Download Literature review of Nutraceutical Treatment for

Dr. Kevin P. Bethel MD CM FAARM
IAT Clinic, PO Box F42689, Freeport, Grand Bahamas, BAHAMAS
242-352-7455, Fax 242-352-3201, [email protected]
14th September 2012
Literature review of Nutraceutical Treatment for Mesothelioma
Prepared For Gary Brunk
Oncol Rep. 2009 Dec;22(6):1283-91.
Modulation of MMP-2 and MMP-9 by cytokines, mitogens and
inhibitors in lung cancer and malignant mesothelioma cell lines.
Roomi MW, Monterrey JC, Kalinovsky T, Niedzwiecki A, Rath M.
Dr Rath Research Institute, Santa Clara, CA 95050, USA.
Abstract
Matrix metalloproteinases (MMPs) secreted by lung cancer (LC) and malignant mesothelioma (MM),
especially MMP-2 and MMP-9, play crucial roles in tumor invasion and metastasis. We examined the effect
of cytokines, mitogens and inhibitors on MMP-2 and MMP-9 expression in LC and MM cell lines. Human LC
(A-549) and MM (MSTO-211H) cell lines were cultured in appropriate media. At near confluence, the cells
were washed with PBS and incubated in serum-free medium with various concentrations of several
cytokines, mitogens and inhibitors. After 24 h the media were removed and analyzed for MMP-2 and
MMP-9 by gelatinase zymography and quantitated by densitometry. LC expressed MMP-2 whereas MM
expressed MMP-2 and MMP-9. TNF-alpha, IL-1beta, LPS and PMA, stimulated MMP-2 in LC and inhibited
MMP-2 in MM, but had no effect on MMP-9. Doxycycline, EGCG and NM inhibited MMP-2 and MMP-9
expression, in both cell lines. Actinomycin-D, cyclohexamide, retinoic acid and dexamethasone inhibited
MMP-2 in both cancer cell lines and inhibited MMP-9 in MM. Our results show that cytokines and inhibitors
have an up- or down-regulatory effect on MMP-2 and MMP-9 expression in LC and MM, suggesting
the clinical value of targeting these proteases for management of LC and MM and
their pathogenesis.
J Lab Clin Med. 2001 Aug;138(2):101-6.
Inhibition of mesothelioma cell growth in vitro by doxycycline.
Rubins JB, Charboneau D, Alter MD, Bitterman PB, Kratzke RA.
Pulmonary Diseases and Oncology, Department of Medicine, Veterans Affairs Medical Center, Minneapolis,
Minnesota, USA.
Abstract
Malignant mesothelioma causes profound morbidity and nearly universal mortality that is often refractory
to conventional treatment modalities of aggressive surgery, radiotherapy, or chemotherapy. Doxycycline,
a commonly used antibiotic, has anti-tumor activity against several malignancies, but its anti-tumor
effects on malignant mesothelioma have not been evaluated. We report here that concentrations of
doxycycline achievable in serum with typical oral doses had cytostatic effects to varying extent on all
eight of the mesothelioma cell lines studied but did not affect normal lung fibroblasts. Doxycycline
inhibited the production of mitochondrial cytochrome c oxidase, especially in mesothelioma cells more
sensitive to its cytostatic effects, and directly inhibited gelatinase A activity; both of these activities are
putative mechanisms for the cytostatic activity of doxycycline in other tumor cells. Thus doxycycline
may have a role as adjuvant therapy for malignant mesothelioma.
BMC Cancer. 2010 Aug 30;10:464.
COX-2 inhibition improves immunotherapy and is associated with decreased
numbers of myeloid-derived suppressor cells in mesothelioma. Celecoxib
influences MDSC function.
Veltman JD, Lambers ME, van Nimwegen M, Hendriks RW, Hoogsteden HC, Aerts JG, Hegmans JP.
Source
Department of Pulmonary Medicine, Erasmus MC Rotterdam, The Netherlands.
