Lipid raft disruption prevents apoptosis induced by 2-chloro-2′-deoxyadenosine (Cladribine) in leukemia cell lines

Takahashi, Eriko; Inanami, Osamu; Ohta, Toshio; Matsuda, Akira; Kuwabara, Mikinori

doi:10.1016/j.leukres.2006.04.008

Cited by 10 publications

(9 citation statements)

References 42 publications

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“…Our data demonstrated that cholesterol depletion from membranes inhibits fluid flow induced Ca 2þ i mobilization, suggesting cholesterol in cell membranes may be involved in fluid flow induced calcium signaling. These results are consistent with previous studies, in which cholesterol depletion inhibits hyaluronan-mediated and caldribine-induced Ca 2þ i mobilization in endothelial cells (Singleton and Bourguignon, 2004) and leukemia cells (Takahashi et al, 2006), respectively. However, it is the first report that mechanical stimulation (oscillatory fluid flow) induced Ca 2þ i was inhibited by MbCD.…”

Section: Discussionsupporting

confidence: 94%

Effects of membrane cholesterol depletion and GPI‐anchored protein reduction on osteoblastic mechanotransduction

Xing¹,

Gu²,

Xu³

et al. 2011

Journal Cellular Physiology

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We previously demonstrated that oscillatory fluid flow activates MC3T3-E1 osteoblastic cell calcium signaling pathways via a mechanism involving ATP releases and P2Y 2 puringeric receptors. However, the molecular mechanisms by which fluid flow initiates cellular responses are still unclear. Accumulating evidence suggests that lipid rafts, one of the important membrane structural components, may play an important role in transducing extracellular fluid shear stress to intracellular responses. Due to the limitations of current techniques, there is no direct approach to study the role of lipid rafts in transmitting fluid shear stress. In this study, we targeted two important membrane components associated with lipid rafts, cholesterol and glycosylphosphatidylinositol-anchored proteins, to disrupt the integrity of cell membrane structures. We first demonstrated that membrane cholesterol depletion with the treatment of methyl-β-cyclodextrin inhibits oscillatory fluid flow induced intracellular calcium mobilization and ERK1/2 phosphorylation in MC3T3-E1 osteoblastic cells. Secondly, we used a novel approach to decrease the levels of glycosylphosphatidylinositol-anchored proteins on cell membranes by overexpressing glycosylphosphatidylinositol specific phospholipase D in MC3T3-E1 osteoblastic cells. This resulted in significant inhibition of intracellular calcium mobilization and ERK1/2 phosphorylation in response to oscillatory fluid flow. Finally, we demonstrated that cholesterol depletion inhibited oscillatory fluid flow induced ATP releases, which were responsible for the activation of calcium signaling pathways in MC3T3-E1 osteoblastic cells. Our findings suggest that cholesterol and GPI-anchored proteins, two membrane structural components related to lipid rafts, may play an important role in osteoblastic cell mechanotransduction.

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Section: Discussionsupporting

confidence: 94%

Effects of membrane cholesterol depletion and GPI‐anchored protein reduction on osteoblastic mechanotransduction

Xing¹,

Gu²,

Xu³

et al. 2011

Journal Cellular Physiology

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“…In acute promyelocytic leukemia and lymphoblastic leukemia cells, changes in intracellular calcium levels occurred after treatment with all the tested derivatives 31 . Studies suggest that lymphocytes express L-type Ca 2+ channels that are activated in a non-voltage-gated manner 32 . The obtained data revealed that compounds 1 and 2 are potent to activate caspase 3, the enzyme which is involved in proteolysis of numerous proteins (e.g.…”

Section: Discussionmentioning

confidence: 99%

Antileukemic activity of novel adenosine derivatives

Poczta

Rogalska

Łukawska

et al. 2019

Sci Rep

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The present study investigated the effect of cladribine (CLA) and six of its derivatives containing a formamidine group at position 6 (CLA-FDM, CLA-FPAZ, CLA-FPIR, CLA-FPIP, CLA-FHEX, and CLA-FMOR) on acute promyelocytic, lymphoblastic, and acute monocytic leukemia cells. The role of ATR kinase in deoxycytidine kinase (dCK) activation in response to DNA damage was assessed. The presence of DNA lesions was assessed by measurement phosphorylation of H2AX and by using the alkaline comet assay with proteinase K post-treatment following assessment of the cell cycle. Apoptotic events such as alterations in intracellular calcium concentration, caspase-3/7 activity and increased sub-G1 cell population were measured. CLA derivatives were highly effective against leukemic cells, showing high cytotoxicity, causing DNA fragmentation, and inducing DNA-protein cross-links in leukemic cells. CLA-FMOR showed the highest efficacy. CLA derivatives increased the levels of intracellular calcium ions, caspase-3/7 and the percentage of sub-G1 apoptotic cells and blocked cells in the S phase of the cell cycle to a greater extent than free CLA. The selective ATR inhibitor VE-821 significantly suppressed the increase in dCK activity and decreased basal dCK activity. The present results suggested that ATR kinase controls dCK activity in response to synthetic CLA derivatives.

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“…Akt/PKB [62]. The effects of raft disruption on pro-apoptotic signaling have also been demonstrated in B cells, where lipid rafts play a crucial role in CD20-induced caspase activation [63] or in leukemic cells where lipid rafts disruption prevents cladribine induced apoptosis [64]. Finally, by using MβCD and filipin, it was also demonstrated a role for lipid rafts in cell sensitization to cathepsin B-dependent apoptosis via lipopolysaccaride [65].…”

Section: The Role Of Lipid Rafts In Apoptosismentioning

confidence: 94%

Dynamics of lipid raft components during lymphocyte apoptosis: The paradigmatic role of GD3

et al. 2007

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Several investigations have been carried out since many years in order to precisely address the function of lipid rafts in cell life and death. On the basis of the biochemical nature of lipid rafts, composed by sphingolipids, including gangliosides, sphingomyelin, cholesterol and signaling proteins, a plethora of possible interactions with various subcellular structures has been suggested. Their structural and functional role at the plasma membrane as well as in cell organelles such as endoplasmic reticulum and Golgi apparatus has been analyzed in detail in several studies. In particular, a specific activity of lipid rafts has been hypothesized to contribute to cell death by apoptosis. Although detected in various cell types, the role of lipid rafts in apoptosis has however been mostly studied in lymphocytes where the physiological apoptotic program occurs after CD95/Fas triggering. In this review, the possible contribution of lipid rafts to the cascade of events leading to T cell apoptosis after CD95/Fas ligation are summarized. Particular attention has been given to the mitochondrial raft-like microdomains, which may represent preferential sites where some key reactions can take place and can be catalyzed, leading to either survival or death of T cells.

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Lipid raft disruption prevents apoptosis induced by 2-chloro-2′-deoxyadenosine (Cladribine) in leukemia cell lines

Abstract: These results indicated that lipid rafts partly contributed to 2CdA-induced apoptosis by regulating Ca 2+ influx via the plasma membrane.3

Cited by 10 publications

References 42 publications

Effects of membrane cholesterol depletion and GPI‐anchored protein reduction on osteoblastic mechanotransduction

Effects of membrane cholesterol depletion and GPI‐anchored protein reduction on osteoblastic mechanotransduction

Antileukemic activity of novel adenosine derivatives

Dynamics of lipid raft components during lymphocyte apoptosis: The paradigmatic role of GD3

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