Glutathione,
Whey protein and Cancer
[Scientific Research Abstracts]
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Glutathione and whey protein
in Cancer Prevention and Treatment
Enchancing
effect of patented whey protein isolate on cytotoxicity of an
anticancer drug
Tsai WY, Chang WH, Chen CH, Lu FJ. [Nutr Cancer. 2000;38(2):200-8.]
To determine the enhancing effect of a whey protein isolate on
the cytotoxicity of a potential anticancer drug, baicalein, the
human hepatoma cell line Hep G2 was assigned to grow in different
media for four days, and cell growth and apoptosis were investigated.....survival
rate was significantly lower in cells grown in baicalein + un-denatured
whey protein than in cells grown in baicalein alone.....In conclusion,
un-denatured whey protein seemed to enhance the cytotoxicity of
baicalein by inducing more apoptosis... This is the first study
to demonstrate, in vitro, that un-denatured whey protein may function
as an adjuvant in cancer treatments.
Nutriceutical
Modulation Of Glutathione With A Humanized Native Milk Serum Protein
Isolate: Application In AIDS And Cancer
S. Baruchel, G. Viau, R. Olivier, G. Bounous, M.A. Wainberg
[Oxidative Stress in Cancer, AIDS, and Neurodegenerative Diseases
V Luc Montagnier et al., (Ed.) Marcel Dekker Inc., New York: 447-461,
1998 . ABSTRACT V] The biological activity of the proteins isolated
from cow's milk in un-denatured
whey protein
depends on the preservation of those labile proteins which share
with the predominant human milk proteins the same extremely rare
glutathione (GSH)-promoting components. In a pilot study, this
type of whey protein concentrate was found to be well tolerated
in children with AIDS and wasting syndrome and was found associated
with an improvement of the nutritional status of the patient.
Whey
proteins in cancer prevention
Bounous G, Batist G, Gold P. [Cancer Lett. 1991 May 1;57(2):91-4.
Review.] Epidemiological and experimental studies suggest that
dietary milk products may exert an inhibitory effect on the development
of several types of tumors......the antitumor activity of the
dairy products is in the protein fraction and more specifically
in the whey protein component of milk......Whey protein is particularly
rich in substrates for GSH synthesis. We suggest that whey protein
may be exerting its effect on carcinogenesis by enhancing GSH
concentration.
Whey
protein concentrate (WPC) and glutathione modulation in cancer
treatment
Bounous G. [Anticancer Res. 2000 Nov-Dec;20(6C):4785-92. Review.]
Whey protein concentrate has been shown to represent an effective
and safe cysteine donor for GSH replenishment during GSH depletion
in immune deficiency states........the concentrates of whey proteins
also exhibit anti-carcinogenesis and anticancer activity........and
may have anti-tumor effect on low volume of tumor via stimulation
of immunity through the GSH pathway......Case reports.....strongly
suggest an anti-tumor effect of a whey protein dietary supplement
in some urogenital cancers. This non toxic dietary intervention,
which is not based on the principles of current cancer chemotherapy,
will hopefully attract the attention of laboratory and clinical
oncologists.
In
vitro selective modulation of cellular glutathione by a humanized
native milk protein isolate in normal cells and rat mammary carcinoma
model
Baruchel S, Viau G. [Anticancer Res. 1996 May-Jun;16(3A):1095-9.]
We report the in vitro selective inhibitory activity of a humanized
whey protein concentrate on growth of mammary carcinoma cells
and Jurkat T cells in comparison to normal peripheral blood mononuclear
cells. We relate this inhibitory activity to a selective
depletion of intracellular glutathione synthesis. The use of humanized
whey protein concentrate as a food supplementation may have direct
implication in clinical trial with adjuvant chemotherapy.
Effect
of adding glutathione (GSH) to cisplatin (CDDP) in the treatment
of stage I-IV ovarian cancer
(Meeting abstract). Bowman A; Perren T; Wilkinson P; Prescott
RJ; Quinn KJ; Tedeschi M; Smyth [JF Address: ICRF Medical
Oncology Unit, Edinburgh, UK Source: Br J Cancer 1994;71(Suppl
24):14] Abstract: Previous studies have suggested that glutathione
(GSH) can reduce the toxicities of cisplatin (CDDP) chemotherapy.