Abstract
BACKGROUND:
Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immature cells that accumulates in
tumour-bearing hosts. These cells are induced by tumour-derived factors (e.g. prostaglandins) and have a critical role
in immune suppression. MDSC suppress T and NK cell function via increased expression of arginase I and
production of reactive oxygen species (ROS) and nitric oxide (NO). Immune suppression by MDSC was found to be
one of the main factors for immunotherapy insufficiency. Here we investigate if the in vivo immunoregulatory function
of MDSC can be reversed by inhibiting prostaglandin synthesis by specific COX-2 inhibition focussing on ROS
production by MDSC subtypes. In addition, we determined if dietary celecoxib treatment leads to refinement of
immunotherapeutic strategies.
METHODS:
MDSC numbers and function were analysed during tumour progression in a murine model for mesothelioma. Mice
were inoculated with mesothelioma tumour cells and treated with cyclooxygenase-2 (COX-2) inhibitor celecoxib,
either as single agent or in combination with dendritic cell-based immunotherapy.
RESULTS:
We found that large numbers of infiltrating MDSC co-localise with COX-2 expression in those areas where tumour
growth takes place. Celecoxib reduced prostaglandin E2 levels in vitro and in vivo. Treatment of tumour-bearing mice
with dietary celecoxib prevented the local and systemic expansion of all MDSC subtypes. The function of MDSC was
impaired as was noticed by reduced levels of ROS and NO and reversal of T cell tolerance; resulting in refinement of
immunotherapy.
CONCLUSIONS:
We conclude that celecoxib is a powerful tool to improve dendritic cell-based
immunotherapy and is associated with a reduction in the numbers and suppressive
function of MDSC. These data suggest that immunotherapy approaches benefit from
simultaneously blocking cyclooxygenase-2 activity.
Int J Cancer. 2004 Apr 10;109(3):322-8.
Preclinical evaluation of the nonsteroidal anti-inflammatory agent celecoxib
on malignant mesothelioma chemoprevention.
Catalano A, Graciotti L, Rinaldi L, Raffaelli G, Rodilossi S, Betta P, Gianni W, Amoroso S, Procopio A.
Source
Department of Molecular Pathology and Innovative Therapies, Polytechnic University of Marche, Ancona, Italy.
[email protected]
Abstract
Malignant mesothelioma (MM) remains the most lethal pleural, peritoneal and pericardial cancer. Here, we
characterize the effects of nonsteroidal anti-inflammatory agents (NSAIDs) on in vitro and in vivo experimental MM
models. Unlike primary normal mesothelial cells, the selective cyclooxygenase (COX)-2 inhibitor celecoxib reduced
the in vitro proliferation of several MM cells derived from previously untreated MM patients. Moreover, celecoxib
significantly inhibited MM cell colony formation in soft agarose (63-78% at 5 x 10(-5) M; p < or = 0.05) and it elicited
remarkable antitumor activity, leading to long-term survival in >37% of nude mice bearing intraperitoneal MM.
Celecoxib was more efficient in inhibiting MM cell growth than acetylsalicylic acid (10(-6) M-10(-2) M), indometacin
(10(-6) M-10(-2) M) and the COX-2 inhibitor NS-398 (10(-6) M-10(-4) M). Efficacy of these different compounds was
not related to the amount of COX-2 protein levels present on MM cells. Celecoxib, in a dose- and time-dependent
manner, induced MM cell apoptosis, which involved decreased Akt phosphorylation, loss of Bcl-2 and Survivin protein
expression and caspase-3 activation. Furthermore, vascular endothelial growth factor (VEGF), an MM autocrine
growth factor and Akt inducer, rescued celecoxib-induced apoptosis and Akt dephosphorylation. When the VEGF
receptor (KDR/Flk-1) inhibitor, SU-1498, was used in combination with celecoxib, IC50 of celecoxib in vitro was
reduced up to 65%. These data demonstrate that celecoxib may have antitumor properties in MM and
provide a rationale for the therapeutic use of celecoxib in combination with a selective VEGF
inhibitor.
Gan To Kagaku Ryoho. 2004 Dec;31(13):2191-4.
[A case report of disseminated malignant mesothelioma of peritoneum
responding remarkably to thalidomide, celecoxib, vinorelbine and CDDP].
Source
Dept. of Surgical, Ashitaka Hospital.
