Iron chelator mimosine in lung and breast cancer

<<snip>>
mimosine exerts anti-cancer effect in vivo and might be useful in the
therapy of lung cancer
<<snip>>

Modulation of cell cycle regulatory protein expression and suppression
of tumor growth by mimosine in nude mice
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Chang, Hui-Chiu; Weng, Ching-Feng; Yen, Ming-Hong; Chuang, Lea-Yea;
Hung, Wen-Chun 2000

International Journal of Oncology 17(4): 659-665

Our previous results demonstrated that the plant amino acid mimosine
blocked cell cycle progression and suppressed proliferation of human
lung cancer cells in vitro by multiple mechanisms. Inhibition of
cyclin D1 expression or induction of cyclin-dependent kinase inhibitor
p21WAF1 expression was found in mimosine-treated lung cancer cells.
However, whether mimosine may modulate the expression of these cell
cycle regulatory proteins and suppress tumor growth in vivo is
unknown. In this study, we examined the anti-cancer effect of mimosine
on human H226 lung cancer cells grown in nude mice. Our results
demonstrated that mimosine inhibits cyclin D1 and induces p21WAF1
expression in vivo. Furthermore, results of TUNEL analysis indicated
that mimosine may induce apoptosis to suppress tumor growth in nude
mice. Collectively, these results suggest that mimosine exerts anti-
cancer effect in vivo and might be useful in the therapy of lung
cancer.

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Toxicol Appl Pharmacol. 1996 Aug;139(2):356-64. Links
Mimosine blocks cell cycle progression by chelating iron in
asynchronous human breast cancer cells.Kulp KS, Vulliet PR.
Department of Molecular Biosciences, School of Veterinary Medicine,
University of California, Davis, California 95616-8643, USA.

Mimosine is a toxic nonprotein amino acid that is a major constituent
of the tropical legumes Leucaena and Mimosa. Mimosine has been shown
to cause acute and chronic toxicosis in livestock fed from forage
containing these plants. Recently, mimosine has been demonstrated to
reversibly block cell cycle progression in mammalian cells in culture.
In this study, we compared the effects of mimosine to desferrioxamine
(DFO), a well-characterized iron chelator, and found that both
chemicals similarly altered cell cycle progression in MDA-MB-453 human
breast cancer cells. Mimosine (400 microM) and DFO (150 microM) both
reduced DNA synthesis by greater than 90% of control within 4 hr of
treatment, and suppressed total proline-directed protein kinase
activity to less than 10% of control after 16 hr treatment. These
effects were antagonized by the addition of iron as ferrous sulfate
(250 microM), which is bound to transferrin and imported into the cell
via transferrin receptor endocytosis, or as hemin (100 microM), which
passes through the cell membrane and releases iron into the cytosol.
After 24 hr treatment with the chelators, a large portion of the
available transferrin receptors moved to the cell surface, indicating
that the cells were iron-starved. Our data demonstrate that mimosine,
through iron chelation, blocks cell cycle progression in MDA-MB-453
human breast cancer cells.

PMID: 8806853 [PubMed - indexed for MEDLINE]

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Journal of Clinical Oncology, 2005 ASCO Annual Meeting Proceedings.
Vol 23, No 16S (June 1 Supplement), 2005: 3200
© 2005 American Society of Clinical Oncology

Antiproliferative effect of mimosine in ovarian cancer
A. Restivo, L. Brard, C. O. Granai and N. Swamy
Women and Infants Hospital/Brown Univ, Providence, RI

3200

Objective: Iron plays a critical role in cell proliferation and
survival making it a potential target for cancer therapy. Iron
chelators have recently been shown to possess selective anti-
neoplastic properties. Mimosine, a plant amino acid, acts as a potent
iron chelator, but its use in gynecologic malignancies has yet to be
tested. It is a naturally occurring plant amino acid known to arrest
cell-cycle progression at the G1-S border in cultured cells. The
objective of our study was to evaluate the anti-proliferative and pro-
apoptotic effects of mimosine on human and rat ovarian cancer cells.
Methods: Human (CaOV-3 & OvCAR) and rat (NuTu 19) ovarian cancer cell
lines were treated for 24-72 hours with mimosine at varying doses
ranging from 50 to 800 micro-molar concentrations. Untreated cells
were used as a control. Cell viability was measured by MTS reduction
assay and cell proliferation was determined by BrdU incorporation.
Apoptosis was analyzed by DNA fragmentation. Iron challenge studies
were performed to determine the role of iron in the cytotoxic effect
of mimosine. Results: Mimosine demonstrated dose dependent anti-
proliferative effects on all the ovarian cancer cells tested. Cell
viability was inhibited over 70% at a dose of 200µM mimosine. Mimosine
also inhibited DNA synthesis as revealed by BrdU incorporation assay.
Fifty percent inhibition in DNA synthesis was observed at 100 µM dose
level of mimosine. Addition of ferric ion effectively reversed the
effects of mimosine, indicating that the effect of mimosine is
mediated by iron chelation. In addition, mimosine induced apoptosis.
DNA fragmentation analysis confirmed apoptosis. Further testing
revealed mimosine to have significant dose-dependent antiproliferative
effects on vulvar and cervical cancer cell lines and only a minimal
effect on endometrial and colorectal cells. Conclusions: Mimosine, an
iron chelator, has potent cytotoxic and anti-proliferative effects on
a human and rat ovarian cancer cells. Iron challenge studies imply
that the anti-proliferative effect of mimosine is mediated by iron
chelation. Mimosine induced apoptosis.

No significant financial relationships to disclose.


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http://www2.ccmp.gov.tw/index-e/deve...=CCMP88-RD-043

Abstract

Year of 88 Number： CCMP88-RD-043
Study of the anti-cancer effect of mimosine in vivo
Wen-Chun Hung

School of Technology for Medical Sciences Kaohsiung Medical College
Our previous study demonstrated that mimosine, a plant specific
amino acid extracted from the seeds of Leucaena Glauca Benth,
inhibited proliferation of human hepatoma and lung cancer cells by
suppressing cyclin D1 and by activating cyclin-dependent kinase
inhibitor p21WAF1 gene expression. In addition, this amino acid could
induce apoptosis in these cancer cells. The aim of this study is to
examine the anti-cancer effect of mimosine in vivo and to evaluate the
potential of this drug for clinical application. We established the in
vivo tumorigenesis animal model by injecting hepatoma and lung cancer
cells subcutaneously into nude mice. We examine the effect of mimosine
on the expression of cyclin D1 and p21WAF1 in established tumors by
Northern and Western blotting and immunohistochemical staining and
investigate the effect of this amino acid on the growth of tumors in
nude mice.. Finally, we used TUNEL assays to investigate the apoptosis-
inducing activity of mimosine alone or in combination with
chemotherapeutic drug (cisplatin) in vivo. Our results demonstrated
that mimosine inhibited the proliferation of hepatoma and lung cancer
cells in nude mice. This drug reduced the expression of cyclin D1 and
PCNA and increased the expression of p21WAF1 in established hepatoma
and lung tumors. Additionally, mimosine induced apoptosis in these
tumors. There is an additive cytocidal effect of mimosine in
combination with chemotherapeutic drug (cisplatin) in vivo. These
results suggest that mimosine exerts potent anti-cancer effect in vivo
and may act additively with cisplatin in the treatment of hepatoma and
lung cancer.
Key Word：Mimosine; cyclin D1; p21WAF1 ; chernotherapeutic drug


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