Endoplasmic-reticulum stress pathway-associated mechanisms of action of proteasome inhibitors in multiple myeloma

Ri, Masaki

doi:10.1007/s12185-016-2016-0

Cited by 79 publications

(89 citation statements)

References 40 publications

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“…It has been reported that CDK5 may touch upon the resistance of MM to proteasome inhibitors, but only the preliminary mechanism has been discussed, which is thought be related to miR-27a-5p or PSMB5 (15,17,29). The correlation between the expression of CDK5 in bone marrow biopsies and the response of MM patients to proteasome inhibitors bortezomib was analyzed.…”

Section: Discussionmentioning

confidence: 99%

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CDK5 inhibition in�vitro and in vivo induces cell death in�myeloma and overcomes the obstacle of bortezomib resistance

Tang

Cen

et al. 2020

Int J Mol Med

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The emergence of new drugs is a major feature of the treatment history of multiple myeloma (MM), which also reflects the current incurability of MM. As a unique member of cyclin dependent kinase (cdK) family, cdK5 participates in numerous tumorigenic or non-tumorigenic processes. The aim of this study is to investigate the effects of cdK5 on the viability of MM cells and bortezomib resistance using western blotting, immunohistochemistry, transient transfection, MTT assays, cell cycle analysis, apoptosis assays and a myeloma xenograft mouse model. The present study found that MM patients with high CDK5 expression in the bone marrow do not respond well to bortezomib, have higher DS stage and worse prognosis. Genetic and pharmacological (dinaciclib) inhibition of CDK5 triggers MM cell viability inhibition. Dinaciclib induces G2/M arrest and apoptosis of MM cells.In vivo experiments with myeloma xenograft mice indicate that dinaciclib significantly reduces the volume of tumors with good tolerance. Dinaciclib combined with bortezomib exerts a synergistic anti-myeloma activity accompanied by inhibiting the activation of the nuclear factor-κB pathway. This study demonstrates the important role of cdK5 in the pathogenesis, viability, prognosis and resistance to bortezomib of MM, laying a solid theoretical foundation for further clinical use of CDK5 inhibitors.

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Section: Discussionmentioning

confidence: 99%

“…At present, the studies on the relationship between CDK5 and cancer are mostly limited to solid tumors. A small quantity of studies have shown that high expression of CDK5 is associated with poor prognosis and bortezomib resistance in MM patients, so further exploration of the specific mechanism is still needed (15)(16)(17).…”

Section: Introductionmentioning

confidence: 99%

CDK5 inhibition in�vitro and in vivo induces cell death in�myeloma and overcomes the obstacle of bortezomib resistance

Tang

Cen

et al. 2020

Int J Mol Med

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“…A growing body of evidence indicates that the accumulation of unfolding/misfolding proteins by the suppression of Hsp90 function assists several stresses, including ER stress overload, the ROS over-generation, and a functional disorder of the intracellular proteins, ultimately leading to ER stress-induced apoptosis, if unfolding is overwhelming54555657. The unfolding protein response (UPR) is distinguished by three ER transmembrane receptors: protein kinase RNA-like ER kinase (PERK), activating transcription factor 6 (ATF6) and inositol-requiring enzyme 1 (IRE1), which involve both transcriptional and translational regulation of genes to expand the processing capacity of the ER and return this organelle to homeostasis5859.…”

Section: Discussionmentioning

confidence: 99%

Antileukemic Scalarane Sesterterpenoids and Meroditerpenoid from Carteriospongia (Phyllospongia) sp., Induce Apoptosis via Dual Inhibitory Effects on Topoisomerase II and Hsp90