Abstract
Malignant mesothelioma (MM) is a rare neoplasm that is commonly fatal within 12-17 months after diagnosis. There
are no widely accepted curative approaches. It recurs even after the most aggressive surgical resection. MM is
resistant to chemotherapy and radiation. Most of the chemotherapeutics have been evaluated in MM, however, no
drugs have a response rate greater than 20%. The combination of drugs has no increased efficacy compared with
single agents. Vinorelbine has useful clinical activity against MM with a response rate of 24%. Vascular endothelial
growth factor (VEGF) is expressed in MM and pleural effusion of MM. There is a significant inverse correlation
between serum VEGF levels and MM patient survival. Cyclooxygenase-2 (COX-2) is expressed in MM. COX-2 plays
an important role in tumor growth, invasion, and angiogenesis. VEGF and COX-2 are potential targets in MM. The
downregulation of bFGF, VEGF, and maybe some other angiogenesis stimulators, is one of the antiangiogenic
mechanisms of thalidomide. Celecoxib is a potent selective COX-2 inhibitor. Here we report a case of
disseminated malignant mesothelioma of peritoneum responding remarkably to thalidomide,
celecoxib, vinorelbine and CDDP.
Exp Lung Res. 2006 Mar-Apr;32(3-4):69-79.
Inhibition of malignant mesothelioma cell matrix
metalloproteinase production and invasion by a novel nutrient
mixture.
Roomi MW, Ivanov V, Kalinovsky T, Niedzwiecki A, Rath M.
Dr. Rath Research Institute, Cancer Division, Santa Clara, California, USA.
Abstract
Malignant mesothelioma (MM), an asbestos-associated cancer with no known cure, is a highly aggressive
tumor causing profound morbidity and nearly universal mortality. Extracellular matrix (ECM) matrix
metalloproteinases (MMPs) produced by tumor and stromal cells play a key role in tumor invasion and
metastasis. Prevention of ECM degradation by MMP inhibition has been shown to be a promising
therapeutic approach to inhibition of cancer development. Based on reported anticancer properties, the
authors investigated the effect of a mixture (NM) containing lysine, proline, ascorbic acid, and
green tea extract on MM cell line MSTO-211 H proliferation (by [MTT] [3-(4,5-dimethylthiazol-2-yl)2,5-diphenyl tetrazolium bromide] assay), MMP secretion (by gelatinase zymography), invasion (through
Matrigel), and morphology (by hematoxylin and eosin [H&E] staining). MMP-2 and phorbol 12-myristate
13-acetate (PMA)-induced MMP-9 secretion were inhibited by NM in a dose-dependent fashion, with
virtual total inhibition at 500 microg/ml NM. Invasion through Matrigel was inhibited at 50, 100, and 500
microg/ml by 27%, 36%, and 100%, respectively. NM was not toxic to the MM cell line, and H&E staining
did not indicate any changes at and below 100 microg/ml concentration. In conclusion, NM significantly
inhibited MM cell MMP secretion and invasion-both important parameters for cancer prevention,
suggesting NM is an effective treatment strategy for MM.
J Clin Oncol. 2001 Mar 15;19(6):1830-8.
Phase I trial of oral green tea extract in adult patients with
solid tumors.
Pisters KM, Newman RA, Coldman B, Shin DM, Khuri FR, Hong WK, Glisson BS, Lee JS.
Department of Thoracic/Head & Neck Medical Oncology, University of Texas, M. D. Anderson Cancer
Center, Houston, TX 77030, USA. [email protected]
Abstract
PURPOSE: This trial was designed to determine the maximum-tolerated dose, toxicity, and pharmacology
of oral green tea extract (GTE) once daily or three times daily.
PATIENTS AND METHODS: Cohorts of three or more adult cancer patients were administered oral GTE
with water after meals one or three times daily for 4 weeks, to a maximum of 6 months, depending on
disease response and patient tolerance. Pharmacokinetic analyses were encouraged but optional.
RESULTS: Dose levels of 0.5 to 5.05 g/m(2) qd and 1.0 to 2.2 g/m(2) tid were explored. A total of 49
patients were studied. Patient characteristics: median age, 57 years (range, 27 to 77 years); 23 patients
were women (47%); 98% had a Zubrod PS of 1%; 98% had PS of 1; and 21 had non-small-cell lung, 19
had head & neck cancer, three had mesothelioma, and six had other. Mild to moderate toxicities were
seen at most dose levels and promptly reversed on discontinuation of GTE. Dose-limiting toxicities were
caffeine related and included neurologic and gastrointestinal effects. The maximum-tolerated dose was
4.2 g/m(2) once daily or 1.0 g/m(2) three times daily. No major responses occurred; 10 patients with
stable disease completed 6 months of GTE. Pharmacokinetic analyses found accumulation of caffeine
levels that were dose dependent, whereas epigallocatechin gallate levels did not accumulate nor appear
dose related.
