DNC News

 

DNC NEWS: Glioblastoma; some considerations for adjuvant treatments

April 30, 2005

Subject: a short review of nutritional supplements which have benefit in treating glioblastomas.

 

A glioblastoma is a type of a primary brain tumor. Primary brain tumors are those that arise from the brain itself rather than traveling or metastasizing from another location in the body. Approximately 17,000 new cases of primary brain tumors are treated each year in the United States .

 

Primary brain tumors can either be benign or malignant. Benign brain tumors (eg. meningiomas, acoustic neuromas, pituitary gland tumors) usually grow slowly and can often be removed by surgery depending upon their specific location in the brain. Malignant brain tumors, such as glioblastomas and anaplastic astrocytomas, among others, tend to grow rapidly spreading into the surrounding brain tissue and often cannot be entirely removed surgically.

 

Primary brain tumors can occur in both children as well as adults. The most common age groups are children 3 to 12 and adults ages 40-70. Metastatic brain tumors, such as glioblastomas, are much more common in adults than in children.

 

There are many different types of brain tumors. One type, know as astrocytomas, are tumors that arise from astrocyte cells - part of the supportive (neuroglial) tissue of the brain. Astrocytomas account for about half of all primary brain and spinal cord tumors.

Glioblastomas are fast growing astrocytomas that contain areas of dead (necrotic) tumor cells. In adults, glioblastoma occurs most often in the cerebrum, especially in the frontal and temporal lobes of the brain. They rarely occur in the cerebellum or brain stem.

Glioblastoma are difficult to treat although surgery, radiation therapy, steroids, and chemotherapy have shown the ability to prolong survival.

 

Having a glioblastoma is about as bleak a diagnosis as anyone can have. Median survival with treatment in 2004 was about one year. Yet there are exceptions to the rule.

 

One example is Ben Williams who was diagnosed with glioblastoma in 1995.

The following is from his website (http://virtualtrials.com/williams.cfm):

 

 

“Treatment for GBMs and other high-grade gliomas is changing rapidly. Until the last five years there was a standard treatment in the USA , including surgery, radiation, and chemotherapy with a nitrosourea, either BCNU alone or CCNU combined with procarbazine and vincristine (known as the PCV combination). While this treatment has worked for a small minority of people, its 5-year survival rate has been only 2-5%. Alternatives to this traditional treatment regimen are imperative if GBM patients are to have any realistic hope of surviving their disease. Fortunately, new treatments are now being introduced at a rapid rate. But unfortunately, most still are not available outside of clinical trials and there is no consensus about what is the best treatment for this deadly disease.

 

"There are two general premises to the approach to treatment that will be described. The first of these is borrowed from the treatment approach that has evolved in the treatment of AIDS. Both HIV and cancer involve biological entities that mutate at high rates. This implies that unless a treatment is immediately effective the dynamics of evolution will create new forms that are resistant to whatever the treatment may be. However, if several different treatments are used simultaneously (instead of sequentially, which is typically the case), any given mutation has a much smaller chance of being successful.

 

"A second general principle is that any successful treatment will need to be systemic in nature because it is impossible to identify all of the extensions of the tumor into normal tissue. Moreover, cancer cells are typically evident in locations in the brain distant from the main tumor, indicating that metastases within the brain can occur, although the great majority of tumor recurrences are within or proximal to the original tumor site. Localized treatments such as radiosurgery may be beneficial in terms of buying time, but they are unlikely to provide a cure. Even if the localized treatment eradicates 99.9% of the tumor, the small amount of residual tumor will expand geometrically and soon will cause significant clinical problems .

 

"Until recently, the only systemic treatment available has been chemotherapy, which historically has been ineffective except for a small percentage of patients . An important issue, therefore, is whether chemotherapy can be made to work substantially better than it typically does. Agents that facilitate or augment its effects are critically important. Such agents are available but not widely used. Also becoming available are new systemic treatments that are much less toxic than traditional chemotherapy. The availability of these treatments raises the possibility that some combination of these new agents can be packaged that is substantially less toxic and yet provides effective treatment based on several different independent principles. Thus, the AIDS-type of combination approach is now a genuine possibility whereas it would not have been ten years ago. Because oncologists have been slow to appreciate the significance of the increased availability of these relatively nontoxic treatments, patients learn about them piecemeal if at all. Thus, patients themselves need to become familiar with these new agents and the evidence available regarding their clinical effectiveness . It is possible, although by no means proven, that some combination of these new agents offers the best possibility for survival.

