Autophagy: A New Mechanism of Prosurvival and Drug Resistance in Multiple Myeloma

Desantis, Vanessa; Saltarella, Ilaria; Lamanuzzi, Aurelia; Mariggiò, Maria Addolorata; Racanelli, Vito; Vacca, Angelo; Frassanito, Maria Antonia

doi:10.1016/j.tranon.2018.08.014

Cited by 65 publications

(57 citation statements)

References 98 publications

(111 reference statements)

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“…Myeloma PCs are characterized by reduced proteasome expression but an increased proteasome workload (likely due to immunoglobulin (Ig) synthesis) and greater apoptotic sensitivity to bortezomib [44,45]. In the presence of a proteasome inhibitor, a potential PC survival strategy is the activation of autophagy, an alternative cellular mechanism of protein degradation [19]. Proteasome inhibition by bortezomib in tumor PCs results in the accumulation of unfolded/misfolded proteins in the endoplasmic reticulum (ER), a response referred to as ER stress, accompanied by the overproduction of reactive oxygen species in the ER, and the activation of unfolded protein cascade components, especially the protein kinase R-like (PKR-like) ER kinase, resulting in the induction of autophagy [46].…”

Section: Discussionmentioning

confidence: 99%

“…Consequently, the development of new therapeutic strategies, such as combination therapies, that overcome bortezomib resistance is urgently needed [17,18]. Proto-oncogene, serine/threonine kinase Bortezomib resistance may be mediated by the activation of the autophagy pathway, as an alternative mechanism of protein degradation [19,20]. Autophagy is a catabolic process that is well conserved among all mammals because it modulates homeostasis, by clearing and recycling damaged or useless cell constituents [21].…”

Section: Introductionmentioning

confidence: 99%

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Bortezomib Treatment Modulates Autophagy in Multiple Myeloma

Lernia

Leone

Solimando

et al. 2020

JCM

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Although the introduction of bortezomib as a therapeutic strategy has improved the overall survival of multiple myeloma (MM) patients, 15–20% of high-risk patients do not respond to bortezomib over time or become resistant to treatment. Therefore, the development of new therapeutic strategies, such as combination therapies, is urgently needed. Methods: Given that bortezomib resistance may be mediated by activation of the autophagy pathway as an alternative mechanism of protein degradation, and that an enormous amounts of misfolded protein is generated in myeloma plasma cells (PCs), we investigated the effect of the simultaneous inhibition of proteasome by bortezomib and autophagy by hydroxychloroquine (HCQ) treatment on PCs and endothelial cells (ECs) isolated from patients with monoclonal gammopathy of undetermined significance (MGUS) and MM. Results: We found that bortezomib combined with HCQ induces synergistic cytotoxicity in myeloma PCs whereas this effect is lost on ECs. Levels of microtubule-associated protein light chain beta (LC3B) and p62 are differentially modulated in PCs and ECs, with effects on cell viability and proliferation. Conclusions: Our results suggest that treatment with bortezomib and HCQ should be associated with an anti-angiogenic drug to prevent the pro-angiogenic effect of bortezomib, the proliferation of a small residual tumor PC clone, and thus the relapse.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Bortezomib Treatment Modulates Autophagy in Multiple Myeloma

Lernia

Leone

Solimando

et al. 2020

JCM

Self Cite

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“…Autophagy is an intracellular self-degradative process that plays a key role in regulating cell growth and metabolism. 13 Unlike the ubiquitin-proteasome system, which is also involved in cell degradation, the substrate of autophagy is endogenous, and autophagy is the process responsible for cellular degeneration and the destruction of certain organelles or the local cytoplasm. 14 PAK proteins are critical modulators of nuclear signal transduction and cytoskeletal reorganization; among the PAK proteins, p21 (RAC1)-activated kinase 1 (PAK1) modulates a wide range of signals involved in a large number of biological activities.…”

Section: Ivermectin Induces Cell Death In Cancer Cellsmentioning

confidence: 99%

<p>Progress in Understanding the Molecular Mechanisms Underlying the Antitumour Effects of Ivermectin</p>

Liu

Zhang

Cheng

et al. 2020

DDDT

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Ivermectin, a dihydro derivative of avermectin (AVM), was introduced into the veterinary, agricultural and aquaculture markets for animal health in 1981. Ivermectin was soon adopted in 1987 as a human medicine that was originally used for the treatment of onchocerciasis, a parasitic infection. Since then, ivermectin has also been used to control other human diseases and has exerted a significant effect on human health and welfare. In the past decade, many published studies have attempted to determine the role of ivermectin in cancer. In this review, we summarize the published studies to define the current progress in the characterization of ivermectin. Ivermectin causes cell death in cancer cell lines by inducing PAK1-mediated cytostatic autophagy, caspase-dependent apoptosis and immunogenic cell death (ICD) through the modulation of some pathways, including the WNT-T cell factor (TCF), Hippo and Akt/ mTOR pathways. Ivermectin can affect the growth and proliferation of cancer cells and plays several different roles, such as its functions as an RNA helicase, a small-molecule mimetic of the surface-induced dissociation (SID) peptide, an activator of chloride channel receptors, and an inducer of mitochondrial dysfunction and oxidative stress. In addition, ivermectin induces the multidrug resistance protein (MDR), has potent anti-mitotic activity, targets angiogenesis and inhibits cancer stem-like cells (CSCs). Many studies have proven that ivermectin exerts antitumour effects and might thus benefit patients with cancer after sufficient clinical trials.

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“…Thus, activation of autophagic cell death may represent a promising approach for treatment of MM (32)(33)(34)(35)(36). Recent studies have demonstrated that autophagy mediates drug resistance in MM cells and leads to development of clinical complications for MM, while inhibition of autophagy may reverse the response to drugs (37,38). However, the clinical role, particularly the prognostic role of ARGs in MM, has yet to be determined.…”

Section: Introductionmentioning

confidence: 99%

A predicted risk score based on the expression of 16 autophagy‑related genes for multiple myeloma survival

Zhu¹,

Wang

Zeng³

et al. 2019

Oncol Lett

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Autophagy has an important role in the pathogenesis of plasma cell development and multiple myeloma (MM); however, the prognostic role of autophagy-related genes (ARGs) in MM remains undefined. In the present study, the expression profiles of 234 ARGs were obtained from a Gene Expression Omnibus dataset (accession GSE24080), which contains 559 samples of patients with MM analyzed with 54,675 probes. Univariate Cox regression analysis identified 55 ARGs that were significantly associated with event-free survival of MM. Furthermore, a risk score with 16 survival-associated ARGs was developed using multivariate Cox regression analysis, including ATIC,

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Autophagy: A New Mechanism of Prosurvival and Drug Resistance in Multiple Myeloma

Cited by 65 publications

References 98 publications

Bortezomib Treatment Modulates Autophagy in Multiple Myeloma

Bortezomib Treatment Modulates Autophagy in Multiple Myeloma

<p>Progress in Understanding the Molecular Mechanisms Underlying the Antitumour Effects of Ivermectin</p>

A predicted risk score based on the expression of 16 autophagy‑related genes for multiple myeloma survival

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