CONCLUSION: A dose of 1.0 g/m(2) tid (equivalent to 7 to 8 Japanese cups [120 mL] of
green tea three times daily) is recommended for future studies. The side effects of this
preparation of GTE were caffeine related. Oral GTE at the doses studied can be taken safely
for at least 6 months.
Mol Cell Biochem. 2011 Nov;357(1-2):83-94. Epub 2011 May 19.
Curcumin suppresses growth of mesothelioma cells in vitro and in vivo, in
part, by stimulating apoptosis.
Wang Y, Rishi AK, Wu W, Polin L, Sharma S, Levi E, Albelda S, Pass HI, Wali A.
Source
John D. Dingell VA Medical Center, Karmanos Cancer Institute, Wayne State University, VAMC, 4646 John R.,
Detroit, MI, 48201, USA.
Abstract
Malignant pleural mesothelioma (MPM) is an aggressive, asbestos-related malignancy of the thoracic pleura.
Although, platinum-based agents are the first line of therapy, there is an urgent need for second-line therapies to treat
the drug-resistant MPM. Cell cycle as well as apoptosis pathways are frequently altered in MPM and thus remain
attractive targets for intervention strategies. Curcumin, the major component in the spice turmeric, alone or in
combination with other chemotherapeutics has been under investigation for a number of cancers. In this study, we
investigated the biological and molecular responses of MPM cells to curcumin treatments and the mechanisms
involved. Flow-cytometric analyses coupled with western immunoblotting and gene-array analyses were conducted to
determine mechanisms of curcumin-dependent growth suppression of human (H2373, H2452, H2461, and H226) and
murine (AB12) MPM cells. Curcumin inhibited MPM cell growth in a dose- and time-dependent manner while
pretreatment of MPM cells with curcumin enhanced cisplatin efficacy. Curcumin activated the stress-activated p38
kinase, caspases 9 and 3, caused elevated levels of proapoptotic proteins Bax, stimulated PARP cleavage, and
apoptosis. In addition, curcumin treatments stimulated expression of novel transducers of cell growth suppression
such as CARP-1, XAF1, and SULF1 proteins. Oral administration of curcumin inhibited growth of murine MPM cellderived tumors in vivo in part by stimulating apoptosis. Thus, curcumin targets cell cycle and promotes apoptosis to
suppress MPM growth in vitro and in vivo. Our studies provide a proof-of-principle rationale for further
in-depth analysis of MPM growth suppression mechanisms and their future exploitation in
effective management of resistant MPM.
Eur J Cancer Clin Oncol. 1983 Feb;19(2):263-70.
Activity of camptothecin, harringtonin, cantharidin and
curcumae in the human tumor stem cell assay.
Jiang TL, Salmon SE, Liu RM.
Abstract
The antitumor activity of four investigational natural products (camptothecin, harringtonin, cantharidin
and curcumae) obtained from China were tested on human tumor biopsies in an in vitro soft agar
clonogenic assay system. Significant antitumor activity was seen with camptothecin against human
ovarian cancer and some other adenocarcinomas. Antitumor activity was also observed for harringtonin
against adenocarcinoma and sarcoma. Both drugs also appeared to show activity in melanoma and
mesothelioma. However, cantharidin and curcumae were relatively ineffective on the human tumors
tested. For purposes of comparing the intensity of antitumor effects with standard cytotoxic drugs to
those of the four new agents, the ID50 values were calculated. The ratio of ID50S of new drugs to the
standard agents doxorubicin, cis-platinum and vinblastine (ID50 of the standard drug/ID50 of tested drug)
were 10.2, 64.1 and 1.9 for camptothecin and 1.5, 10.3 and 0.9 for harrington respectively. A relationship
was observed between the duration of drug exposure (1 hr prior to plating vs continuous contact in the
agar) and inhibition of clonogenic tumor cells for camptothecin, harringtonin and doxorubicin.
