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Erybraedin C and bitucarpin A,
two structurally related pterocarpans purified from Bituminaria
bituminosa, induced apoptosis in human colon adenocarcinoma cell lines
MMR- and p53-proficient and -deficient in a dose-, time-, and
structure-dependent fashion.
Maurich
T, Iorio
M, Chimenti
D, Turchi
G.
Biochemistry and Mutagenesis in Somatic Cells Unit,
IBF, CNR, Via G. Moruzzi 1, 50124 Pisa, Italy.
Pterocarpans, the
second group of natural isoflavonoids, have received considerable
interest on account of their medicinal properties. These drugs are
employed as antitoxins, but display antifungal, antiviral and
antibacterial properties as well. Erybraedin C and bitucarpin A are two
new structurally related pterocarpans recently purified and
characterized. Bitucarpin A differs from erybraedin C for the absence of
a prenyl group in 5' position and the presence of a methoxylate hydroxyl
group in 7, 4' positions. These compounds proved not to be clastogens in
human lymphocytes per se but displayed anticlastogenic activity against
mytomicin C and bleomycin C. Here we extended the study of their
antiproliferative and apoptosis-inducing mechanism on human cell lines.
Two human adenocarcinoma cell lines, LoVo and HT29, as examples of
slow-growing solid tumors, proficient and deficient in mismatch repair
system (MMR), p53 and Bcl-2, were used to evaluate the cytotoxicity of
the drugs and their effects on the cell cycle, measured by flow
cytometry. Erybraedin C similarly affects the survival of HT29 (MMR +/+,
p53 -/- and Bcl-2 +/+) and LoVo (MMR -/-, p53 +/+ and Bcl-2 -/-) cells
(LD(50): 1.94 and 1.73mug/ml, respectively). By contrast, bitucarpin A
exhibits a differential cytotoxicity in the cell lines (LD(50):
6.00mug/ml, HT29, and 1.84mug/ml, LoVo). The cell cycle distributions of
the LoVo and HT29 cells treated with erybraedin C lacked a specific
checkpoint arrest, whereas they underwent a characteristic sub-G(1)
peak, time- and drug-concentration dependent. So that apoptotic process
induced by erybraedin C in both adenocarcinoma cell lines is independent
of cell cycle arrest and of phenotypic status of the cells as well. By
contrast, bitucarpin A affects cell cycle progression on both cell
lines, inducing a transient block in G(0)/G(1) along 24-96h, and induces
apoptosis with a cell density and treatment time dependency. Similar
results were obtained with the positive control drug etoposide. The
programmed cellular death on human adenocarcinoma cell lines may be
efficiently activated, via a topoisomerase II poison pattern, by
erybraedin C, the drug containing regio-specific hydroxyl and prenyl
groups. The apoptotic effect induced by the methoxylated bitucarpin A
proved to be conditioned by cell density and required higher dose
(5-fold-LD(50)) and longer treatment time. The present study provides
evidences that erybraedin C may act as a potent growth inhibitory
compound, at low and high cell density, comparable to other clinically
important antineoplastic natural drugs including etoposide, on human
colon adenocarcinoma cells. Bitucarpin A proved less active because it
was conditioned by cell density effect, but this finding may represent a
clinical advantage against early micrometastatic diseases.
PMID:
16271357 [PubMed - as supplied by publisher]
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