Myristyl Trimethyl Ammonium Bromide and Octadecyl Trimethyl Ammonium Bromide Are Surface-Active Small Molecule Dynamin Inhibitors that Block Endocytosis Mediated by Dynamin I or Dynamin II

Quan, Annie; McGeachie, Andrew B.; Keating, Damien J.; Dam, Ellen M. van; Rusak, Jenny; Chau, Ngoc; Malladi, Chandra S.; Chen, Chen; McCluskey, Adam; Cousin, Michael A.; Robinson, Phillip J.

doi:10.1124/mol.107.034207

Cited by 113 publications

(144 citation statements)

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“…In support of this idea, after 7 days of treatment with MiTMAB and OcTMAB, sufficient numbers of fibroblast cells, but not cancer cells, were viable and their proliferation was restored after MiTMAB washout. We have previously shown that washout of MiTMABs can restore dynamin-dependent receptor-mediated endocytosis in COS7 cells following a short 15-minute exposure to the drug (32). This reversible characteristic makes these small molecules a very powerful research tool for studying the functional role of dynII during cytokinesis.…”

Section: Discussionmentioning

confidence: 99%

“…It is important to note that although it inhibits the activity of purified dynamin in vitro (Table 1), it does not inhibit dynamin-mediated endocytosis in cells (32). This is because it is a prodrug that is rapidly cleaved to myristic acid (which is inactive) and dimethylamino ethanol by endogenous intracellular esterases (32). Therefore, 2-DiMA(EM) was used as a negative control throughout our study.…”

Section: Mitmab and Octmab Reduce Cell Proliferation And Viabilitymentioning

confidence: 99%

“…Dynasore inhibits dynamin GTPase function, which blocks clathrinmediated endocytosis in nonneuronal cells and synaptic vesicle endocytosis in hippocampal neurons (31). We have reported a series of dimeric tyrphostins (Bis-Ts), long-chain amines and ammonium salts [collectively known as MiTMABs (myristyl trimethyl ammonium bromides)], and dynoles (28,29,32) as novel inhibitors of dynamin GTPase activity with a broad range of IC 50 values. The Bis-Ts inhibit dynamin GTPase activity in vitro.…”

Section: Introductionmentioning

confidence: 99%

“…MiTMABs inhibit dynamin GTPase activity by disrupting the PH (pleckstrin homology) domain-phospholipid interaction (28). Consequently, these are pan-dynamin inhibitors that also inhibit dynII-dependent receptormediated endocytosis in U2OS osteosarcoma cells and dynI-dependent synaptic vesicle endocytosis in neurons (32). Two of the most potent MiTMABs are myristyl trimethyl ammonium bromide (MiTMAB) and octadecyltrimethyl ammonium bromide (OcTMAB).…”

Section: Introductionmentioning

confidence: 99%

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The Dynamin Inhibitors MiTMAB and OcTMAB Induce Cytokinesis Failure and Inhibit Cell Proliferation in Human Cancer Cells

Joshi

Perera²,

Gilbert³

et al. 2010

Molecular Cancer Therapeutics

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100

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The endocytic protein dynamin II (dynII) participates in cell cycle progression and has roles in centrosome cohesion and cytokinesis. We have described a series of small-molecule inhibitors of dynamin [myristyl trimethyl ammonium bromides (MiTMAB)] that competitively interfere with the ability of dynamin to bind phospholipids and prevent receptor-mediated endocytosis. We now report that dynII functions specifically during the abscission phase of cytokinesis and that MiTMABs exclusively block this step in the cell cycle. Cells treated with MiTMABs (MiTMAB and octadecyltrimethyl ammonium bromide) and dyn-depleted cells remain connected via an intracellular bridge for a prolonged period with an intact midbody ring before membrane regression and binucleate formation. MiTMABs are the first compounds reported to exclusively block cytokinesis without affecting progression through any other stage of the cell cycle. Thus, MiTMABs represent a new class of antimitotic compounds. We show that MiTMABs are potent inhibitors of cancer cell growth and have minimal effect on nontumorigenic fibroblast cells. Thus, MiTMABs have toxicity and antiproliferative properties that preferentially target cancer cells. This suggests that dynII may be a novel target for pharmacologic intervention for the treatment of cancer.

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Section: Discussionmentioning

confidence: 99%

Section: Mitmab and Octmab Reduce Cell Proliferation And Viabilitymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

The Dynamin Inhibitors MiTMAB and OcTMAB Induce Cytokinesis Failure and Inhibit Cell Proliferation in Human Cancer Cells

Joshi

Perera²,

Gilbert³

et al. 2010

Molecular Cancer Therapeutics

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100

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“…Protein Internalization Is Mediated by a Macropinocytic Mechanism-To understand the mechanism of LC internalization, studies with endocytosis inhibitors were performed. Before OG LC proteins were added, RFP-AC16 cells were treated with: Dynasore (DYN), a dynamin-GTPase inhibitor that blocks clathrin-mediated endocytosis (26 -28); tetradecyl trimethyl ammonium bromide (MiTMAB), a dynamin inhibitor that specifically blocks receptor-mediated endocytosis in nonneuronal cells (29,30); genistein (GEN), a GTPase inhibitor that prevents the clathrin-independent endocytic pathway; and cytochalasin D (CYT), an inhibitor of actin polymerization required for membrane-ruffling and macropinosome formation (31).…”