Oncogene. 2004 Jun 24;23(29):5032-40.
Growth inhibition and induction of apoptosis in mesothelioma cells by
selenium and dependence on selenoprotein SEP15 genotype.
Apostolou S, Klein JO, Mitsuuchi Y, Shetler JN, Poulikakos PI, Jhanwar SC, Kruger WD, Testa JR.
Human Genetics Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111-2497, USA.
Abstract
Malignant mesotheliomas (MMs) are aggressive tumors derived from mesothelial cells lining the lungs, pericardium
and peritoneum, and are often associated with occupational asbestos exposure. Suppression subtractive
hybridization was used to identify genes differentially expressed in MM cells compared to normal mesothelial cells. A
gene, SEP15, encoding a 15-kDa selenium-containing protein was isolated using this approach and was
subsequently shown to be downregulated in approximately 60% of MM cell lines and tumor specimens. A SEP15
polymorphic variant, 1125A, resides in the SECIS recognition element in the 3'-UTR and may influence the efficiency
of Sec incorporation into the protein during translation. Since previous studies have implicated a potential role of the
trace element selenium as a chemopreventive agent in animal models and in several types of human cancer, we
investigated the effect of selenium on MM cells and its dependence on SEP15 genotype. Selenium was shown to
inhibit cell growth and induce apoptosis in a dose-dependent manner in MM cells but had minimal effect on normal
mesothelial cells. However, MM cells with downregulated SEP15 or the 1125A variant were somewhat less
responsive to the growth inhibitory and apoptotic effects of selenium than MM cells expressing wild-type protein.
RNAi-based knockdown studies demonstrated that SEP15 inhibition makes sensitive MM cells more resistant to
selenium. These
data imply that selenium may be useful as a chemopreventive agent in
individuals at high risk of MM due to asbestos exposure, although those with the 1125A
polymorphism may be less responsive to the protective benefits of dietary selenium
supplementation.
J Biol Chem. 2001 Aug 10;276(32):30183-7. Epub 2001 Jun 25.
The human type 2 iodothyronine deiodinase is a selenoprotein highly
expressed in a mesothelioma cell line.
Curcio C, Baqui MM, Salvatore D, Rihn BH, Mohr S, Harney JW, Larsen PR, Bianco AC.
Department of Medicine, Thyroid Division, Brigham and Women's Hospital and Harvard Medical School, Boston,
Massachusetts 02115, USA.
Abstract
Types 1 and 3 iodothyronine deiodinases are known to be selenocysteine-containing enzymes. Although a putative
human type 2 iodothyronine deiodinase (D2) gene (hDio2) encoding a similar selenoprotein has been identified, basal
D2 activity is not selenium (Se)-dependent nor has D2 been labeled with (75)Se. A human mesothelioma cell line
(MSTO-211H) has recently been shown to have approximately 40-fold higher levels of hDio2 mRNA than mesothelial
cells. Mesothelioma cell lysates activate thyroxine (T(4)) to 3,5,3'-triiodothyronine with typical characteristics of D2
such as low K(m) (T(4)), 1.3 nm, resistance to propylthiouracil, and a short half-life ( approximately 30 min). D2
activity is approximately 30-fold higher in Se-supplemented than in Se-depleted medium. An antiserum prepared
against a peptide deduced from the Dio2 mRNA sequence precipitates a (75)Se protein of the predicted 31-kDa size
from (75)Se-labeled mesothelioma cells. Bromoadenosine 3'5' cyclic monophosphate increases D2 activity and
(75)Se-p31 approximately 2.5-fold whereas substrate (T(4)) reduces both D2 activity and (75)Se-p31 approximately
2-3-fold. MG132 or lactacystin (10 microm), inhibitors of the proteasome pathway by which D2 is degraded, increase
both D2 activity and (75)Se-p31 3-4-fold and prevent the loss of D2 activity during cycloheximide or substrate (T(4))
exposure. Immunocytochemical studies with affinity-purified anti-hD2 antibody show a Se-dependent increase in
immunofluorescence. Thus, human D2 is encoded by hDio2 and is a member of the selenodeiodinase family
accounting for its highly catalytic efficiency in T(4) activation.
Tumori. 1988 Jun 30;74(3):339-45.
Melatonin increase as predictor for tumor objective
response to chemotherapy in advanced cancer patients.
