Probing for chemotherapy-induced peripheral neuropathy in live dorsal root ganglion neurons with atomic force microscopy

Au, Ngan Pan Bennett; Fang, Yuqiang; Xi, Ning; Lai, King Wai Chiu; Eddie, Chi Him

doi:10.1016/j.nano.2014.03.002

Cited by 29 publications

(33 citation statements)

References 47 publications

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“…In vitro studies show that paclitaxel nearly doubles the compressive modulus of DRG cell bodies (Au, Fang et al,2014), at a much lower dose than that used in this 13 study. Paclitaxel additionally modifies the tensile response of cultured DRG axons (Dennerll, Lamoureux et al,1989), and may increase tensile axonal stiffness, though this observation was not discussed by the authors and only reflected a single sample in each group (figures 4 and 11 in (Dennerll, Lamoureux et al,1989)).…”

Section: Mechanical Properties Of Paclitaxel-treated Sensory Nervesmentioning

confidence: 57%

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Paclitaxel alters sensory nerve biomechanical properties

Bober

Shah

2015

Journal of Biomechanics

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Paclitaxel is an effective chemotherapeutic that, despite its common use, frequently causes debilitating peripheral sensory neuropathy. Paclitaxel binds to and stabilizes microtubules, and through unknown mechanisms, causes abnormal microtubule aggregation. Given that microtubules contribute to the mechanical properties of cells, we tested the hypothesis that paclitaxel treatment would alter the stiffness of sensory nerves. Rat sural nerves were excised and soaked in Ringer's solution with or without paclitaxel. Nerves were secured between a force transducer and actuator, and linearly strained. Stress-strain curves were generated, from which elastic moduli were calculated. Paclitaxel treated nerves exhibited significantly higher moduli in both linear and transition regions of the curve. A composite-tissue model was then generated to estimate the stiffness increase in the cellular fraction of the nerve following paclitaxel treatment. This model was supported experimentally by data on mechanical properties of sural nerves stripped of their epineurium, and area fractions of the cellular and connective tissue components of the rat sural nerve, calculated from immunohistochemical images. Model results revealed that the cellular components of the nerve must stiffen 12x to 115x, depending on the initial axonal modulus assumed, in order to achieve the observed tissue level mechanical changes. Consistent with such an increase, electron microscopy showed increased microtubule aggregation and cytoskeletal packing, suggestive of a more cross-linked cytoskeleton. Overall, our data suggests that paclitaxel treatment induces increased microtubule bundling in axons, which leads to alterations in tissue-level mechanical properties.

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Section: Mechanical Properties Of Paclitaxel-treated Sensory Nervesmentioning

confidence: 57%

“…For example, a recent study demonstrated, using atomic force microscopy, that paclitaxel increases the compressive modulus of cell bodies in cultured dorsal root ganglia (Au et al,2014). Paclitaxel also alters the response of central neurons to damage during high strain-rate loading (TangSchomer et al,2010).…”

Section: Introductionmentioning

confidence: 99%

Paclitaxel alters sensory nerve biomechanical properties

Bober

Shah

2015

Journal of Biomechanics

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“…The capacity of CD44 to bind to a ligand can depend on intracellular interactions with 1 Cells contain cytoskeletal networks that not only regulate cell morphology but also define the cellular mechanical properties of the cell and participate in the transduction of signals from various surface receptors to the cell nucleus. 22,[30][31][32] Thus, these results indicate that DTIC disrupts the local linkage of CD44 to the cytoskeleton, which may influence the interactions of the CD44 ligand-receptor.…”

mentioning

confidence: 80%

Effect of dacarbazine on CD44 in live melanoma cells as measured by atomic force microscopy-based nanoscopy

Huang

Zhang

et al. 2017

IJN

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CD44 ligand–receptor interactions are known to be involved in regulating cell migration and tumor cell metastasis. High expression levels of CD44 correlate with a poor prognosis of melanoma patients. In order to understand not only the mechanistic basis for dacarbazine (DTIC)-based melanoma treatment but also the reason for the poor prognosis of melanoma patients treated with DTIC, dynamic force spectroscopy was used to structurally map single native CD44-coupled receptors on the surface of melanoma cells. The effect of DTIC treatment was quantified by the dynamic binding strength and the ligand-binding free-energy landscape. The results demonstrated no obvious effect of DTIC on the unbinding force between CD44 ligand and its receptor, even when the CD44 nanodomains were reduced significantly. However, DTIC did perturb the kinetic and thermodynamic interactions of the CD44 ligand–receptor, with a resultant greater dissociation rate, lower affinity, lower binding free energy, and a narrower energy valley for the free-energy landscape. For cells treated with 25 and 75 μg/mL DTIC for 24 hours, the dissociation constant for CD44 increased 9- and 70-fold, respectively. The CD44 ligand binding free energy decreased from 9.94 for untreated cells to 8.65 and 7.39 kcal/mol for DTIC-treated cells, which indicated that the CD44 ligand–receptor complexes on DTIC-treated melanoma cells were less stable than on untreated cells. However, affinity remained in the micromolar range, rather than the millimolar range associated with nonaffinity ligands. Hence, the CD44 receptor could still be activated, resulting in intracellular signaling that could trigger a cellular response. These results demonstrate DTIC perturbs, but not completely inhibits, the binding of CD44 ligand to membrane receptors, suggesting a basis for the poor prognosis associated with DTIC treatment of melanoma. Overall, atomic force microscopy-based nanoscopic methods offer thermodynamic and kinetic insight into the effect of DTIC on the CD44 ligand-binding process.

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“…(2) Root-mean-squared roughness, defined as [4,49]. In optical image-based measurement, because the pixel numbers could be several hundreds to thousands in a field of view, one may also use the standard deviation of the heights measured at all pixels as the membrane roughness [45].…”

Section: Monitoring the Membrane Responses To External Stimulationsmentioning

confidence: 99%

Mechanoprofiling on membranes of living cells with atomic force microscopy and optical nano-profilometry

Lee

Wang

Lee

2017

Advances in Physics: X

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Membrane topography of living cells has been considered as an effective parameter that reflects cellular statuses. With the improvements in spatial and temporal resolutions of various measurement techniques, the changes of membrane topography in response to various external stimulations in the culture environments can be accurately recorded. Membrane roughness is a useful parameter to evaluate the changes in membrane topography. At present, atomic force microscopy (AFM) is the most common technique to measure the membrane topography and roughness of living cells. On the other hand, with the non-contact profiling capability, many optical techniques are also employed in this field of research. This review briefly introduces the evolution and applications of AFM on measuring membrane roughness. Meanwhile, quantifying the cell membrane topography and roughness with a non-scanning, non-contact, and label-free optical technique, non-interferometric wide-field optical profilometry (NIWOP), is also presented.

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Probing for chemotherapy-induced peripheral neuropathy in live dorsal root ganglion neurons with atomic force microscopy

Cited by 29 publications

References 47 publications

Paclitaxel alters sensory nerve biomechanical properties

Paclitaxel alters sensory nerve biomechanical properties

Effect of dacarbazine on CD44 in live melanoma cells as measured by atomic force microscopy-based nanoscopy

Mechanoprofiling on membranes of living cells with atomic force microscopy and optical nano-profilometry

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