 

"Patients may or may not learn about the treatments that will be described from their physicians. To appreciate why this may be, it is important to understand how American medicine has been institutionalized. For most medical problems there is an accepted standard of what is the best available treatment. Ideally this is based on phase III clinical trials. Treatments that have been studied only in nonrandomized phase II trials will rarely be offered as a treatment option, even if the accepted "best available treatment" is generally ineffective. What happens instead is that patients are encouraged to participate in clinical trials. The problem with this approach is that most medical centers offer few options for an individual patient. Thus, even though a given trial for a new treatment may seem very promising, patients can participate only if that trial is offered by their medical facility. An even more serious problem is that clinical trials with new treatment agents almost always study that agent in isolation, usually with patients with recurrent tumors who have the worst prognoses. For newly diagnosed patients this is at best a last resort. What is needed instead is access to the most promising new treatments, in the optimum combinations, at the time of initial diagnosis.

 

"Physicians rarely will inform a patient about clinical trials being conducted elsewhere. Moreover, the idea that several different agents from separate phase II clinical trials might be combined will be met with great resistance. Patients themselves will therefore need to become informed about what options are available, and which kinds of combinations seem most promising. In addition to the information that will be presented here, other information, especially about which new clinical trials are available, are available elsewhere on this website (address: www.virtualtrials.com ).” [i]

 

 

 

From the point of view of naturopathic medicine there are a number of agents which should be used to augment the effects of chemotherapy and radiation treatments for glioblastoma. Following Mr. Williams' suggestion, it makes great sense to use as many simultaneous treatment options as possible to increase the effective kill of the tumor cells. Sequential treatments allow the cells to adapt and become resistant. With this in mind I searched the literature today ( April 30, 2005 ). The following list of nutritional supplements is far from a comprehensive list of things useful in treating cancer. I've limited this list to things which are of particular interest when treating glioblastoma. Other supplements should also be considered especially ones which have a systemic effect on the immune system.

 

 

Berberine: Berberine is a yellow colored alkaloid commonly used in herbal medicine. It is found in a number of different medicinal herbs; the most popular is Golden seal (Hydrastis Canadensis), but also in Oregon grape and Chinese Isatis. The later two have become more common sources as Goldenseal has become rare from over harvesting.

Berberine increases the benefit of chemotherapy .

In one laboratory study of using both various kinds of glioma cell cultures and implanted tumors in rodents (156), the cytotoxic effects of berberine were compared to those of BCNU and to the combination of berberine and BCNU. Berberine used alone produced a 91% kill rate in cell cultures, compared to 43% for BCNU. The combination produced a kill rate of 97%. [ii] [reference].

Berberine increases the benefit of radiation treatment . It makes glioblastoma cells more sensitive to radiation damage [iii] without effecting healthy brain cells. Doses of 300 mg. several times a day are safe and provide maximum serum concentrations.

 

Vitamin K   

Both Vitamin K-2 and Vitamin K-3 inhibit the growth of glioblastoma cells. Vitamin K-3 has a greater effect. [iv] In research focused on other cancer types, a combination of vitamin K-3 and vitamin C causes a specific form of cell death called autoschizis. [v] Pretreatment with this Vitamin K-3 and C combination makes other cancer cell types more sensitive to chemotherapy [vi] and radiation. [vii] There is no reason not to assume the same effect will occur with glioblastoma cells.

 

 

Melatonin:

Low melatonin levels increase risk for all types of cancer. In a clinical trial in which melatonin was administered to patients being treated with radiation therapy for glioblastoma a very significant increase in one year survival was seen. [viii]

 

Selenium:

Selenium inhibits the growth of some lines of human glioblastoma cells. [ix]

 

Vitamin D :

Vitamin D kills glioblastoma cells. [x]

 

Vitamin E :

The succinate form of vitamin E makes chemotherapy treatment of glioblastoma cells more effective. [xi] In other types of cancer this same form of vitamin E makes the cancer cells more sensitive to radiation treatment. The same may apply to glioblastoma. [xii]

 

Boswellia:

The resins of the Indian herb Boswellia are commonly used for treating inflammation. They are useful in decreasing the brain swelling associated with glioblastoma allowing a decrease in the use of prednisone and the resulting side effects. [xiii] Boswellia also kills glioblastoma cells [xiv] in a dose dependent manner. [xv]

Soy:

Certain saponin extracts of soy beans inhibit or kill glioblastoma cells. [xvi]

 

Other Treatments:

There is every reason to believe that many of the other nutritional and botanical treatments found useful in treating other types of cancer may also apply to treating glioblastoma but I am not going to list them here.

