Hyperthermia enhances bortezomib-induced apoptosis in human white blood cancer cells

Saliev, Timur; Feril, Loreto B.; Begimbetova, Dinara; Baiskhanova, Dinara; Klodzinskyi, Anton; Bobrova, Xeniya; Aipov, Rassulbek; Baltabayeva, Tolkyn; Tachibana, Katsuro

doi:10.1016/j.jtherbio.2017.04.009

Cited by 10 publications

(3 citation statements)

References 27 publications

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“…Not surprisingly, promoting protein unfolding in myeloma cell lines with increased temperatures (even by only 2°C) and inhibiting degradation with BTZ synergistically triggered PARP cleavage and apoptosis. Although heat shock and BTZ were also reported to have additive toxicities in certain nonmyeloma cells (45)(46)(47), the synergistic killing was much more pronounced for the five myeloma lines (Fig. 4B) than for the seven nonmyeloma lines studied here (SI Appendix, Fig.…”

Section: Discussionmentioning

confidence: 75%

Multiple myeloma cells are exceptionally sensitive to heat shock, which overwhelms their proteostasis network and induces apoptosis

Sha

Goldberg

2020

Proc. Natl. Acad. Sci. U.S.A.

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Proteasome inhibitors, such as bortezomib (BTZ), are highly effective and widely used treatments for multiple myeloma. One proposed reason for myeloma cells’ exceptional sensitivity to proteasome inhibition is that they produce and continually degrade unusually large amounts of abnormal immunoglobulins. We, therefore, hypothesized that, heat shock may also be especially toxic to myeloma cells by causing protein unfolding, increasing further the substrate load on proteasomes, and, thus, putting further stress on their capacity for protein homeostasis. After a shift from 37 to 43 °C, all four myeloma lines studied underwent extensive apoptosis in 4 h, unlike 13 nonmyeloma cell lines, even though the myeloma cells induced heat-shock proteins and increased protein degradation similar to other cells. Furthermore, two myeloma lines resistant to proteasome inhibitors were also more resistant to 43 °C. Shifting myeloma cells to 43, 41, or 39 °C (which was not cytotoxic) dramatically increased their killing by proteasome inhibitors and inhibitors of ubiquitination or p97/VCP. Combining increased temperature with BTZ increased the accumulation of misfolded proteins and substrate load on the 26S proteasome. The apoptosis seen at 43 °C and at 39 °C with BTZ was mediated by caspase-9 and was linked to an accumulation of the proapoptotic Bcl-2-family member Noxa. Thus, myeloma cells are exceptionally sensitive to increased temperatures, which greatly increase substrate load on the ubiquitin-proteasome system and eventually activate the intrinsic apoptotic pathway. Consequently, for myeloma, mild hyperthermia may be a beneficial approach to enhance the therapeutic efficacy of proteasome inhibitors.

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Section: Discussionmentioning

confidence: 75%

Multiple myeloma cells are exceptionally sensitive to heat shock, which overwhelms their proteostasis network and induces apoptosis

Sha

Goldberg

2020

Proc. Natl. Acad. Sci. U.S.A.

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“…The PLGA-Fe 3 O 4 -IBUP solutions, obtained by dispersing ~14 mg of lyophilized microspheres in deionized water, were introduced into the Dewar vial and subjected to three magnetic fields, with powers representing 60%, 80%, and 100% from the maximum output power. The temperature evolution of each sample was recorded up to 50 °C (slightly above the 42–45 °C temperature range associated with the occurrence of apoptosis and necrosis of cancer cells) [49,86,87] by using an optical fiber supplied with a TS4 sensor (precision ± 0.2 °C) from Optocon (Dresden, Germany) connected to a PC. In all experiments, deionized water was used as blank specimen.…”