Lissoni P, Tancini G, Barni S, Crispino S, Paolorossi F, Rovelli F, Cattaneo G, Fraschini F.
Source
Division of Radiation Oncology, Ospedale San Gerardo, Monza, Milano, Italia.
Abstract
Clinical studies have demonstrated an altered pineal function in cancer patients. Owing to the
documented antineoplastic activity of the pineal gland, these anomalies could have a prognostic
significance. This study was carried out to monitor changes in blood levels of melatonin, the
most important pineal hormone, in relation to the clinical response to chemotherapy in human
neoplasms. The study included 42 cancer patients of both sexes (breast cancer, 10; lung cancer,
13; colon cancer, 11; soft tissue sarcoma, 4; testicular cancer, 1; Hodgkin's disease, 1; peritoneal
mesothelioma, 2). Melatonin serum levels were measured by radioimmunoassay before and 28
days after each cycle of chemotherapy. The results showed that, irrespectively of the type of
tumor and chemotherapeutic regimen, 12/16 patients (75%) whose melatonin markedly enhanced
after chemotherapy had an objective regression. In contrast, 2/26 patients only (8%) whose
melatonin did not enhance after chemotherapy had a clinical response. The percentage of
objective responses was statistically significantly higher in patients with a chemotherapy-induced
melatonin increase than in those with no melatonin increase (p less than 0.001). This study seems
to demonstrate that melatonin determination can be used as a predictor of the objective response
to chemotherapy in cancer patients. Moreover, it suggests that the antineoplastic effect of
cytotoxic drugs may require participation of the pineal gland.
J Biol Regul Homeost Agents. 1997 Jul-Sep;11(3):119-22.
Anticancer neuroimmunomodulation by pineal hormones
other than melatonin: preliminary phase II study of the
pineal indole 5-methoxytryptophol in association with lowdose IL-2 and melatonin.
Lissoni P, Fumagalli L, Paolorossi F, Rovelli F, Roselli MG, Maestroni GJ.
Source
Division of Oncological Radiotherapy, S. Gerardo Hospital, Monza, Milano.
Abstract
Despite several years of experimental observations, the clinical application of the
neuroimmunomodulation is still at the beginning. The pineal gland plays a main role in
mediating the link between psychoneuroendocrine and immune systems. Melatonin (MLT),
which is the main pineal hormone produced during the night, has appeared to amplify IL-2
anticancer activity. Other pineal hormones, however, would have immunomodulatory activity, in
particular 5-methoxytryptophol (5-MTT), which is mainly produced during the light phase of the
day. Previous clinical studies have shown that low-dose IL-2 plus MLT may have therapeutic
efficacy in advanced cancer patients with neoplasms generally resistant to IL-2 alone, with a
tumor regression rate generally less than 20% and an acceptable toxicity. The present study was
carried out to evaluate the efficacy of low-dose IL-2 in association with both MLT and 5-MTT.
The study included 14 untreatable advanced solid tumor patients (lung cancer: 4; gastric cancer:
3; mesothelioma: 2; hepatocarcinoma: 2; pancreatic cancer: 1; melanoma: 1; colon cancer: 1).
IL-2 was injected subcutaneously at 3 MIU/day for 6 days/week for 4 weeks, by repeating a
second cycle after a 21- day rest period. Both MLT and 5-MTT were given orally at 40 mg/day
in the evening and at 1 mg/day at noon. The clinical results, as evaluated by WHO criteria after
each cycle, consisted of partial response (PR) in 4/14 (29%) (lung cancer: 2; hepatocarcinoma: 1;
mesothelioma: 1), stable disease (SD) in 6 and progressive disease in the last 4 patients. The
treatment was extremely well tolerated in all patients, and in particular no fever greater than 38
degrees C occurred. These preliminary results show that the neuroimmunotherapy with lowdose IL-2 plus two pineal hormones, MLT and 5-MTT, is a well tolerated and potentially
effective cancer therapy of untreatable advanced solid tumor patients, with results
apparently superior with respect to those previously described with IL-2 plus MLT alone.
Biochem Biophys Res Commun. 2010 Apr 2;394(2):249-53. Epub 2010 Feb 19.
High dose of ascorbic acid induces cell death in
mesothelioma cells.
