Pre‐Treatment of human osteosarcoma cells with N‐methylformamide enhances P‐glycoprotein expression and resistance to doxorubicin

Scotlandi, Katia; Serra, Massimo; Manara, Maria Cristina; Lollini, Pier‐Luigi; Maurici, Daniela; Bufalo, Donatella Del; Baldini, Nicola

doi:10.1002/ijc.2910580116

Cited by 15 publications

(11 citation statements)

References 21 publications

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“…Doxorubicin is widely used as a chemotherapeutic agent in the treatment of malignant cancers, including osteosarcoma (37,38). The cytotoxic effects mediated by doxorubicin on malignant cells have been shown to involve: i) DNA base-pair intercalation; ii) the interaction of drug molecules with topoisomerase II to induce the formation of DNA-cleavable complexes; and iii) the interaction of drug molecules with electron transport chain, which may result in the generation of superoxide anion radicals in the cells (39).…”

Section: Discussionmentioning

confidence: 99%

DHFR and MDR1 upregulation is associated with chemoresistance in osteosarcoma stem-like cells

Lee

Yang

et al. 2017

Oncology Letters

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Tumor-initiating cells (TICs) are defined as a specialized subset of cells with tumor-initiating capacity that can initiate tumor growth, tumor relapse and metastasis. In the present study, osteosarcoma TICs (OS-TICs) were isolated and enriched from the osteosarcoma U2OS and MG-63 cell lines using sphere formation assays and serum-depleted media. These enriched OS-TICs showed the expression of several typical cancer stemness markers, including octamer-binding transcription factor 4, Nanog homeobox, cluster of differentiation (CD)117, Nestin and CD133, and the expression of ATP binding cassette subfamily G member 2, multidrug resistance protein 1 (MDR1) and dihydrofolate reductase (DHFR). Notably, in vitro and in vivo tumorigenic properties were enhanced in these OS-TICs. Additionally, methotrexate and doxorubicin are the most widely used anticancer agents against osteosarcoma, and the observed enhanced chemoresistance of OS-TICs to these two agents could be associated with the upregulation of DHFR and MDR1. These findings suggest that the upregulation of DHFR and MDR1 is associated with the development of chemoresistance of OS-TICs.

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Section: Discussionmentioning

confidence: 99%

DHFR and MDR1 upregulation is associated with chemoresistance in osteosarcoma stem-like cells

Lee

Yang

et al. 2017

Oncology Letters

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“…A 585-bp fragment of the plasmid specific for human uPAR kindly provided by Dr. F. Blasi (25), a 717-bp fragment of human Sp1 kindly provided by Dr. R. C. Simmen (26), and a probe for glyceraldehyde-3-phosphate dehydrogenase (27) were used.…”

Section: Cell Lines and Cell Cultures-m14 Human Melanoma Cells Mcf7mentioning

confidence: 99%

bcl-2 Induction of Urokinase Plasminogen Activator Receptor Expression in Human Cancer Cells through Sp1 Activation