Section: Methodsmentioning

confidence: 99%

Nanomagnetite-embedded PLGA Spheres for Multipurpose Medical Applications

et al. 2019

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We report on the synthesis and evaluation of biopolymeric spheres of poly(lactide-co-glycolide) containing different amounts of magnetite nanoparticles and Ibuprofen (PLGA-Fe3O4-IBUP), but also chitosan (PLGA-CS-Fe3O4-IBUP), to be considered as drug delivery systems. Besides morphological, structural, and compositional characterizations, the PLGA-Fe3O4-IBUP composite microspheres were subjected to drug release studies, performed both under biomimetically-simulated dynamic conditions and under external radiofrequency magnetic fields. The experimental data resulted by performing the drug release studies evidenced that PLGA-Fe3O4-IBUP microspheres with the lowest contents of Fe3O4 nanoparticles are optimal candidates for triggered drug release under external stimulation related to hyperthermia effect. The as-selected microspheres and their chitosan-containing counterparts were biologically assessed on macrophage cultures, being evaluated as biocompatible and bioactive materials that are able to promote cellular adhesion and proliferation. The composite biopolymeric spheres resulted in inhibited microbial growth and biofilm formation, as assessed against Staphylococcus aureus, Pseudomonas aeruginosa, and Candida albicans microbial strains. Significantly improved antimicrobial effects were reported in the case of chitosan-containing biomaterials, regardless of the microorganisms’ type. The nanostructured composite biopolymeric spheres evidenced proper characteristics as prolonged and controlled drug release platforms for multipurpose biomedical applications.

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“…Superparamagnetic iron oxide nanoparticles (SPIONs) are well known to display magnetization only when a magnetic field is applied. , Moreover, they can generate heat upon application of a local high frequency alternating magnetic field (HAMF). ,− This is particularly interesting when considering cancer therapy since cancer cells hardly survive heating to 45 °C. − Indeed, over 42 °C, the natural enzymatic processes ensuring the cells to be alive are destroyed, and the cancer cells become very sensitive to temperature. , With regard to the magnetic hyperthermia properties, the development of SPIONs for cancer therapy using magnetic hyperthermia is an increasing research field. Furthermore, the use of these nano-objects is also envisioned for imaging and theranostics.…”

Section: Introductionmentioning

confidence: 99%

Doxorubicin-Loaded Thermoresponsive Superparamagnetic Nanocarriers for Controlled Drug Delivery and Magnetic Hyperthermia Applications

Ferjaoui

Dine

Kulmukhamedova

et al. 2019

ACS Appl. Mater. Interfaces

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This study reports on the development of thermoresponsive core/shell magnetic nanoparticles (MNPs) based on an iron oxide core and a thermoresponsive copolymer shell composed of 2-(2-methoxy)ethyl methacrylate (MEO2MA) and oligo(ethylene glycol)methacrylate (OEGMA) moieties. These smart nano-objects combine the magnetic properties of the core and the drug carrier properties of the polymeric shell. Loading the anticancer drug doxorubicin (DOX) in the thermoresponsive MNPs via supramolecular interactions provides advanced features to the delivery of DOX with spatial and temporal controls. The so coated iron oxide MNPs exhibit superparamagnetic behavior with a saturation magnetization of around 30 emu g–1. Drug release experiments confirmed that only a small amount of DOX was released at room temperature, while almost 100% drug release was achieved after 52 h at 42 °C with Fe3−δO4@P(MEO2MA60OEGMA40), which grafted polymer chains displaying a low critical solution temperature of 41 °C. Moreover, the MNPs exhibit magnetic hyperthermia properties as shown by specific absorption rate measurements. Finally, the cytotoxicity of the core/shell MNPs toward human ovary cancer SKOV-3 cells was tested. The results showed that the polymer-capped MNPs exhibited almost no toxicity at concentrations up to 12 μg mL–1, whereas when loaded with DOX, an increase in cytotoxicity and a decrease of SKOV-3 cell viability were observed. From these results, we conclude that these smart superparamagnetic nanocarriers with stealth properties are able to deliver drugs to tumor and are promising for applications in multimodal cancer therapy.

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Hyperthermia enhances bortezomib-induced apoptosis in human white blood cancer cells

Cited by 10 publications

References 27 publications

Multiple myeloma cells are exceptionally sensitive to heat shock, which overwhelms their proteostasis network and induces apoptosis

Multiple myeloma cells are exceptionally sensitive to heat shock, which overwhelms their proteostasis network and induces apoptosis

Nanomagnetite-embedded PLGA Spheres for Multipurpose Medical Applications

Doxorubicin-Loaded Thermoresponsive Superparamagnetic Nanocarriers for Controlled Drug Delivery and Magnetic Hyperthermia Applications

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