Source
Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo, 38-1 Komaba, Meguro-ku, Tokyo 153-8902, Japan.
Abstract
Malignant mesothelioma is an asbestos-related fatal disease with no effective cure. Recently,
high dose of ascorbate in cancer treatment has been reexamined. We studied whether high dose
of ascorbic acid induced cell death of four human mesothelioma cell lines. High dose of ascorbic
acid induced cell death of all mesothelioma cell lines in a dose-dependent manner. We further
clarified the cell killing mechanism that ascorbic acid induced reactive oxygen species and
impaired mitochondrial membrane potential. In vivo experiment, intravenous administration of
ascorbic acid significantly decreased the growth rate of mesothelioma tumor inoculated in mice.
These data suggest that ascorbic acid may have benefits for patients with mesothelioma.
Am J Respir Cell Mol Biol. 2011 Jan;44(1):108-17. Epub 2010 Mar 4.
Selective ascorbate toxicity in malignant mesothelioma: a
redox Trojan mechanism.
Source
Department of Environment and Life Sciences, DiSAV, University of Piemonte Orientale
Amedeo Avogadro, Viale T. Michel 11, Alessandria, Italy. [email protected]
Abstract
We studied the mechanism of ascorbate toxicity in malignant mesothelioma (MMe) cells.
Neutral red uptake showed that ascorbate, but not dehydroascorbate, was highly toxic in the
MMe cell lines REN and MM98, and less toxic in immortalized (human mesothelial cells-htert)
and primary mesothelial cells. Ascorbate transport inhibitors phloretin, sodium azide, and
ouabain did not reduce ascorbate toxicity. Ascorbate promoted the formation of H(2)O(2) in the
cell medium, and its toxicity was suppressed by extracellular catalase, but the concentration of
endogenous catalase was higher in MMe cells than in normal cells. The confocal imaging of cells
loaded with the dihydrhodamine 123 reactive oxygen species probe showed that ascorbate
caused a strong increase of rhodamine fluorescence in MMe cells, but not in mesothelial cells.
MMe cells showed a higher production of superoxide and NADPH oxidase (NOX)4 expression
than did mesothelial cells. Two inhibitors of cellular superoxide sources (apocynin and rotenone)
reduced ascorbate toxicity and the ascorbate-induced rise in rhodamine fluorescence. NOX4
small interfering RNA also reduced ascorbate toxicity in REN cells. Taken together, the data
indicate that ascorbate-induced extracellular H(2)O(2) production induces a strong oxidative
stress in MMe cells because of their high rate of superoxide production. This explains the
selective toxicity of ascorbate in MMe cells, and suggests its possible use in the clinical
treatment of malignant mesothelioma.
From the literature review about your mesothelioma above I have prescribed:
1. I would suggest “Turmeric Extract (curcumin) 500 mg” taken as one capsules three
times a day and then increase to 2 capsules three times a day as tolerated. Order
www.vrp.com
2. I would suggest “Green Tea Extract (EGCG) 420 mg” three time a day. Order
www.naturessunshine.com sponsor number 116365 product # 1096-8
3. It would be advisable to supplement with ‘High Potency Protease’ taken three
times a day daily on empty stomach. Order www.naturessunshine.com sponsor
number 116365
4. I would suggest ‘L-lysine’ taken one capsule three times a day. Order
www.naturessunshine.com sponsor # 116365.
5. I would suggest Methylselenocystiene 200 mcg daily. Reorder: www.vrp.com
6. I would suggest “off-label” prescription of Celebrex 100 mg twice a day with meal.
7. I would suggest “off-label” prescription of Doxycycline 100mg twice a day with
meal. NOTE: Take “Probiotic Eleven” from www.naturesunshine.com sponsor
#116365. Taken 2 capsules at bedtime or lunch time, at a time of day different
from the dose of doxycycline.
8. Melatonin 20 mg taken once a night (especially if you are receiving HSP vaccine).
9. Vitamin C 1000 mg (Citrus Bioflavanoids from www.naturessunshine.com) taken 3
times a day as much as is tolerated. Also taken with C-Statin ( from IAT front
office) to maintain Vit C levels in the tumor sites.
Kevin Bethel MD CM FAARM FICT
Life, Liberty, and the Pursuit of Wellness