Trisciuoglio¹,

Iervolino²,

Candiloro³

et al. 2004

Journal of Biological Chemistry

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We have previously demonstrated that Bcl-2 overexpression in human breast carcinoma and melanoma cells synergizes with hypoxia to increase angiogenesis through up-regulation of vascular endothelial growth factor. In this work we demonstrated, for the first time, that Bcl-2 overexpression in cancer cells exposed to hypoxia modulates urokinase plasminogen activator receptor (uPAR) expression through Sp1 transcription factor and that the extracellular signal-regulated kinase (ERK) pathway plays a role in Sp1 transcriptional activity. In particular, an increase in uPAR protein and mRNA expression was found in melanoma bcl-2 transfectants grown under hypoxia when compared with control cells, and a decrease of uPAR protein expression was induced by treatment of cells with specific bcl-2 antisense oligonucleotides. Up-regulation of uPAR expression was accompanied by increased Sp1 protein expression, stability, serine phosphorylation, and DNA binding activity. Treatment of cells with mitramycin A, an inhibitor of Sp1 activity, confirmed the role of Sp1 transcriptional activity in uPAR induction by Bcl-2. The contribution of the ERK pathway in Sp1-increased transcriptional activity was demonstrated by the use of chemical inhibition. In fact, ERK kinase activation was induced in Bcl-2-overexpressing cells exposed to hypoxia, and the ERK kinase inhibitor UO126 was able to down-regulate Sp1 phosphorylation and DNA binding activity. Using a human breast carcinoma line, we obtained data supporting our findings with melanoma cells and identified a link between the induction of Sp1 and uPAR expression as a common bcl-2-controlled phenomenon in human tumors. In conclusion, our results strongly indicate that up-regulation of uPAR expression by Bcl-2 in hypoxia is modulated by Sp1 DNA binding activity through the ERK signaling pathway.Angiogenesis is a fundamental process required for tumor growth, invasion, and metastasis and is strongly induced by hypoxia. In fact, several cell types including tumor cells, macrophages, and endothelial cells respond to hypoxia by producing angiogenic factors, fibrinolytic factors, and adhesion molecules involved in pathologic angiogenesis (1-5). Four sequential steps can be distinguished during angiogenesis: the degradation of the basement membrane and interstitial matrix, endothelial cell migration, endothelial cell proliferation, and the formation of tubular structures with a lumen and a new basement membrane (6). Three of these steps critically depend on proteolytic activity generated by the matrix metalloproteinases and the plasminogen activator/plasmin system. In particular, the role of urokinase plasminogen activator receptor (uPAR) 1 in tumor cell invasion and migration and in the formation of new microvascular structures has been largely demonstrated (7-9).Angiogenesis is also controlled by alterations in oncogene and tumor suppressor gene expression (10 -14). In this context, we previously demonstrated that the bcl-2 oncogene increases in vitro and in vivo angiogenesis in two different t...

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“…Patients with high-grade OS, the most common primary malignant tumor of bone, are currently treated with multiagent, neoadjuvant chemotherapy regimens, in which doxorubicin (DX) and methotrexate (MTX) are the two most important drugs. Although DX-resistant human OS cell lines have been reported to overexpress P-glycoprotein as a result of an amplification and overexpression of the MDR1 (ABCB1) gene (Serra et al, 1993;Scotlandi et al, 1994Scotlandi et al, , 1996, the mechanisms underlying this amplification are still not known. Amplification and consequent overexpression of MDR1 have been observed in a considerable number of drug-resistant cell lines established from different tumor types (Dean et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of gene amplification and evidence of coamplification in drug‐resistant human osteosarcoma cell lines

Hattinger

Stoico

Michelacci

et al. 2008

Genes Chromosomes & Cancer

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Gene amplification and copy number changes play a pivotal role in malignant transformation and progression of human tumor cells by mediating the activation of genes and oncogenes, which are involved in many different cellular processes including development of drug resistance. Since doxorubicin (DX) and methotrexate (MTX) are the two most important drugs for high-grade osteosarcoma (OS) treatment, the aim of this study was to identify genes gained or amplified in six DX- and eight MTX-resistant variants of the human OS cell lines U-2OS and Saos-2, and to get insights into the mechanisms underlying the amplification processes. Comparative genomic hybridization techniques identified amplification of MDR1 in all six DX-resistant and of DHFR in three MTX-resistant U-2OS variants. In addition, progressive gain of MLL was detected in the four U-2OS variants with higher resistance levels either to DX or MTX, whereas gain of MYC was found in all Saos-2 MTX-resistant variants and the U-2OS variant with the highest resistance level to DX. Fluorescent in situ hybridization revealed that MDR1 was amplified in U-2OS and Saos-2/DX-resistant variants manifested as homogeneously staining regions and double minutes, respectively. In U-2OS/MTX-resistant variants, DHFR was amplified in homogeneously staining regions, and was coamplified with MLL in relation to the increase of resistance to MTX. Gene amplification was associated with gene overexpression, whereas gene gain resulted in up-regulated gene expression. These results indicate that resistance to DX and MTX in human OS cell lines is a multigenic process involving gene copy number and expression changes.

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Pre‐Treatment of human osteosarcoma cells with N‐methylformamide enhances P‐glycoprotein expression and resistance to doxorubicin

Cited by 15 publications

References 21 publications

DHFR and MDR1 upregulation is associated with chemoresistance in osteosarcoma stem-like cells

DHFR and MDR1 upregulation is associated with chemoresistance in osteosarcoma stem-like cells

bcl-2 Induction of Urokinase Plasminogen Activator Receptor Expression in Human Cancer Cells through Sp1 Activation

Mechanisms of gene amplification and evidence of coamplification in drug‐resistant human osteosarcoma cell lines

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