Section: Resultsmentioning

confidence: 99%

Cell Damage in Light Chain Amyloidosis

Argany¹,

Lin²,

Misra³

et al. 2016

Journal of Biological Chemistry

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Light chain (AL) amyloidosis is an incurable human disease characterized by the misfolding, aggregation, and systemic deposition of amyloid composed of immunoglobulin light chains (LC). This work describes our studies on potential mechanisms of AL cytotoxicity. We have studied the internalization of AL soluble proteins and amyloid fibrils into human AC16 cardiomyocytes by using real time live cell image analysis. Our results show how external amyloid aggregates rapidly surround the cells and act as a recruitment point for soluble protein, triggering the amyloid fibril elongation. Soluble protein and external aggregates are internalized into AC16 cells via macropinocytosis. AL amyloid fibrils are shown to be highly cytotoxic at low concentrations. Additionally, caspase assays revealed soluble protein induces apoptosis, demonstrating different cytotoxic mechanisms between soluble protein and amyloid aggregates. This study emphasizes the complex immunoglobulin light chain-cell interactions that result in fibril internalization, protein recruitment, and cytotoxicity that may occur in AL amyloidosis. Light chain (AL)2 amyloidosis is a protein misfolding disease characterized by extracellular deposition of immunoglobulin light chains (LC) as amyloid fibrils. LC proteins are comprised of two distinct domains: the variable (V L ) and constant (C L ) domains (also called LC full-length (FL) protein to differentiate with the V L domain). In patients with AL amyloidosis, the LC aggregate and deposit in vital organs, causing organ failure and death (1). The factors governing deposition in individual tissues are unknown. Patients with cardiac AL amyloidosis have the worst prognosis, with a median survival of less than a year (2, 3).The finding that the V L was the primary component of amyloid fibrils influenced previous biophysical studies (4,5). Recent proteomic studies have demonstrated that amyloid deposits are likely heterogeneous in nature and can be formed by FL, V L , C L , or mixtures of all types of LC fragments (6 -8). Thermodynamic studies proposed a stabilizing role for the 3C L domain in the stability and a modulating effect on fibril formation (9). Recently, our laboratory has demonstrated that the C L domain modulates the amyloid formation reaction but has no effect on the stability of the protein (10).Soluble monoclonal LC, isolated from patients with amyloidosis, can impair rat cardiomyocyte function (11) and induce apoptotic events in mouse cardiomyocytes (12, 13). Also, urinederived LC can be internalized into primary rat cardiac fibroblasts (14) and primary human renal mesangial cells (15) through a pinocytic pathway (16) or via receptor, clathrin-mediated mechanisms, respectively (15).Within the amyloid field, it is widely accepted that oligomeric species are potentially more toxic than mature fibrils (17-20). However, toxicity associated with amyloid fibrils may also be pathologically relevant. Engel et al. (21) described a mechanism in which growth of islet amyloid associated polypeptides fibrils is re...

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Pyrimidyn‐Based Dynamin Inhibitors as Novel Cytotoxic Agents

et al. 2021

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Five focused libraries of pyrimidine-based dynamin GTPase inhibitors, in total 69 compounds were synthesised, and their dynamin inhibition and broad-spectrum cytotoxicity examined. Dynamin plays a crucial role in mitosis, and as such inhibition of dynamin was expected to broadly correlate with the observed cytotoxicity. The pyrimidines synthesised ranged from monosubstituted to trisubstituted. The highest levels of dynamin inhibition were noted with di-and tri-substituted pyrimidines, especially those with pendent amino alkyl chains. Short chains and simple heterocyclic rings reduced dynamin activity. There were three levels of dynamin activity noted: 1-10, 10-25 and 25-60 μM. Screening of these compounds in a panel of cancer cell lines: SW480 (colon), HT29 (colon), SMA (spontaneous murine astrocytoma), MCF-7 (breast), BE2-C (glioblastoma), SJ-G2 (neuroblastoma), MIA (pancreas), A2780 (ovarian), A431 (skin), H460 (lung), U87 (glioblastoma) and DU145 (prostate) cell lines reveal a good correlation between the observed dynamin inhibition and the observed cytotoxicity. The most active analogues (31 a,b) developed returned average GI 50 values of 1.0 and 0.78 μM across the twelve cell lines examined. These active analogues were: N 2 -(3-dimethylaminopropyl)-N 4 -dodecyl-6-methylpyrimidine-2,4-diamine (31 a) and N 4 -(3-dimethylaminopropyl)-N 2 -dodecyl-6-methylpyrimidine-2,4-diamine (31 b).

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Myristyl Trimethyl Ammonium Bromide and Octadecyl Trimethyl Ammonium Bromide Are Surface-Active Small Molecule Dynamin Inhibitors that Block Endocytosis Mediated by Dynamin I or Dynamin II

Cited by 113 publications

References 58 publications

The Dynamin Inhibitors MiTMAB and OcTMAB Induce Cytokinesis Failure and Inhibit Cell Proliferation in Human Cancer Cells

The Dynamin Inhibitors MiTMAB and OcTMAB Induce Cytokinesis Failure and Inhibit Cell Proliferation in Human Cancer Cells

Cell Damage in Light Chain Amyloidosis

Pyrimidyn‐Based Dynamin Inhibitors as Novel Cytotoxic Agents

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