In a double-blind phase III study conducted at 9 British oncology
centers... GSH reduced depression and significantly improved 8
other symptoms including emesis and peripheral neurotoxicity.
Thus, the addition of GSH to CDDP allows more cycles of CDDP to
be administered; quality of life is improved and response rates
may be enhanced.
The
use of a whey protein concentrate in the treatment of patients
with metastatic carcinoma: a phase I-II clinical study
Kennedy RS, Konok GP, Bounous G, Baruchel S, Lee TD. [Anticancer
Res. 1995 Nov-Dec;15(6B):2643-9.] Glutathione (GSH) concentration
is high in most tumour cells and this may be an important factor
in resistance to chemotherapy.........experiments have shown a
differential response of tumour versus normal cells to various
cysteine delivery systems.........at concentrations that induce
GSH synthesis in normal human cells, a specially prepared whey
protein concentrate caused GSH depletion and inhibition of proliferation
in human breast cancer cells. On the basis of this information
five patients with metastatic carcinoma of the breast, one of
the pancreas and one of the liver were fed 30 grams of this whey
protein concentrate daily for six months.......The results indicate
that whey protein concentrate might deplete tumour cells of GSH
and render them more vulnerable to chemotherapy.
Dietary
whey protein inhibits the development of dimethylhydrazine induced
malignancy
Bounous G, Papenburg R, Kongshavn PA, Gold P, Fleiszer D.
[Clin Invest Med. 1988 Jun;11(3):213-7.] In conclusion, a whey
protein diet appears to significantly inhibit the incidence and
growth of chemically induced colon tumors in mice.
Dairy
proteins protect against dimethylhydrazine-induced intestinal
cancers in rats
McIntosh GH, Regester GO, Le Leu RK, Royle PJ, Smithers GW. [J
Nutr. 1995 Apr;125(4):809-16.] Whey and casein diets were more
protective against the development of intestinal tumors than were
the red meat or soybean diets......Intracellular concentration
of glutathione, an antioxidant and anticarcinogenic tripeptide,
measured in liver, was greatest in whey protein- and casein-fed
rats and lowest in soybean-fed animals.....Whatever the mechanism(s),
dairy proteins, and whey proteins in particular, offer considerable
protection to the host against dimethylhydrazine-induced tumors
relative to the other protein sources examined.
Effect
of whey protein isolate on intracellular glutathione and oxidant-induced
cell death in human prostate epithelial cells
Kent KD, Harper WJ, Bomser JA. [Toxicol In Vitro. 2003
Feb;17(1):27-33.] The objective of this study was to determine
whether enzymatically hydrolyzed whey protein isolate (WPI) could
increase intracellular GSH concentrations and protect against
oxidant-induced cell death in a human prostate epithelial cell
line (designated RWPE-1). Treatment of RWPE-1 cells with hydrolyzed
WPI significantly increased intracellular GSH by 64%, compared
with control cells receiving no hydrolyzed WPI. A similar increase
in GSH was observed with N-acetylcysteine, a cysteine-donating
compound known to elevate intracellular GSH. Hydrolyzed WPI significantly
protected RWPE-1 cells from oxidant-induced cell death, compared
with controls receiving no WPI. The results of this study indicate
that WPI can increase GSH synthesis and protect against oxidant-induced
cell death in human prostate cells.
Whey
protein isolate increases glutathione levels in human prostate
epithelial cells
K. D. Kent, J. A. Bomser, and W. J. Harper. [Annual Meeting
and Food Expo - Anaheim, California, Session 73, Dairy Foods:
Probiotics and bioactive components in milk] Prostate cancer is
the second leading cause of cancer death among American men. Studies
suggest that dietary whey proteins may reduce the risk for cancer
by increasing cellular levels of the antioxidant glutathione.
Whey proteins are rich in cysteine, the hypothesized rate-limiting
amino acid for glutathione synthesis. Supplementation with
whey protein isolate may represent a means to increase glutathione
synthesis within the prostate. The objective of this study
was to determine the effect of whey protein isolate supplementation
on glutathione levels in human prostate epithelial cells (RWPE-1)....
an increase in available cysteine is responsible for the elevation
of glutathione within the prostate epithelial cells.... hydrolyzed
whey protein isolate can significantly increase glutathione levels
within the prostate epithelium. This represents a potential mechanism
by which whey protein isolate can provide protection against
the development of prostate cancer.