The drug and radiation protocols for treating glioblastoma are changing rapidly. Information on the most current treatments and drug trials can be found at:

http://virtualtrials.com/index.cfm

 

 

 

References and abstracts:

[i] http://virtualtrials.com/williams.cfm

Treatment Options for Glioblastoma and other Gliomas

Prepared by Ben A. Williams

Glioblastoma Diagnosis, March, 1995

 

A more extensive account of Mr. Williams' philosophy of treatment, and the reasons for it, are provided in his (2002) book, 'Surviving "Terminal" Cancer: Clinical Trials, Drug Cocktails, and Other Treatments Your Doctor Won't Tell You About'. It can be ordered elsewhere on this website, from Amazon.com, from your local bookstore, or directly from the publisher: Fairview Press

2450 Riverside Ave.

Minneapolis , MN 55454

1-800-544-8207

FAX: 612.672.4980

www.fairviewpress.org

 

[ii] Zhang, R. X., et al . Laboratory studies of berberine used alone and in combination with 1,3-bis(2-chloroethyl)-1-nitrosourea to treat malignant brain tumors . Chinese Medical Journal, 1990, 103, 658-665

 

[iii] Integrative Cancer Therapeutics

Integrative Tumor Board: Glioblastoma Multiforme: Nutritional and Botanical Approach

Wallace Integr Cancer Ther.2004; 3: 152-163.

 

The identification of nontoxic agents that can enhance the efficacy of postoperative radiotherapy

for patients with glioblastoma multiforme (GBM) remains a challenge in oncology. We evaluated

human GBM cell lines for their responsiveness to berberine, an alkaloid compound used commonly in

Asia as an antibiotic. In experiments measuring clonogenic survival, treatment with a nontoxic dose

of berberine rendered GBM cells more sensitive than vehicle-treated control cells to x-rays. Such

radiosensitization was not observed in parallel experiments with primary human glial cultures.

These data suggest that berberine could be integrated with postoperative radiotherapy to selectively promote residual GBM tumor cell death.

 

[iv] Acta Neurol Belg. 2004 Sep;104(3):106-10

Comparison of vitamins K1, K2 and K3 effects on growth of rat glioma and human glioblastoma multiforme cells in vitro .

Oztopcu P, Kabadere S, Mercangoz A, Uyar R.

Osmangazi University Art and Sciences Faculty Department of Biology, Eskisehir , Turkiye.

 

Glioblastoma multiforme is characterized as highly invasive and rapidly growing astrocytomas, and scientists have sought for efficient treatment against malignant gliomas for a long time. Therefore, we compared the respond of rat glioma (C6) and glioblastoma multiforme cells derived from two patients to vitamins K1, K2 and K3. The cells were exposed to 100, 250, 500, 750 and 1000 microM of vitamins K1 and K2 , and 1, 10, 25, 50, 75 and 100 microM of vitamin K3 for 24 hours in an incubator atmosphere of 5% CO2, 37 degrees C and 100% humidity. Cell viability was estimated by MTT assay. Vitamin K1 showed no growth effect on all the glioma cells examined. Vitamin K2 did not cause any change in number of C6, however induced growth inhibition in a dose-dependent manner on glioblastoma multiforme. The IC50 values of vitamin K2 were 960 microM and 970 microM for glioblastoma multiforme, respectively. Vitamin K3 had also growth inhibitory effect in a dose-dependent manner on both C6 and glioblastoma multiforme. The IC50 values were 41 microM, 24 microM and 23 microM for vitamin K3, respectively. We concluded that vitamin K3 is more effective than vitamin K2 for inhibition of cancer cell growth, and might have an alternative value as an anticancer drug against glioblastoma multiforme.

 

PMID: 15508263 [PubMed - indexed for MEDLINE]

 

[v] Scanning. 1998 Nov;20(8):564-75.

