Targeting Reactive Oxygen Species Metabolism to Induce Myeloma Cell Death

Caillot, Mélody; Dakik, Hassan; Mazurier, Frédéric; Sola, Brigitte

doi:10.3390/cancers13102411

Cited by 13 publications

(30 citation statements)

References 223 publications

(294 reference statements)

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“…Our previous data supported the interest to promote an oxidative stress in an anti-MM strategy [18]. In particular, increasing ROS to high levels may provide a unique tool to kill myeloma cells [28]. Indeed, we recently reported that modulating the redox balance of MM cells could be an effective therapy for refractory or post-treatment patients [18].…”

Section: Discussionsupporting

confidence: 61%

5,6-Epoxycholesterol Isomers Induce Oxiapoptophagy in Myeloma Cells

Jaouadi

Limam

Abdelkarim

et al. 2021

Cancers

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Multiple myeloma (MM) is an incurable plasma cell malignancy with frequent patient relapse due to innate or acquired drug resistance. Cholesterol metabolism is reported to be altered in MM; therefore, we investigated the potential anti-myeloma activity of two cholesterol derivatives: the 5,6 α- and 5,6 β-epoxycholesterol (EC) isomers. To this end, viability assays were used, and isomers were shown to exhibit important anti-tumor activity in vitro in JJN3 and U266 human myeloma cell lines (HMCLs) and ex vivo in myeloma patients’ sorted CD138+ malignant cells. Moreover, we confirmed that 5,6 α-EC and 5,6 β-EC induced oxiapoptophagy through concomitant oxidative stress and caspase-3-mediated apoptosis and autophagy. Interestingly, in combination treatment a synergistic interaction was observed between 5,6 α-EC and 5,6 β-EC on myeloma cells. These data highlight a striking anti-tumor activity of 5,6 α-EC and 5,6 β-EC bioactive molecules against human myeloma cells, paving the way for their potential role in future therapeutic strategies in MM.

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Section: Discussionsupporting

confidence: 61%

5,6-Epoxycholesterol Isomers Induce Oxiapoptophagy in Myeloma Cells

Jaouadi

Limam

Abdelkarim

et al. 2021

Cancers

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“…Recent studies have reported that some of oxysterols, including 5,6-Epoxycholesterol isomers and 25-HC, induce cell death through the death receptor-mediated extrinsic and mitochondria-dependent intrinsic apoptosis pathways [ 19 , 41 ]. Especially mitochondria-dependent intrinsic apoptosis is closely associated with the loss of mitochondrial membrane potential (ΔΨm) that is resulted in mitochondrial membrane permeabilization and the production of ROS [ 41 , 42 ]. Sequentially, highly increasing ROS also act as inducers of apoptotic cell death in various types of cells, including fibroblast cells [ 41 , 42 , 43 ].…”

Section: Discussionmentioning

confidence: 99%

“…Especially mitochondria-dependent intrinsic apoptosis is closely associated with the loss of mitochondrial membrane potential (ΔΨm) that is resulted in mitochondrial membrane permeabilization and the production of ROS [ 41 , 42 ]. Sequentially, highly increasing ROS also act as inducers of apoptotic cell death in various types of cells, including fibroblast cells [ 41 , 42 , 43 ]. In addition, the increasing ROS induce the increase of autophagosome [ 44 ].…”

Section: Discussionmentioning

confidence: 99%

25-Hydroxycholesterol-Induced Oxiapoptophagy in L929 Mouse Fibroblast Cell Line

et al. 2021

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25-hydroxycholesterol (25-HC) is an oxysterol synthesized from cholesterol by cholesterol-25-hydroxylase during cholesterol metabolism. The aim of this study was to verify whether 25-HC induces oxiapoptophagy in fibroblasts. 25-HC not only decreased the survival of L929 cells, but also increased the number of cells with condensed chromatin and altered morphology. Fluorescence-activated cell sorting results showed that there was a dose-dependent increase in the apoptotic populations of L929 cells upon treatment with 25-HC. 25-HC-induced apoptotic cell death was mediated by the death receptor-dependent extrinsic and mitochondria-dependent intrinsic apoptosis pathway, through the cascade activation of caspases including caspase-8, -9, and -3 in L929 cells. There was an increase in the levels of reactive oxygen species and inflammatory mediators such as inducible nitric oxide synthase, cyclooxygenase-2, nitric oxide, and prostaglandin E2 in L929 cells treated with 25-HC. Moreover, 25-HC caused an increase in the expression of beclin-1 and microtubule-associated protein 1A/1B-light chain 3, an autophagy biomarker, in L929 cells. There was a significant decrease in the phosphorylation of protein kinase B (Akt) in L929 cells treated with 25-HC. Taken together, 25-HC induced oxiapoptophagy through the modulation of Akt and p53 cellular signaling pathways in L929 cells.

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“…Since multiple myeloma cells also express high levels of Kv1.3 [22] (also see https://www. proteinatlas.org/ENSG00000177272-KCNA3/single+cell+type (accessed on 25 February 2022) for RPMI-8226) and are characterized by high intracellular ROS levels [23], here we investigated the effects of these novel Kv1.3 inhibitors on different multiple myeloma cell lines as well as in patient-derived primary multiple myeloma cells.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial Kv1.3 Channels as Target for Treatment of Multiple Myeloma

Kadow

Schumacher

Krämer

et al. 2022

Cancers

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Despite several new developments in the treatment of multiple myeloma, all available therapies are only palliative without curative potential and all patients ultimately relapse. Thus, novel therapeutic options are urgently required to prolong survival of or to even cure myeloma. Here, we show that multiple myeloma cells express the potassium channel Kv1.3 in their mitochondria. The mitochondrial Kv1.3 inhibitors PAPTP and PCARBTP are efficient against two tested human multiple myeloma cell lines (L-363 and RPMI-8226) and against ex vivo cultured, patient-derived myeloma cells, while healthy bone marrow cells are spared from toxicity. Cell death after treatment with PAPTP and PCARBTP occurs via the mitochondrial apoptotic pathway. In addition, we identify up-regulation of the multidrug resistance pump MDR-1 as the main potential resistance mechanism. Combination with ABT-199 (venetoclax), an inhibitor of Bcl2, has a synergistic effect, suggesting that mitochondrial Kv1.3 inhibitors could potentially be used as combination partner to venetoclax, even in the treatment of t(11;14) negative multiple myeloma, which represent the major part of cases and are rather resistant to venetoclax alone. We thus identify mitochondrial Kv1.3 channels as druggable targets against multiple myeloma.

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Targeting Reactive Oxygen Species Metabolism to Induce Myeloma Cell Death

Cited by 13 publications

References 223 publications

5,6-Epoxycholesterol Isomers Induce Oxiapoptophagy in Myeloma Cells

5,6-Epoxycholesterol Isomers Induce Oxiapoptophagy in Myeloma Cells

25-Hydroxycholesterol-Induced Oxiapoptophagy in L929 Mouse Fibroblast Cell Line

Mitochondrial Kv1.3 Channels as Target for Treatment of Multiple Myeloma

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