A galactosidase-responsive doxorubicin-folate conjugate for selective targeting of acute myelogenous leukemia blasts

Clarhaut, Jonathan; Fraineau, Sylvain; Guilhot, Joëlle; Péraudeau, Elodie; Tranoy-Opalinski, Isabelle; Thomas, Mikaël; Renoux, Brigitte; Randriamalala, Edouard; Bois, Patrick; Chatelier, Aurélien; Monvoisin, Arnaud; Cronier, Laurent; Papot, Sébastien; Guilhot, François

doi:10.1016/j.leukres.2013.04.026

Cited by 15 publications

(12 citation statements)

References 39 publications

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“…The folate transporter gene, SLC19A1 , was downregulated, whereas neither FOLR1 nor FOLR3 receptor genes showed concerted expression changes. These results are in agreement with earlier studies that suggested the distinctive role of FOLR2 in the cytotoxicity of folate-targeted doxorubicin [ 100 ]. Additionally, multiple expression changes listed in Table 1 in response to doxorubicin confirm earlier reports that downregulation of MBD2 , MECP2 , and SLC19A1 and upregulation of GADD45 and ALDH2 were a part of an MSigDB molecular signature in mouse cell lines undergoing apoptosis in response to the high concentration (1000 nM) of doxorubicin [ 72 , 98 ].…”

Section: Resultssupporting

confidence: 94%

Concerted changes in transcriptional regulation of genes involved in DNA methylation, demethylation, and folate-mediated one-carbon metabolism pathways in the NCI-60 cancer cell line panel in response to cancer drug treatment

et al. 2016

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BackgroundAberrant patterns of DNA methylation are abundant in cancer, and epigenetic pathways are increasingly being targeted in cancer drug treatment. Genetic components of the folate-mediated one-carbon metabolism pathway can affect DNA methylation and other vital cell functions, including DNA synthesis, amino acid biosynthesis, and cell growth.ResultsWe used a bioinformatics tool, the Transcriptional Pharmacology Workbench, to analyze temporal changes in gene expression among epigenetic regulators of DNA methylation and demethylation, and one-carbon metabolism genes in response to cancer drug treatment. We analyzed gene expression information from the NCI-60 cancer cell line panel after treatment with five antitumor agents, 5-azacytidine, doxorubicin, vorinostat, paclitaxel, and cisplatin. Each antitumor agent elicited concerted changes in gene expression of multiple pathway components across the cell lines. Expression changes of FOLR2, SMUG1, GART, GADD45A, MBD1, MTR, MTHFD1, and CTH were significantly correlated with chemosensitivity to some of the agents. Among many genes with concerted expression response to individual antitumor agents were genes encoding DNA methyltransferases DNMT1, DNMT3A, and DNMT3B, epigenetic and DNA repair factors MGMT, GADD45A, and MBD1, and one-carbon metabolism pathway members MTHFD1, TYMS, DHFR, MTR, MAT2A, SLC19A1, ATIC, and GART.ConclusionsThese transcriptional changes are likely to influence vital cellular functions of DNA methylation and demethylation, cellular growth, DNA biosynthesis, and DNA repair, and some of them may contribute to cytotoxic and apoptotic action of the drugs. This concerted molecular response was observed in a time-dependent manner, which may provide future guidelines for temporal selection of genetic drug targets for combination drug therapy treatment regimens.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-016-0240-3) contains supplementary material, which is available to authorized users.

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Section: Resultssupporting

confidence: 94%

Concerted changes in transcriptional regulation of genes involved in DNA methylation, demethylation, and folate-mediated one-carbon metabolism pathways in the NCI-60 cancer cell line panel in response to cancer drug treatment

et al. 2016

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“…In addition, the surface of liposomes can be modified with ligands for receptors over expressed on cancer cells; hence, active targeting is also possible. Previous studies demonstrated that the folate receptor is highly expressed in cancer cells (5)(6)(7)(8)(9)(10). Therefore, this membrane receptor appears as an attractive target to develop appropriate folate-based drug delivery systems for anticancer therapy.…”

Section: Discussionmentioning

confidence: 99%

“…Several studies have shown that more than 80-90% of ovarian tumors overexpress folic acid receptors (FR) (5,6). In addition, other gynecological cancers as well as pediatric ependymal brain tumors, mesothelioma, and breast, colon, renal, lung tumors, and acute myelogenous leukemia also overexpress FR (7)(8)(9). The total number of tumors that express FR is very large; therefore, FRtargeted strategies could have significant beneficial impact on treatment of several types of cancer (10).…”

Section: Introductionmentioning

confidence: 99%

A Novel Folate-Targeted Nanoliposomal System of Doxorubicin for Cancer Targeting

et al. 2015

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Abstract. Targeted drug delivery systems for cancer improves anti-tumor efficacy and reduces systemic toxicity by restricting availability of cytotoxic drugs within tumors. Targeting moieties, such as natural ligands (folic acid, transferrin, and biotin) which are overexpressed on tumors, have been used to enhance liposome-encapsulated drug accumulation within tumors and resulted in better control. In this report, we explored the scope of targeting ligand folic acid, which is incorporated in liposome systems using folic acidmodified cholesterol (CPF), enabled highly selective tumor-targeted delivery of liposome-encapsulated doxorubicin and resulted in increased cytotoxicity within tumors. Folate-tagged poloxamer-coated liposomes (FDL) were found to have significantly higher cellular uptake than conventional poloxamer-coated liposomes (DL), as confirmed by fluorometric analysis in B16F10 melanoma cells. Biodistribution study of the radiolabeled liposomal system indicated the significantly higher tumor uptake of FDL as compared to DL. Anti-tumor activity of FDL against murine B16F10 melanoma tumor-bearing mice revealed that FDL inhibited tumor growth more efficiently than the DL. Taken together, the results demonstrated the significant potential of the folate-conjugated nanoliposomal system for drug delivery to tumors.

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“…Experimental studies have shown that the blockage of folate receptor ␣ by its monoclonal antibody led to the inhibition of human ovarian tumor cell growth in vitro and in vivo (31), suggesting the critical role of FOLR1 in the maintenance of tumor aggressiveness. However, the role of FOLR1 in the regulation of CSLC phenotypes and function is not clear, although FOLR2 has been found to be overexpressed in acute myeloid leukemia blast cell lines and other hematopoietic progenitor cells (34). Therefore, our triple-marker-positive CSLC model could be a useful model for further investigation with respect to the expression of FOLR1/2 and the cellular consequence of targeting FOLR1/2 in PC.…”

Section: Discussionmentioning

confidence: 97%

Pancreatic Cancer Stem-like Cells Display Aggressive Behavior Mediated via Activation of FoxQ1

Bao¹,

Azmi²,

Aboukameel

et al. 2014

Journal of Biological Chemistry

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A galactosidase-responsive doxorubicin-folate conjugate for selective targeting of acute myelogenous leukemia blasts

Cited by 15 publications

References 39 publications

Concerted changes in transcriptional regulation of genes involved in DNA methylation, demethylation, and folate-mediated one-carbon metabolism pathways in the NCI-60 cancer cell line panel in response to cancer drug treatment

Concerted changes in transcriptional regulation of genes involved in DNA methylation, demethylation, and folate-mediated one-carbon metabolism pathways in the NCI-60 cancer cell line panel in response to cancer drug treatment

A Novel Folate-Targeted Nanoliposomal System of Doxorubicin for Cancer Targeting

Pancreatic Cancer Stem-like Cells Display Aggressive Behavior Mediated via Activation of FoxQ1

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