Influence of Reduced Folate Carrier and Dihydrofolate Reductase Genes on Methotrexate-Induced Cytotoxicity

Yoon, Seong Ae; Choi, Jung Ran; Kim, Jeong Oh; Shin, Jung Young; Zhang, Xianghua; Kang, Jin Hyoung

doi:10.4143/crt.2010.42.3.163

Cited by 52 publications

(35 citation statements)

References 21 publications

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“…This is most likely due to the combined effect of the free amines of the polymer at the NP surface and the cytotoxic potential of the surfactant by itself. Finally, although our overall results were in line with a previous report [10] and showed that MCF-7 cells displayed resistance to MTX, we also proved the greater activity of MTX-CS-NPs against this cell line.…”

Section: Discussionsupporting

confidence: 92%

“…This finding could be related to the mechanism of action of MTX. MTX is a potent inhibitor of the enzyme dihydrofolate reductase, which plays a key role in the synthesis of DNA precursors and cell growth [10]. Therefore, MTX is a chemotherapeutic agent that mainly inhibits cell proliferation, which justifies the lack of LDH release to the cell cytosol due to membrane rupture (late stage of cell death).…”

Section: Discussionmentioning

confidence: 99%

“…MTX is currently widely used as a major chemotherapeutic agent for human malignancies such as acute lymphoblastic leukemia, malignant lymphoma, osteosarcoma, breast cancer and head and neck cancer [10]. However, its clinical efficacy is often compromised by the acquisition of resistance in cancer cells, due to cellular efflux of the molecule [11].…”

Section: Introductionmentioning

confidence: 99%

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In vitro antitumor activity of methotrexate via pH-sensitive chitosan nanoparticles

et al. 2013

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Nanoparticles with pH-sensitive behavior may enhance the success of chemotherapy in many cancers by efficient intracellular drug delivery. Here, we investigated the effect of a bioactive surfactant with pH-sensitive properties on the antitumor activity and intracellular behavior of methotrexate-loaded chitosan nanoparticles (MTX-CS-NPs). NPs were prepared using a modified ionotropic complexation process, in which was included the surfactant derived from N α ,N ε -dioctanoyl lysine with an inorganic lithium counterion. The pH-sensitive behavior of NPs allowed accelerated release of MTX in an acidic medium, as well as membrane-lytic pH-dependent activity, which facilitated the cytosolic delivery of endocytosed materials. Moreover, our results clearly proved that MTX-CS-NPs were more active against the tumor HeLa and MCF-7 cell lines than the free drug. The feasibilty of using NPs to target acidic tumor extracellular pH was also shown, as cytotoxicity against cancer cells was greater in a mildly acidic environment. Finally, the combined physicochemical and pH-sensitive properties of NPs generally allowed the entrapped drug to induce greater cell cycle arrest and apoptotic effects. Therefore, our overall results suggest that pH-sensitive MTX-CS-NPs could be potentially useful as a carrier system for tumor and intracellular drug delivery in cancer therapy.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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In vitro antitumor activity of methotrexate via pH-sensitive chitosan nanoparticles

et al. 2013

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“…While DHFR expression in NHFs was also elevated in the presence of MTX, these cells were still impaired by drug treatment. This is not unexpected since DHFR has previously been noted to increase protein expression in MTX-treated osteosarcoma cells, while mRNA expression decreased (Yoon, et al, 2010). Therefore, it is possible that DHFR protein upregulation was an initial response of the cells to the treatment but could not be sustained.…”

Section: Discussionsupporting

confidence: 52%

Adipose-derived stem cells retain their regenerative potential after methotrexate treatment

Beane

Fonseca

Darling

2014

Experimental Cell Research

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In musculoskeletal tissues like bone, chemotherapy can impair progenitor cell differentiation and proliferation, resulting in decreased bone growth and mineralization throughout a patient's lifetime. In the current study, we investigated the effects of chemotherapeutics on adipose-derived stem cell (ASC) function to determine whether this cell source could be a candidate for repairing, or even preventing, chemotherapy-induced tissue damage. Dose-dependent proliferation rates of ASCs and normal human fibroblasts (NHFs) were quantified after treatment with cytarabine (CY), etoposide (ETO), methotrexate (MTX), and vincristine (VIN) using a fluorescence-based assay. The influence of MTX on the multipotency of ASCs and freshly isolated stromal vascular fraction (SVF) cells was also evaluated using lineage-specific stains and spectrophotometry. ASC and NHF proliferation were equally inhibited by exposure to CY and ETO; however, when treated with MTX and VIN, ASCs exhibited greater resistance. This was especially apparent for MTX-treated samples, with ASC proliferation showing no inhibition for clinically relevant MTX doses ranging from 0.1 to 50 M. Additional experiments revealed that the differentiation potential of ASCs was not affected by MTX treatment and that upregulation of dihydrofolate reductase possibly contributed to this response. Moreover, SVF cells, which include ASCs, exhibited similar resistance to MTX impairment, with respect to cellular proliferation, clonogenicity, and differentiation capability. Therefore, we have shown that the regenerative properties of ASCs resist the cytotoxicity of MTX, identifying these cells as a potential key for repairing musculoskeletal damage in patients undergoing chemotherapy.

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“…4,5 Transport of MTX is an essential determinant for generating a sufficient MTX intracellular concentration. 6 The breast cancer cell lines MCF-7 and MDA-MB-231 both demonstrate resistance to MTX, but by distinct mechanisms. MCF-7 cells display an increased dhfr gene copy number, 7 and overexpression of the dhfr gene is an important mechanism of MTX resistance.…”

mentioning

confidence: 99%

Methotrexate diethyl ester-loaded lipid-core nanocapsules in aqueous solution increased antineoplastic effects in resistant breast cancer cell line

Yurgel

Oliveira

Begnini

et al. 2014

IJN

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Breast cancer is the most frequent cancer affecting women. Methotrexate (MTX) is an antimetabolic drug that remains important in the treatment of breast cancer. Its efficacy is compromised by resistance in cancer cells that occurs through a variety of mechanisms. This study evaluated apoptotic cell death and cell cycle arrest induced by an MTX derivative (MTX diethyl ester [MTX(OEt) 2 ]) and MTX(OEt) 2 -loaded lipid-core nanocapsules in two MTX-resistant breast adenocarcinoma cell lines, MCF-7 and MDA-MB-231. The formulations prepared presented adequate granulometric profile. The treatment responses were evaluated through flow cytometry. Relying on the mechanism of resistance, we observed different responses between cell lines. For MCF-7 cells, MTX(OEt) 2 solution and MTX(OEt) 2 -loaded lipid-core nanocapsules presented significantly higher apoptotic rates than untreated cells and cells incubated with unloaded lipid-core nanocapsules. For MDA-MB-231 cells, MTX(OEt) 2 -loaded lipid-core nanocapsules were significantly more efficient in inducing apoptosis than the solution of the free drug. S-phase cell cycle arrest was induced only by MTX(OEt) 2 solution. The drug nanoencapsulation improved apoptosis induction for the cell line that presents MTX resistance by lack of transport receptors.

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Influence of Reduced Folate Carrier and Dihydrofolate Reductase Genes on Methotrexate-Induced Cytotoxicity

Cited by 52 publications

References 21 publications

In vitro antitumor activity of methotrexate via pH-sensitive chitosan nanoparticles

In vitro antitumor activity of methotrexate via pH-sensitive chitosan nanoparticles

Adipose-derived stem cells retain their regenerative potential after methotrexate treatment

Methotrexate diethyl ester-loaded lipid-core nanocapsules in aqueous solution increased antineoplastic effects in resistant breast cancer cell line

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