Cancer cell necrosis by autoschizis: synergism of antitumor activity of vitamin C: vitamin K3 on human bladder carcinoma T24 cells.

Gilloteaux J, Jamison JM, Arnold D, Ervin E, Eckroat L, Docherty JJ, Neal D, Summers JL.

 

Department of Anatomy, Lake Erie College of Osteopathic Medicine , Pennsylvania 16509-1025 , USA . jgilloteaux@lecom.edu

 

Scanning and transmission electron microscopy and fluorescence light microscopy were employed to characterize the cytotoxic effects of vitamin C (VitC), vitamin K3 (VitK3) or a VitC:VK3 combination on a human bladder carcinoma cell line (T24) following 1-h and 2-h vitamin treatment. T24 cells exposed to VitC alone exhibited membranous damage (blebs and endoplasmic extrusions, elongated microvilli). VitK3-treated cells displayed greater membrane damage and enucleation than those treated with VitC as well as cytoplasmic defects characteristic of cytoskeletal damage. VitC:VitK3-treated cells showed exaggerated membrane damage and an enucleation process in which the perikarya separate from the main cytoplasmic cell body by self-excision. Self-excisions continued for perikarya which contained an intact nucleus surrounded by damaged organelles. After further excisions of cytoplasm, the nuclei exhibited nucleolar segregation and chromatin decondensation followed by nuclear karryorhexis and karyolysis. This process of cell death induced by oxidative stress was named autoschizis because it showed both apoptotic and necrotic morphologic characteristics.

 

[vi] Int J Cancer. 1987 Oct 15;40(4):575-9

Non-toxic potentiation of cancer chemotherapy by combined C and K3 vitamin pre-treatment.

Taper HS, de Gerlache J, Lans M, Roberfroid M.

 

Unite de Biochimie Toxicologique et Cancerologique, Universite Catholique de Louvain, Brussels , Belgium .

 

The influence on the survival of ascitic liver tumor (TLT)-bearing mice of combined vitamins C and K3 administered before or after a single i.p. dose of 6 different cytotoxic drugs, all commonly used in human cancer therapy, was investigated. Combined i.p. administration of these vitamins produced a distinct chemotherapy-potentiating effect for all drugs examined, especially when injected before chemotherapy. This potentiating treatment did not increase the general and organ toxicity that accompanies cancer chemotherapy. The possible generation of peroxides followed by membrane lipid alteration, DNase activation and DNA destruction by combined vitamin C and K3 in catalase-deficient cancer cells might be involved in the mechanisms of this selective potentiation.

 

[vii] Anticancer Res. 1996 Jan-Feb;16(1):499-503.

Potentiation of radiotherapy by nontoxic pretreatment with combined vitamins C and K3 in mice bearing solid transplantable tumor.

Taper HS, Keyeux A, Roberfroid M.

 

Departement des Sciences Pharmaceutiques, Universite Catholique de Louvain, Brussels , Belgium .

 

BACKGROUND: The effect of intraperitoneal and oral pretreatment with combined vitamins C and K3 on the single dose radiotherapy of a transplantable solid mouse tumor have been investigated. MATERIALS AND METHODS: Groups of mice bearing intramuscularly transplanted liver tumors, were orally and parenterally pretreated with combined vitamins C and K3 and locally irradiated with single doses of 20, 30, or 40 Gy of X-rays. After this treatment tumor dimensions were measured twice weekly and the approximate tumor volume in groups of pretreated vitamins and irradiated mice was compared to the groups of mice only irradiated and to the absolute control groups without any therapy. RESULTS: This nontoxic pretreatment produced statistically significant potentiation of radiotherapy induced by 20 to 40 Gy of X-rays doses in groups of 11 to 20 mice. Combined vitamins C with K3 most probably constitute a redox-cycling system producing hydrogen peroxide and other active oxygen species to which cancer cells are selectively sensitive due to their frequent deficiency in enzymatic defense system against free oxyradicals agression. CONCLUSIONS: A possible introduction of such nontoxic and selective potentiation procedure into classical protocols of human cancer therapy appears to be generally accessible and without any additional risk for patients.

 

[viii] Oncology. 1996 Jan-Feb;53(1):43-6.

Increased survival time in brain glioblastomas by a radioneuroendocrine strategy with radiotherapy plus melatonin compared to radiotherapy alone.