Glutathione
depletion causes cell growth inhibition and enhanced apoptosis
in pancreatic cancer cells
Schnelldorfer T, Gansauge S, Gansauge F, Schlosser S, Beger
HG, Nussler AK. [Cancer. 2000 Oct 1;89(7):1440-7.] Recent
studies have demonstrated that various tumors express enhanced
levels of the radical scavenger glutathione (GSH). Moreover, there
are grounds for claiming that GSH plays a crucial role in cell
proliferation and tumor resistance. In the current study, we investigated
the relation between cell growth and GSH levels in the pancreatic
adenocarcinoma cell line, AsPC-1, and the significance of GSH
in tumor resistance to chemotherapy. Analysis of GSH in pancreatic
tissues demonstrated increased GSH levels in cancerous compared
with normal tissue. Our results show enhanced GSH levels in pancreatic
carcinoma and an essential role of GSH in cell proliferation and
in resistance of AsPC-1 cells. Therefore, GSH-depletion may improve
the efficacy of adjuvant therapy in pancreatic carcinoma.
Milk
and dairy products in cancer prevention: focus on bovine lactoferrin
Tsuda H, Sekine K, Ushida Y, Kuhara T, Takasuka N, Iigo M, Han
BS, Moore MA. [Mutat Res 2000 Apr;462(2-3):227-33] Whey protein
may also be beneficial, as shown by both animal and human studies,
and experimental data have demonstrated that the major component
bovine lactoferrin (bLF), inhibits colon carcinogenesis
in the post-initiation stage in male F344 rats treated with azoxymethane
(AOM) without any overt toxicity.... bLF might find application
as a natural ingredient of milk with potential for chemoprevention
of colon and other cancers.
Cancer
prevention by bovine lactoferrin and underlying mechanisms--a
review of experimental and clinical studies
Tsuda H, Sekine K, Fujita K, Ligo M. [Biochem Cell Biol.
2002;80(1):131-6.] In experimental studies, bovine lactoferrin
(bLF) has been found to significantly inhibit colon, esophagus,
lung, and bladder carcinogenesis in rats when administered orally
in the post-initiation stage. Furthermore, concomitant administration
with carcinogens resulted in inhibition of colon carcinogenesis..
Anti-metastatic effects were moreover detected when bLF was given
intragastrically to mice bearing highly metastatic colon carcinoma
26 cells (Co 26Lu), with apparent enhancing influence on local
and systemic immunity. Marked increase in the number of cytotoxic
T and NK cells in the mucosal layer of the small intestine and
peripheral blood cells was thus found, this in turn enhancing
the production of Interleukin 18 (IL-18) and caspase-1 in the
epithelial cells of the small intestine, with possible consequent
induction of interferon (IFN)-gamma positive cells. Furthermore,
bLF has been found to exert anti-hepatitis C virus (HCV) activity
in a preliminary clinical trial in patients with chronic active
hepatitis due to this virus, a main causative factor in hepatocellular
carcinoma development in Japanese. More extensive clinical trials
are now underway in the National Cancer Center Hospital and other
institutes to further explore the preventive potential against
colon carcinogenesis.
Prevention
of colon carcinogenesis and carcinoma metastasis by orally administered
bovine lactoferrin in animals
Tsuda H, Sekine K, Takasuka N, Toriyama-Baba H, Iigo M. [Biofactors
2000;12(1-4):83-8] Bovine lactoferrin (bLF), a milk protein known
to have bacteriostatic properties was examined for its preventive
effects on colon and other organ carcinogenesis and experimental
metastasis. .. Results of those experiments indicate that bLF
remarkably prevents colon carcinogenesis and lung metastasis of
colon carcinoma cells, possibly due to increasing cytotoxic cells
in the peripheral blood.
Modulation
of glutathione by a cysteine pro-drug enhances in vivo tumor response
Wang T, Chen X, Schecter RL, Baruchel S, Alaoui-Jamali M, Melnychuk
D, Batist G. [J Pharmacol Exp Ther 1996 Mar;276(3):1169-73]
Glutathione (GSH) is known to play a role in cellular sensitivity
to some chemotherapeutic agents and to radiation. Depletion
of cellular glutathione increases toxicity of these drugs, and
this approach is being explored in the clinic as a form of biochemical
modulation using the drug buthionine sulfoximine.... some drug-resistant
cell lines have increased GSH levels, ... enhancing glutathione
concentrations in animal tissues protects against a variety of
xenobiotic agents, suggests a different potential approach to
improve anticancer therapy. This report describes evidence that
OTZ provides this effect in an in vivo rat mammary tumor model...
the lack of increased GSH in tumor in response to OTZ.
