الفهرس 
ChemotherapyOnly 14 pages are availabe for public view
 |  | from | 191 |  |  |
| | | from | 191 | | |
Abstract
It was shown in the 1980s that gallium salts may have anti-tumor
activity in animals. Unfortunately, clinical trials with either nitrate or
gallium chloride have failed for a variety of reasons including low
bioavailability, renal toxicity, and rapid onset of gallium resistance. So, the
main task of our work was to prepare and characterize the chemical structure
of some new water-soluble bioavailable gallium complexes derived from
aspartic acid and to study their possible biochemical effects on the activity
of metalloproteinases (collagenases) as a possible promising mechanism to
control the invasion of some metastatic tumors.
In the present study, two water soluble gallium complexes with
formula [Ga(III)LCl], where L stands for the deprotonated form of N-2-
hydroxybenzyl aspartic acid derivatives that were synthesized and
characterized by 1H NMR, 13C NMR, FT-IR, mass spectrometry and
elemental analysis. The analytical data are consistent with a mononuclear
structure in which the gallium (III) cation is liganded by one of the two
carboxylic acid groups, the phenol oxygen and the nitrogen atom of the 2-
hydroxybenzylamino group. In such a structure, the tridendate ligand secures
the binding of the metal ion whereas the carboxylic appendage provides the
water solubility. The cytotoxicity of the gallium complex of (R)-2-(5-chloro-
2-hydroxybenzylamino) succinic acid (GS2) was evaluated against human
breast carcinoma MDA-MB231 and fibrosarcoma HT-1080 cell lines. The
5-chloro derivative GS2 was found to be more cytotoxic than the
unsubstituted derivative and GaCl3. GS2 induces apoptosis through downregulation
of AKT phosphorylation, G2M arrest in cell cycle via activation
of the caspase3/7 pathway. Although, many molecular and cell effects of Ga have been described, including proteasome inhibition and osteoclastic
activities, GS2 appears as the first gallium compound able to decrease AKT
phosphorylation in cancer cells. The activity of GS2 on cell invasion and on
the expression and activity of Matrix Metalloproteinases (MMPs) was
investigated using modified Boyden chamber coated with type I collagen.
The activity of MMPs was analyzed by zymography and enzymatic assay
using high affinity fluorogenic substrates. A selective inhibition of MMP-14
has been reported to block tumor cell migration and invasion. The
expression of MMPs mRNA was analyzed by qRT-PCR. GS2 induces a
decrease in cell invasion. A dose dependent inhibition effect was observed
on MMP-2, MMP-9 and MMP-14 activities. A decrease in MMP-14 mRNA
expression was observed in both cell lines, whereas MMP-2 and MMP-9
mRNA expression was decreased only in MDA-MB231 cells. Thus, the
present study proposes that GS2 compound may be a potential candidate to
decrease the MMP-14 activity in cancer metastatic diseases presenting high
level of MMP-14 expression and activity. Taken together, these data show
that the possible future combination of GS2 with cytotoxic chemotherapy
may be considered one of the promising treatment modes for anti-invasive
and anticancer therapy.
Keywords: gallium, coordination complex, anticancer agent,
metastasis, matrix metalloproteinase.