Magnetic thermoablation stimuli alter BCL2 and FGF-R1 but not HSP70 expression profiles in BT474 breast tumors

Stapf, Marcus; Pömpner, Nadine; Kettering, Melanie; Hilger, Ingrid

doi:10.2147/ijn.s77372

Cited by 8 publications

(9 citation statements)

References 36 publications

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“…Although this finding was in accordance with an earlier publication analyzing the HSP70 expression at 2 h after the short-term application of magnetic heating, this study demonstrated the persistence of HSP70 levels up to 48 h. 17 Due to its chaperon function, HSP70 was reported to be upregulated upon cellular stress as caused by heat or toxic stimuli. 68,69 Therefore, the instant elevation of HSP70 in the MTX/MNP group and the time-dependent upregulation in the MNP group were hypothesized to be based on the application of MTX/MNPs or MNPs which probably were recognized as toxic stimuli.…”

Section: Impairment Of Cellular Survival Signalingsupporting

confidence: 92%

“…15,16 These high temperatures cause necrosis even after a relatively short time of thermal exposure, by inducing irreversible cellular damage, such as the inhibition of DNA repair, and protein denaturation. 17 To further amplify the effect of magnetic heating alone, a combinatory treatment of the target tissue by an additional coupling of drugs (eg, chemotherapeutics) to the MNPs is possible. 18 In this regard, the chemotherapeutic drug methotrexate (MTX), an antifolate which interferes with the cellular nucleotide metabolism and DNA synthesis, was shown to be coupled stably to MNPs (MTX/MNPs) and exhibited a comparable toxicity to free MTX.…”

Section: Introductionmentioning

confidence: 99%

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Methotrexate-coupled nanoparticles and magnetic nanochemothermia for the relapse-free treatment of T24 bladder tumors

Stapf

Teichgräber

Hilger

2017

IJN

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Heat-based approaches have been considered as promising tools due to their ability to directly eradicate tumor cells and/or increase the sensitivity of tumors to radiation- or chemotherapy. In particular, the heating of magnetic nanoparticles (MNPs) via an alternating magnetic field can provide a handy alternative for a localized tumor treatment. To amplify the efficacy of magnetically induced thermal treatments, we elucidated the superior tumor-destructive effect of methotrexate-coupled MNPs (MTX/MNPs) in combination with magnetic heating (nanochemothermia) over the thermal treatment alone. Our studies in a murine bladder xenograft model revealed the enormous potential of nanochemothermia for a localized and relapse-free destruction of tumors which was superior to the thermal treatment alone. Nanochemothermia remarkably fostered the reduction of tumor volume. It impaired proapoptotic signaling (eg, p-p53), cell survival (eg, p-ERK1/2), and cell cycle (cyclins) pathways. Additionally, heat shock proteins (eg, HSP70) were remarkably affected. Moreover, nanochemothermia impaired the induction of angiogenic signaling by decreasing, for example, the levels of VEGF-R1 and MMP9, although an increasing tumor hypoxia was indicated by elevated Hif-1α levels. In contrast, tumor cells were able to recover after the thermal treatments alone. In conclusion, nanochemothermia on the basis of MTX/MNPs was superior to the thermal treatment due to a modification of cellular pathways, particularly those associated with the cellular survival and tumor vasculature. This allowed very efficient and relapse-free destruction of tumors.

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Section: Impairment Of Cellular Survival Signalingsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Methotrexate-coupled nanoparticles and magnetic nanochemothermia for the relapse-free treatment of T24 bladder tumors

Stapf

Teichgräber

Hilger

2017

IJN

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“…[3][4][5][6][7] Moreover, MNP can be heated in an alternating magnetic field, allowing a localized sensitization or destruction of tumor cells or tumor tissue by hyperthermal or even thermoablative temperatures. [8][9][10][11] For magnetic heating purposes, iron oxide MNP with a clustered magnetite or maghemite core and an appropriate coating (polyethylene glycol [PEG], dextran, dimercaptosuccinic acid [DMSA], etc) have been shown to exhibit good heating capabilities and biocompatibility. 10,[12][13][14][15][16] One chemotherapeutic drug that can effectively be coupled to MNP is methotrexate (MTX).…”

Section: Introductionmentioning

confidence: 99%

Heterogeneous response of different tumor cell lines to methotrexate-coupled nanoparticles in presence of hyperthermia