Glutathione
based approaches to improving cancer treatment
Kauvar LM, Morgan AS, Sanderson PE, Henner WD. [Chem Biol Interact.
1998 Apr 24;111-112:225-38.]
The use of cytotoxic chemotherapy for cancer therapy has been
very successful in the treatment and often cure of patients with
particular neoplasms, such as testicular carcinomas and some lymphomas.
In addition, the use of adjuvant chemotherapy in patients whose
primary tumor has been surgically removed contributes significantly
to cure rates in some of the more common malignancies such as
breast carcinoma and colon cancer. Nonetheless, for most patients
with metastatic malignancies, current antineoplastic drugs provide
only brief remissions with few or no long term cures. In addition,
the side effects of therapy lead to substantial morbidity in nearly
all patients. Insights derived from model system studies on two
glutathione based lead compounds, TER286 and TER199, suggest new
clinical strategies and raise interesting basic research questions
regarding the cell biology foundations of cancer chemotherapy.
Selective
modulation of glutathione levels in human normal versus tumor
cells and subsequent differential response to chemotherapy drugs
Russo A., Degraff W., Friedman N., Mitchell EB. [Cancer Res.
26: 2845-48,1986.] Cellular glutathione (GSH) levels were found
to be 7-fold higher in a human lung adenocarcinoma cell line (A549)
than in a normal human lung fibroblast line (CCL-210). These studies
demonstrate that selective differential chemotherapy responses
of normal versus tumor cells is possible by manipulating the GSH
synthetic cycle.... such manipulation in GSH levels might yield
a therapeutic gain for carefully selected chemotherapy drugs.
Glutathione
and glutathione-dependent enzymes in cancer drug resistance
McLellan LI, Wolf CR. [Drug Resist Updat 1999 Jun;2(3):153-164]
Glutathione and glutathione-dependent enzymes play a central role
in cellular defence against toxic environmental agents. Modulation
of cellular glutathione homeostasis can also have a profound effect
on the sensitivity of cancer cells to a wide range of drugs used
in chemotherapy. New data demonstrating the importance of these
pathways in cytoprotection and greater understanding of the mechanisms
which regulate their function reveal a number of new targets for
novel anti-cancer agents.
Glutathione
level and its relation to radiation therapy in patients with cancer
of uterine cervix
Mukundan H, Bahadur AK, Kumar A, Sardana S, Naik SL, Ray A,
Sharma BK.[Indian J Exp Biol. 1999 Sep;37(9):859-64.] The
study was aimed to determine plasma glutathione as well as erythrocyte
glutathione and glutathione peroxidase in patients with invasive
cervical carcinoma before initiation and after completion of radiotherapy
and subsequently, at the time of first three monthly follow-up
visit. The levels of plasma glutathione, erythrocyte glutathione
and glutathione peroxidase activity were found to be lower in
all cervical cancer patients as compared to age matched normal
control women. The study indicates a change in antioxidant status
in relation with the glutathione system among patients with invasive
carcinoma of the uterine cervix. This study also demonstrates
the effect of radiation therapy on this antioxidant system.
Role
of cysteine and glutathione in HIV infection and cancer cachexia:
therapeutic intervention with N-acetylcysteine
Droge W. et al. [Adv Pharm 38: 581-600, 1997.] No abstract
available.
Glutathione
and lipid peroxidation levels in human breast tumors
Coban T, Mabsout A, Eke BC, Bulbul D, Berberoglu U, Iscan
M. [Neoplasma. 1998;45(3):151-6.] The levels of reduced glutathione
(GSH) and lipid peroxidation (LP) of breast tumor and surrounding
tumor free (normal) tissues of 39 breast cancer female patients
with infiltrating ductal carcinoma and the relationship between
these two parameters were investigated. Large interindividual
variations in the levels of GSH and LP were found in both tumor
and normal tissues. The mean GSH levels of tumors were significantly
higher than those of normal tissues. This tendency did not change
with the stage and grade (excluding grade 1) of the malignancy,
menopausal status and chemotherapy treatment. These results reveal
that the GSH, but not LP, could be a marker of breast malignancy
and that the increase in GSH level is not sufficient to lower
the LP level in human breast tumors.
