Canna~Fangled Abstracts

Acylamido analogs of endocannabinoids selectively inhibit cancer cell proliferation.

By October 31, 2013No Comments

pm2Acylamido analogs of endocannabinoids selectively inhibit cancer cell proliferation.

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Department of Biochemistry and Molecular Pharmacology, The University of Massachusetts Medical School, Worcester, MA 01605, USA. sumner.burstein@umassmed.edu

Abstract

A series of amide derivatives of long-chain fatty acids has been studied for their effects on the proliferation of cancer cells in vitro. Fatty acids ranged from palmitic to higher polyunsaturated types containing 22 carbon atoms. The amino portions of the molecules included ammonia, ethanolamine, various amino acids and dopamine. Several cell lines were used as models and these included HTB-125 (normal human breast cells), HTB-126 (human breast cancer cells), HeLa (cervical cancer cells), WI-38 (human embryonic lung cells), RAW264.7 (mouse macrophage tumor cells) and RBL-2H3 (rat basophilic leukemia cells). The HTB lines were obtained from the same donor, so, could be considered a matched pair, that is, normal control versus cancer cells and thus, provide a model for testing specificity of action for the acylamido analogs. While many compounds were efficacious in inhibiting the proliferation of various cell lines, only two analogs showed a high degree of specificity in the matched HTB cell lines. N-palmitoyl dopamine and N-palmitoyl tyrosine each demonstrated complete specificity of action at a concentration of 10muM and were highly efficacious in both cases. No clear structure-activity pattern could be derived from these studies since the intensity of the inhibitory action seemed to depend on three factors, namely, the fatty acid, the amine group and the cell type.
PMID:

 

18951802

 

[PubMed – indexed for MEDLINE]

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Figure 1.

Chemical structures. (a) N-acyl amides. (b) N-acyl ethanolamides. (c) N-acyl amino acids (elmiric acids) R′ = H, CH3, (d) N-acyl dopamine. (e) N-acyl GABA (γ-aminobutyric acid).

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Figure 2.

Time course in HTB-126 breast cancer cells. Cells derived from a human tumor were obtained from ATCC and seeded in 18 wells of four 24 well plates at 2000 cells/well under the conditions described in Section 6.1.1. Following a 24 h incubation period, each plate was treated with vehicle, N-palmitoyl tyrosine and AJA (N = 6). After 60 min, one plate was subjected to the cell proliferation assay (see Section 6.1.1), a second plate was assayed after 24 h, a third after 48 h and the last after 72 h. Both agents were given at a final concentration of 10 μM from a 100× stock solution in DMSO. Values shown are in relative fluorescence units.

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Figure 3.

Selective inhibition of human breast cancer cells (HTB-126) versus normal (HTB-125) cells by acylamido analogs. Cells were grown and treated under conditions similar to those described in Figure 2 except that 96 well plates were used and four replicates were done for each point. The cell proliferation assay was performed at 48 h following drug treatment and the values in (A–E) are expressed as a percentage of the vehicle treated wells. In (F), the antagonist rimonabant (10 μM) was added 30 min prior to the treatment with N-palmitoyl tyrosine (10 μM) and the assay performed 48 h later. Here the values are shown as fluorescence units since there are two control treatments.

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Figure 4.

Effects of acyl dopamide analogs on proliferation of cervical cancer (HeLa) Cells. The cells were seeded in 96 well plates and cultured as described in Section 6.1.1. Treatments were made at 24 h after seeding and the assays performed at 48 h post treatment. Four replicates were done for each and the concentrations are shown as the numbers in brackets in μM units. DH = dihomo. Values are mean ± SEM.

Table 1.Effects of acylamides on human embryonic lung (WI-38) and mouse macrophage tumor (RAW264.7) cell proliferation.
 
Cell culture conditions and treatment procedures are described in Section 6.1.1 and in Figure 3.
 
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Table 2.Effects of acylethanolamides on human embryonic lung (WI-38) and mouse macrophage tumor (RAW264.7) cell proliferation.
 
Cell culture conditions and treatment procedures are described in Section 6.1.1 and in Figure 3.
 
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Table 3.The effects of N-acyl dopamide conjugates on human embryonic lung (WI-38) and mouse macrophage tumor (RAW264.7) cell proliferation.
 
Cell culture conditions and treatment procedures are described in Section 6.1.1 and in Figure 3.
 
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Table 4.Effects of N-palmitoyl and N-arachidonoyl derivatives on rat basophilic leukemia (RBL-2H3) cell proliferation.
 
Ninety-six-well plates with 500 mast cells/well/100 μl media with serum were incubated for 24 h. Media were then changed to 100 μl of serum free RPMI and incubated for 4 h. Cells were treated as indicated in the table and incubated for 1 h. LPS (10 ng/ml) was then added to each well and the incubation continued for 24 h. Cell numbers were then obtained using the CellTiter-Glo assay.
 
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