Stapf¹,

Pömpner²,

Teichgräber³

et al. 2016

IJN

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Today, the therapeutic efficacy of cancer is restricted by the heterogeneity of the response of tumor cells to chemotherapeutic drugs. Since those therapies are also associated with severe side effects in nontarget organs, the application of drugs in combination with nanocarriers for targeted therapy has been suggested. Here, we sought to assess whether the coupling of methotrexate (MTX) to magnetic nanoparticles (MNP) could serve as a valuable tool to circumvent the heterogeneity of tumor cell response to MTX by the combined treatment with hyperthermia. To this end, we investigated five breast cancer cell lines of different origin and with different mutational statuses, as well as a bladder cancer cell line in terms of their response to exposure to MTX as a free drug or after its coupling to MNP as well as in presence/absence of hyperthermia. We also assessed whether the effects could be connected to the cell line-specific expression of proteins related to the uptake and efflux of MTX and MNP. Our results revealed a very heterogeneous and cell line-dependent response to an exposure with MTX-coupled MNP (MTX–MNP), which was almost comparable to the efficacy of free MTX in the same cell line. Moreover, a cell line-specific and preferential uptake of MTX–MNP compared with MNP alone was found (probably by receptor-mediated endocytosis), agreeing with the observed cytotoxic effects. Opposed to this, the expression pattern of several cell membrane transport proteins noted for MTX uptake and efflux was only by tendency in agreement with the cellular toxicity of MTX–MNP in different cell lines. Higher cytotoxic effects were achieved by exposing cells to a combination of MTX–MNP and hyperthermal treatment, compared with MTX or thermo-therapy alone. However, the heterogeneity in the response of the tumor cell lines to MTX could not be completely abolished – even after its combination with MNP and/or hyperthermia – and the application of higher thermal dosages might be necessary.

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“…In our recent study, immunohistochemical analysis of tumor tissue slices revealed a distinct downregulation of BCL2 and FGF-R1 on the protein level, whereas the HSP70 level remained unchanged. At the same time, tumor tissue exhibited large apoptotic and necrotic areas in regions with high MNP concentration [33]. Importantly, multidrug resistance-associated proteins (MRPs) are known to be responsible for many therapeutic failures in current oncological treatments.…”

Section: Impact Of Magnetic Heating Of Cells and Tissuesmentioning

confidence: 99%

Means to increase the therapeutic efficiency of magnetic heating of tumors

Kettering

Grau

Pömpner

et al. 2015

Biomedical Engineering / Biomedizinische Technik

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Abstract:The treatment of tumors via hyperthermia has gained increased attention in the last years. Among the different modalities available so far, magnetic hyperthermia has the particular advantage of offering the possibility of depositing the heating source directly into the tumor. In this study, we summarized the present knowledge we gained on how to improve the therapeutic efficiency of magnetic hyperthermia using magnetic nanoparticles (MNPs), with particular consideration of the intratumoral infiltration of the magnetic material. We found that (1) MNPs will be mainly immobilized at the tumor area and that this aspect has to be considered when estimating the heating potential of MNPs, (2) the intratumoral distribution patterns via slow infiltration might well be modulated by specific MNP coating and magnetic targeting, (3) imaging of the nanoparticle depositions within the tumor might allow to correct the distribution pattern via multiple applications, (4) multiple therapeutic sessions are feasible because MNPs are not delivered from the tumor site during the heating process, (5) the utilization of MNPs that internalize into cells will favor the production of intracellular heating spots rather than extracellular ones, (6) utilization of MNPs functionalized with chemotherapeutic agents will allow us to exploit the additive effects of both therapeutic modalities, and (7) distinct cytopathological and histopathological alterations in target tissues are induced as a result of magnetic hyperthermia. However, the accumulation at the tumor via intravenous application remains a matter of challenge.

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Magnetic thermoablation stimuli alter BCL2 and FGF-R1 but not HSP70 expression profiles in BT474 breast tumors

Cited by 8 publications

References 36 publications

Methotrexate-coupled nanoparticles and magnetic nanochemothermia for the relapse-free treatment of T24 bladder tumors

Methotrexate-coupled nanoparticles and magnetic nanochemothermia for the relapse-free treatment of T24 bladder tumors

Heterogeneous response of different tumor cell lines to methotrexate-coupled nanoparticles in presence of hyperthermia

Means to increase the therapeutic efficiency of magnetic heating of tumors

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