N-acetylcysteine
suppression of the proliferative index in the colon of patients
with previous adenomatous colonic polyp
Estensen RD, Levy M, and others. [Cancer Lett 1999 Dec 1;147(1-2):109-14.]
"This investigation is part of an effort to develop chemoprevention
for carcinogenesis of the large bowel. The agent investigated
is N-acetylcysteine (NAC). Patients with previous adenomatous
colonic polyps are a cohort with increased risk for colon cancer
and an increased PI of colonic crypts. Since this decrease in
proliferative index may be an indicator of decreased risk of colon
cancer, more extensive studies of the potential of NAC as a chemopreventive
agent for colon cancer appear warranted."
Colon
cancer: dietary modifications required for a balanced protective
diet
McIntosh GH. [Prev
Med 1993 Sep;22(5):767-74] When comparing differing protein sources,
whey protein concentrate was found to be very protective relative
to red meat and other protein sources. Protein sources such as
whey protein concentrate, insoluble dietary fiber from barley
grain, and high calcium intake seem to be very promising. They
may provide greater potential than attempts to lower the fat in
the human diet.
The
role of the thiol N-acetylcysteine in the prevention of tumor
invasion and angiogenesis
Morini M, Cai T, Aluigi MG, Noonan DM, Masiello L, De Flora
S, D'Agostini F, Albini A, Fassina G. [Int J Biol Markers.
1999 Oct-Dec;14(4):268-71. Review.] We have extensively studied
the effects of N-acetylcysteine (NAC), a cytoprotective drug that
can prevent in vivo carcinogenesis. Here we review our findings
NAC completely inhibits gelatinolytic activity of metalloproteases
and chemotactic and invasive activities of tumor cells. In addition,
NAC reduces the number of lung metastases when malignant murine
melanoma cells are injected into nude mice. NAC treatment decreases
the weight of primary tumors and produces a dose-related increase
in tumor latency. Moreover, oral administration of NAC reduces
the formation of spontaneous metastases. In experimental metastasis
assays, we have found a synergistic reduction in the number of
lung metastases after treatment with doxorubicin (DOX) and NAC
in nude mice. In tumorigenicity and spontaneous metastasis assays,
the combined administration of DOX and oral NAC again has shown
synergistic effects on the frequency and weight of primary tumors
and local recurrences and completely prevented the formation of
lung metastases. The addition of NAC to endothelial cells strongly
reduces their invasive activity in response to angiogenic stimuli.
Oral administration of NAC reduces the angiogenic response induced
by KS tumor cell products, confirming the ability of NAC to inhibit
the invasive activity of endothelial cells in vivo and thereby
blocking angiogenesis.
Breast
cancer: pretreatment drug resistance parameters (GSH-system, ATase,
P-glycoprotein) in tumor tissue and their correlation with clinical
and prognostic characteristics
Buser K, Joncourt F, Altermatt HJ, Bacchi M, Oberli A, Cerny
T. [Ann Oncol. 1997 Apr;8(4):335-41.] The identification
of new factors predicting relapse, outcome and response to systemic
therapy in breast cancer is warranted. High levels of GSH, GST
and GPx were associated with favorable clinical characteristics
and good prognosis, whereas low levels of GSH and GST activity
were associated with more aggressive or more advanced disease.
Antioxidant
action via p53-mediated apoptosis
Liu M, Pelling JC, Ju J, Chu E, Brash DE. [Cancer Res.
1998 Apr 15;58(8):1723-9.] Sulfur-containing antioxidants such
as N-acetylcysteine and dimercaptopropanol induced apoptosis in
several transformed cell lines and transformed primary cultures
but not in normal cells. In contrast, chain-breaking antioxidants
such as vitamin E lacked this activity. An increased glutathione
level was not required for apoptosis; however, all apoptosis-inducing
antioxidants elevated the total cellular thiol levels. N-Acetylcysteine
elevated p53 expression posttranscriptionally by increasing the
rate of p53 mRNA translation rather than by altering the protein
stability. Manipulating p53-dependent apoptosis with nontoxic
antioxidants may have a direct clinical application.
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Glutathione and
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