Lissoni P, Meregalli S, Nosetto L, Barni S, Tancini G, Fossati V, Maestroni G.

 

Division of Oncological Radiotherapy, San Gerardo Hospital, Monza , Italy .

 

The prognosis of brain glioblastoma is still very poor and the median survival time is generally less than 6 months. At present, no chemotherapy has appeared to influence its prognosis. On the other hand, recent advances in brain tumor biology have suggested that brain tumor growth is at least in part under a neuroendocrine control, mainly realized by opioid peptides and pineal substances. On this basis, we evaluated the influence of a concomitant administration of the pineal hormone melatonin (MLT) in patients with glioblastoma treated with radical or adjuvant radiotherapy (RT). The study included 30 patients with glioblastoma, who were randomized to receive RT alone (60 Gy) or RT plus MLT (20 mg/daily orally) until disease progression. Both the survival curve and the percent of survival at 1 year were significantly higher in patients treated with RT plus MLT than in those receiving RT alone (6/14 vs. 1/16). Moreover, RT or steroid therapy-related toxicities were lower in patients concomitantly treated with MLT. This preliminary study suggests that a radioneuroendocrine approach with RT plus the pineal hormone MLT may prolong the survival time and improve the quality of life of patients affected by glioblastoma.

 

PMID: 8570130 [PubMed - indexed for MEDLINE]

 

[ix] Biol Trace Elem Res. 1995 Jul;49(1):1-7.

Effect of selenium on malignant tumor cells of brain.

Zhu Z, Kimura M, Itokawa Y, Nakatsu S, Oda Y, Kikuchi H.

 

Department of Hygiene, Faculty of Medicine, Kyoto University , Japan .

 

Some reports have demonstrated that selenium can inhibit tumorigenesis in some tissues of animal. However, little is known about the inhibitory effect on malignant tumor cells of brain. The purpose of our study was to determine the biological effect of selenium on growth of rat glioma and human glioblastoma cell lines. Cell lines C6 and A172 were obtained from Japanese Cancer Research Resources Bank, Tokyo , Japan (JCRB). Cells were cultured in Dulbecco's Modified Eagle's Medium (DMEM) supplemented with 10% fetal calf serum at 37 degrees C in a humidified atmosphere of air and 5% CO2. Antiproliferative effects of selenium were evaluated using growth rate assay quantifying cell number by MTT assay. An antiproliferative effect of selenium was found in two cell lines, which was more effective on human A172 glioblastoma and less effective on rat C6 glioma.

 

PMID: 7577318 [PubMed - indexed for MEDLINE]

 

 

[x] Acta Neurochir (Wien). 1998;140(7):707-13; discussion 713-4.

Vitamin D metabolites activate the sphingomyelin pathway and induce death of glioblastoma cells.

Magrassi L, Adorni L, Montorfano G, Rapelli S, Butti G, Berra B, Milanesi G.

Department of Surgery, University of Pavia-IRCCS Policlinico S. Matteo, Italy .

 

1 alpha, 25-dihydroxyvitamin D3 was previously shown to induce cell death in brain tumour cell lines when added to the medium at micromolar concentration. In this paper we show that Cholecalciferol, a poor ligand of the vitamin D receptor, also induces cell death of HU197 human glioblastoma cell line and early passages cultures derived from a recurrent human glioblastoma. This finding suggests that the effects of vitamin D metabolites on brain tumour cells are at least partially independent from the activation of the classic nuclear receptor pathway. Vitamin D metabolites have been shown to activate the sphingomyelin pathway inducing an increase in cellular ceramide concentration. We determined the levels of sphingomyelin ceramide and ganglioside GD3 in Hu197 cells after treatment with cholecalciferol. A significant increase in ceramide concentration and a proportional decrease in sphingomyelin was already present after 6 hours of cholecalciferol treatment when no morphological changes were visible in the cultures. Treatment with ceramides (N-acetylsphingosine or natural ceramide from bovine brain) of the same cells also induces cell death. Similarly, treatment of the same cells with bacterial Sphingomyelinase also results in cell death. The demonstration of an increase in intracellular ceramide after cholecalciferol treatment and the ability of ceramide to induce cell death suggest that the sphingomyelin pathway may be implicated in the effect of vitamin D metabolites on human glioblastoma cells. Inhibition of ceramide biosynthesis by fumonisin B1 treatment did not alter the dose response curve of HU197 cells to cholecalciferol. Insensitivity to fumonisin B1 together with a decrease in sphingomyelin content after cholecalciferol treatment indicate that activation of sphingomyelinase should be responsible for the increase in intracellular ceramide concentration.

