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

Stapf, Marcus; Pömpner, Nadine; Teichgräber, Ulf; Hilger, Ingrid

doi:10.2147/ijn.s94384

Cited by 20 publications

(21 citation statements)

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“…20 In combination with the observed high internalization of MTX/MNPs, these results point out the suitability of MTX/ MNPs for a tumor-localized nanochemothermal treatment with a low MTX diffusion after intratumoral MTX/MNP application, resulting in a minimization of cellular adaptability toward emerging cellular stress. For a systemic application, ~500 mg/m 2 MTX is administered intravenously.…”

Section: Discussionmentioning

confidence: 64%

“…Hence, we hypothesized that the MTX-dependent internalization can well be attributed to a receptor-mediated endocytosis by folate receptors, because T24 cells were reported to exhibit a high expression of these MTX-internalizing receptors due to their high metabolic and proliferative activity. 20 As the uptake of native MNPs was negligible in comparison to the internalization of MTX/ MNPs, it is reasonable that the measured iron content in the MTX/MNP group must be related to an internalization of MTX/MNPs rather than to the native MNPs.…”

Section: Discussionmentioning

confidence: 98%

“…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. 19,20 This combinatory "nanochemothermal" approach is thought to allow a more efficient treatment of tumors, as the MNPs, and therefore the MTX, will remain in the tumor region over several days, allowing a repeated thermal, and a constant chemotherapeutic treatment, which is localized to the tumor region. 20,21 Moreover, the utilization of magnetic heating in combination with MTX/MNPs has the ability to interfere with multiple phases of the cell cycle.…”

Section: Introductionmentioning

confidence: 99%

“…19,20 This combinatory "nanochemothermal" approach is thought to allow a more efficient treatment of tumors, as the MNPs, and therefore the MTX, will remain in the tumor region over several days, allowing a repeated thermal, and a constant chemotherapeutic treatment, which is localized to the tumor region. 20,21 Moreover, the utilization of magnetic heating in combination with MTX/MNPs has the ability to interfere with multiple phases of the cell cycle. In particular, heat-based treatments are reported to interfere mostly with later phases of the cell cycle (eg, S or M phase), whereas MTX acts in earlier phases, such as at G1/S transition.…”

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: Discussionmentioning

confidence: 64%

Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Stapf

Teichgräber

Hilger

2017

IJN

Self Cite

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“…DHFR was amplified in a small portion of cells, given that tumor cells responded heterogeneously to MTX. Regardless, the effects of the drug would be dissimilar, even if the cells were grown in the same conditions 50, 51 . This could lead to bioinformatics difficulties in finding accurate amplified patterns and repetitive sequences in previous as well as future studies.…”

Section: Discussionmentioning

confidence: 99%

Genomic and transcriptomic analyses reveal a tandem amplification unit of 11 genes and mutations of mismatch repair genes in methotrexate-resistant HT-29 cells

Kim

Shin

Seo

2020

Preprint

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DHFR gene amplification is present in methotrexate (MTX)-resistant colon cancer cells and acute lymphoblastic leukemia. However, little is known about DHFR gene amplification due to difficulties in quantifying amplification size and recognizing the repetitive rearrangements involved in the process. In this study, we have proposed an integrative framework to characterize the amplified region by using a combination of single-molecule real time sequencing, next-generation optical mapping, and chromosome conformation capture (Hi-C). Amplification of the DHFR gene was optimized to generate homogenously amplified patterns. The amplification units of 11 genes, from the DHFR gene to the ATP6AP1L gene position on chromosome 5 (~2.2Mbp), and a twenty-fold tandemly amplified region were verified using longrange genome and RNA sequencing data. In doing so, a novel inversion at the start and end positions of the amplified region as well as frameshift insertions in most of the MSH and MLH genes were detected. These might stimulate chromosomal breakage and cause the dysregulation of mismatch repair pathways. Using Hi-C technology, high adjusted interaction frequencies were detected on the amplified unit and unsuspected position on 5q, which could have a complex network of spatial contacts to harbor gene amplification. Characterizing the tandem gene-amplified unit and genomic variants as well as chromosomal interactions on intra-chromosome 5 can be critical in identifying the mechanisms behind genomic rearrangements. These findings may give new insight into the mechanisms underlying the amplification process and evolution of drug resistance. Results Determination of MTX-resistant HT-29 cellsWhile generating MTX-resistant HT-29 cells (selected clone: C1-2) from singe-cell selection and MTX sensitization as previously described 15 , dramatic morphological changes in the cells themselves were detected in the form of rounded and circular shapes at the 1 st cycle of sensitization as well as rod and irregular shapes at the 2 nd cycle (Supplementary Fig. 1). The original shapes were again observed at the 3 rd cycle of sensitization, which might indicate that the HT-29 cells were becoming resistant to MTX and rapidly grew up under high MTX concentration.As expected, DHFR expression, which was normalized by the B2M housekeeping gene, was steadily increased from the 1 st to 3 rd cycle, as the HT-29 clones became resistant to MTX (Supplementary Fig. 2a). After confirming these morphological changes and increased DHFR expression, the DHFR copy number was measured in several clones.The clones' cycle quantification values (Ct) were used to compute the rate of copy number. These values dropped from 26.04 to 19.99, as the number of cycles increased ( Supplementary Table 1). Interestingly, there was a dramatic increase in the DHFR copy number between the 1 st (0.97 copies) and 2 nd (54.83 copies) cycles ( Supplementary Fig. 2b).Based on these results, we ascertained that a specific time period and set of conditions were required for clones to su...

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(Nano)platforms in bladder cancer therapy: Challenges and opportunities

Ashrafizadeh

Zarrabi

Karimi‐Maleh

et al. 2022

Bioengineering & Transla Med

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Urological cancers are among the most common malignancies around the world. In particular, bladder cancer severely threatens human health due to its aggressive and heterogeneous nature. Various therapeutic modalities have been considered for the treatment of bladder cancer although its prognosis remains unfavorable. It is perceived that treatment of bladder cancer depends on an interdisciplinary approach combining biology and engineering. The nanotechnological approaches have been introduced in the treatment of various cancers, especially bladder cancer. The current review aims to emphasize and highlight possible applications of nanomedicine in eradication of bladder tumor. Nanoparticles can improve efficacy of drugs in bladder cancer therapy through elevating their bioavailability. The potential of genetic tools such as siRNA and miRNA in gene expression regulation can be boosted using nanostructures by facilitating their internalization and accumulation at tumor sites and cells. Nanoparticles can provide photodynamic and photothermal therapy for ROS overgeneration and hyperthermia, respectively, in the suppression of bladder cancer. Furthermore, remodeling of tumor microenvironment and infiltration of immune cells for the purpose of immunotherapy are achieved through cargo‐loaded nanocarriers. Nanocarriers are mainly internalized in bladder tumor cells by endocytosis, and proper design of smart nanoparticles such as pH‐, redox‐, and light‐responsive nanocarriers is of importance for targeted tumor therapy. Bladder cancer biomarkers can be detected using nanoparticles for timely diagnosis of patients. Based on their accumulation at the tumor site, they can be employed for tumor imaging. The clinical translation and challenges are also covered in current review.

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

Cited by 20 publications

References 57 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

Genomic and transcriptomic analyses reveal a tandem amplification unit of 11 genes and mutations of mismatch repair genes in methotrexate-resistant HT-29 cells

(Nano)platforms in bladder cancer therapy: Challenges and opportunities

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