitabine plus cisplatin) chemotherapy regimen were the control group (40 cases). Changes in liver function indexes before and after treatment were observed, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and total bilirubin (TBil). RT-qPCR was used for detection of relative expression levels of serum dihydrofolate reductase (DHFR) and vascular endothelial growth factor (VEGF) before and after treatment in the two groups. The clinical efficacy after treatment and adverse reactions during treatment were observed in the two groups. There was no significant difference in the clinical remission rate (RR) nor in the serum ALT, AST, ALP and TBil levels between the study and the control groups (P>0.05). Concentrations of serum ALT, AST, ALP and TBil were significantly higher than those before treatment in both groups (P<0.05). Serum ALT, AST, ALP and TBil concentrations in study group were significantly lower than those in control group (P<0.05). There was no significant difference in the incidence of thrombocytopenia and leukopenia between the two groups (P>0.05). There was no significant difference in relative expression levels of serum DHFR mRNA and VEGF mRNA before treatment between the study and control groups (P>0.05). Those after treatment were significantly lower than those before treatment in both groups (P<0.05), and those after treatment in study group were significantly lower than those in control group (P<0.05). PTX combined with PAL can reduce adverse reactions of nausea and vomiting and liver function impairment during treatment and suppress tumor neovascularization. This is achieved possibly by inhibiting expression levels of DHFR and VEGF, thereby killing cancer cells. PTX combined with PAL may become a new method for the treatment of bladder cancer patients. DHFR and VEGF are expected to become novel therapeutic targets for the treatment of bladder cancer.

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Coupling to a cancer-selective heparan-sulfate-targeted branched peptide can by-pass breast cancer cell resistance to methotrexate

Cited by 22 publications

References 39 publications

Patient-derived osteosarcoma cells are resistant to methotrexate

Patient-derived osteosarcoma cells are resistant to methotrexate

Proteoglycans—Biomarkers and Targets in Cancer Therapy

Clinical efficacy and mechanism of Pralatrexate combined with Palbociclib Isethionate in treatment of bladder cancer patients

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