 

PMID: 9781285 [PubMed - indexed for MEDLINE]

 

 

[xi] Cancer Lett. 2005 Jan 20;217(2):181-90.

Potentiation by alpha-tocopheryl succinate of the etoposide response in multidrug resistance protein 1-expressing glioblastoma cells.

 

Kang YH, Lee E, Youk HJ, Kim SH, Lee HJ, Park YG, Lim SJ.

 

Research Institute, National Cancer Center , 809 Madu-Dong, Ilsan-gu, Goyang, Gyeonggi 411-769, South Korea .

 

Multidrug resistance protein 1 (MRP1) is one of the representative members of the ATP-binding cassette superfamily of transporters that is involved in resistance to chemotherapeutic agents in cancer patients. MRP1 functions as an efflux pump of drugs, primarily those conjugated to glutathione (GSH). Decreases in the intracellular concentration of GSH have been shown to enhance the response of MRP1-overexpressing cells to MRP1-substrate drugs by limiting the available drug-GSH conjugates. We report here that alpha-tocopheryl succinate (TOS), a vitamin E analogue, decreased intracellular GSH concentration and blocked MRP1 function in glioblastoma cells. Functional blockade by TOS of MRP1 was confirmed by the enhanced accumulation of etoposide (VP-16), an MRP1-substrate drug. As a result, co-treatment of TOS with VP-16 or treatment with liposomes containing both TOS and VP-16 greatly enhanced the response of MRP1-expressing glioblastoma cells to VP-16. TOS may be a promising adjuvant for enhancing the therapeutic efficacy of VP-16 in patients with MRP1-expressing glioblastomas.

 

PMID: 15617835 [PubMed - indexed for MEDLINE]

 

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Int J Cancer. 2004 Nov 10;112(3):385-92.

Role of reactive oxygen species in the induction of apoptosis by alpha-tocopheryl succinate.

Kang YH, Lee E, Choi MK, Ku JL, Kim SH, Park YG, Lim SJ.

 

Research Institute, National Cancer Center , Goyang, Gyeonggi , Korea .

 

Alpha-tocopheryl succinate (TOS), a vitamin E analog, is a promising anticancer agent due to its abilities to inhibit proliferation and to induce apoptosis in a variety of human malignant cell lines, while being relatively less active toward normal cells. However, the molecular mechanisms underlying the apoptotic effects of TOS are not precisely understood. Reports that TOS can generate reactive oxygen species (ROS) prompted us to investigate the role of ROS in TOS-induced apoptosis in cancer cells. We found that the human lung cancer A549 and H460 cell lines were much more sensitive to TOS-induced apoptosis than the human glioblastoma T98G and U87MG cell lines. Our data suggested that the differential TOS sensitivity was not caused by differences in the uptake and retention of TOS between TOS-sensitive and -resistant cancer cells. The differential ability of cancer cells to generate ROS in response to TOS appears to be an important factor in determining the susceptibility of cells to TOS-induced apoptosis. Our results further suggest that TOS-induced generation of ROS is involved in caspase-independent apoptosis. Taken together, our findings suggest an important role of ROS generation in TOS-induced, caspase-independent apoptosis of cancer cells.

 

PMID: 15382062 [PubMed - indexed for MEDLINE]

 

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[xii] Clinical Cancer Research Vol. 8, 863-869, March 2002

Tobias Weber, Min Lu, Ladislav Andera, Harald Lahm, Nina Gellert, Marc W. Fariss, Vladimir Korinek, Wolfgang Sattler, David S. Ucker, Alexei Terman, Andreas Schröder, Wolfgang Erl, Ulf T. Brunk, Robert J. Coffey, Christian Weber and Jiri Neuzil2