Lai

Liu

et al. 2016

Sci Rep

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Two new scalarane sesterterpenoids, 12β-(3′β-hydroxybutanoyloxy)-20,24-dimethyl-24-oxo-scalara-16-en-25-al (1) and 12β-(3′β-hydroxypentanoyloxy)-20,24-dimethyl-24-oxo-scalara-16-en-25-al (2), along with one known tetraprenyltoluquinol-related metabolite (3), were isolated from the sponge Carteriospongia sp. In leukemia Molt 4 cells, 1 at 0.0625 μg/mL (125 nM) triggered mitochondrial membrane potential (MMP) disruption and apoptosis showing more potent effect than 2 and 3. The isolates inhibited topoisomerase IIα expression. The apoptotic-inducing effect of 3 was supported by the in vivo experiment through suppressing the volume of xenograft tumor growth (47.58%) compared with the control. Compound 1 apoptotic mechanism of action in Molt 4 cells was further elucidated through inducing ROS generation, calcium release and ER stress. Using the molecular docking analysis, 1 exhibited more binding affinity to N-terminal ATP-binding pocket of Hsp90 protein than 17-AAG, a standard Hsp90 inhibitor. The expression of Hsp90 client proteins, Akt, p70S6k, NFκB, Raf-1, p-GSK3β, and XIAP, MDM 2 and Rb2, and CDK4 and Cyclin D3, HIF 1 and HSF1 were suppressed by the use of 1. However, the expression of Hsp70, acetylated tubulin, and activated caspase 3 were induced after 1 treatment. Our results suggested that the proapoptotic effect of the isolates is mediated through the inhibition of Hsp90 and topoisomerase activities.

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“…Aβ peptides exacerbate the overexpression of ROS, which damage proteins, DNA, lipids, and other compounds [19, 61]. Many studies consider oxidative stress and ER stress as closely linked events playing crucial roles in cell homeostasis and apoptosis [62, 63]. As shown here, ER stress response can alter the cellular respiration and perturb mitochondrial bioenergetics, inducing ROS overproduction [64].…”

Section: Discussionmentioning

confidence: 99%

Bajijiasu Ameliorates β-Amyloid-Triggered Endoplasmic Reticulum Stress and Related Pathologies in an Alzheimer’s Disease Model

Zhang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Alzheimer disease (AD) is a common neurodegenerative disease that is characterized by the deposition of beta-amyloid peptide and formation of intracellular neurofibrillary tangles. Due to the failure of various clinical trials of novel drugs for AD, effective drugs for AD treatment are urgently required. Methods: In this study, we used the classic APP/PS1 mouse model to explore the neuroprotective effects of a new compound, bajijiasu, and the mechanisms involved. Behavioral tests and western blotting were performed to assess the beneficial effects of bajijiasu in APP/PS1 mice. Results: Morris water maze and Y-maze test results showed that oral administration of bajijiasu (35 mg/kg/day and 70 mg/kg/day) improved learning and memory abilities in APP/PS1 mice. Bajijiasu reduced ROS and MDA levels in both the hippocampus and cortex. Moreover, western blotting results showed that bajijiasu protected neurons from apoptosis, elevated the expression levels of neurotrophic factors, and alleviated endoplasmic reticulum stress in both the hippocampus and cortex. Conclusion: These results indicate that the mechanisms underlying the effects of bajijiasu on AD might be related to beta-amyloid-downstream pathologies, particularly endoplasmic reticulum stress.

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Endoplasmic-reticulum stress pathway-associated mechanisms of action of proteasome inhibitors in multiple myeloma

Cited by 79 publications

References 40 publications

CDK5 inhibition in�vitro and in vivo induces cell death in�myeloma and overcomes the obstacle of bortezomib resistance

CDK5 inhibition in�vitro and in vivo induces cell death in�myeloma and overcomes the obstacle of bortezomib resistance

Antileukemic Scalarane Sesterterpenoids and Meroditerpenoid from Carteriospongia (Phyllospongia) sp., Induce Apoptosis via Dual Inhibitory Effects on Topoisomerase II and Hsp90

Bajijiasu Ameliorates β-Amyloid-Triggered Endoplasmic Reticulum Stress and Related Pathologies in an Alzheimer’s Disease Model

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