-Tocopheryl succinate (-TOS), a redox-inactive analogue of vitamin E, is a strong inducer of apoptosis, whereas -tocopherol (-TOH) lacks apoptogenic activity (J. Neuzil et al., FASEB J., 15: 403–415, 2001). Here we investigated the possible antineoplastic activities of -TOH and -TOS and further explored the potential of -TOS as an antitumor agent. Using nude mice with colon cancer xenografts, we found that -TOH exerted modest antitumor activity and acted by inhibiting tumor cell proliferation. In contrast, -TOS showed a more profound antitumor effect, at both the level of inhibition of proliferation and induction of tumor cell apoptosis. -TOS was nontoxic to normal cells and tissues, triggered apoptosis in p53-/- and p21Waf1/Cip1(-/-) cancer cells, and exerted a cooperative proapoptotic activity with tumor necrosis factor-related apoptosis-inducing ligand (Apo2 ligand) due to differences in proapoptotic signaling. Finally, -TOS cooperated with tumor necrosis factor-related apoptosis-inducing ligand in suppression of tumor growth in vivo. Vitamin E succinate is thus a potent and highly specific anticancer agent and/or adjuvant of considerable therapeutic potential.

 

link to full text: http://clincancerres.aacrjournals.org/cgi/content/full/8/3/863ck=nck

 

 

[xiii] [xiii] SOLIDE TUMOREN

Klin Padiatr 2000; 212: 189-195

DOI: 10.1055/s-2000-9676

Boswellic acids in the palliative therapy of children with progressive or relapsed brain tumors

 

Boswellias uren in der palliativen Therapie bei Kindern mit progredienten oder rezidivierenden Hirntumoren:

G. Jan en1, U. Bode2, H. Breu, B. Dohrn, V. Engelbrecht, U. G bel1

Abstract:

19 children and adolescents with intracranial tumors received a palliative therapy with H 15 at a maximum dose of 126 mg/kg BW/day. All patients had previously been treated with conventional therapy. No side effects were observed during a median 9 months application. The recently reported antiedematous effect of H 15 was documented by MRI in one patient with a peritumoral edema, thus sparing steroid therapy with its typical side effects. Five/19 children reported an improvement of their general health status; this might be a psychological effect of hope for tumor response during palliative care. Three/17 patients with malignant tumors showed a mainly transient improvement of neurological symptoms such as pareses and ataxia. Three further patients showed an increased muscular strength and one cachectic patient achieved a weight gain. These improvements might be attributed to the antiedematous effect of H 15. Because of the palliative situation of these patients, H 15 application was performed without prior rebiopsy for histological evaluation. Overlapping effects with a previous radiotherapy or chemotherapy may have occurred. An antiproliferative effect cannot be stated. To prevent an uncritical use of H 15, further studies with prospective central documentation have to be initiated to evaluate the clinical indications for H 15 in palliative therapy, optimal dosage and duration of application.

 

 

 

[xiv]   Planta med 2002; 68: 397-401 DOI: 10.1055/s-2002-32090

Cytotoxic Action of Acetyl-11-keto-ß-Boswellic Acid (AKBA) on Meningioma Cells

Yong Seok Park, Joung H. Lee, Judy Bondar, Jyoti A. Harwalkar, Hasan Safayhi, Mladen Golubic

Abstract

Acetyl-11-keto-ß-boswellic acid (AKBA) is a naturally occurring pentacyclic triterpene isolated from the gum resin exudate of the tree Boswellia serrata (frankincense). Because pentacyclic triterpenes have antiproliferative and cytotoxic effects against different tumor types, we investigated whether AKBA would act in a similar fashion on primary human meningioma cell cultures. Primary cell cultures were established from surgically removed meningioma specimens. The number of viable cells in the absence/presence of AKBA was determined by the non-radioactive cell proliferation assay. The activation status of the proliferative cell marker, extracellular signal-regulated kinase-1 and -2 (Erk-1 and Erk-2) was determined by immunoblotting with the antibody that recognizes the activated form of these proteins. Treatment of meningioma cells by AKBA revealed a potent cytotoxic activity with half-maximal inhibitory concentrations in the range of 2 - 8 µM. At low micromolar concentrations, AKBA rapidly and potently inhibited the phosphorylation of Erk-1/2 and impaired the motility of meningioma cells stimulated with platelet-derived growth factor BB. The cytotoxic action of AKBA on meningioma cells may be mediated, at least in part, by the inhibition of the Erk signal transduction pathway. Because of the central role the Erk pathway plays in signal transduction and tumorigenesis, further investigation into the potential clinical use for AKBA and related boswellic acids is warranted.

 

[xv] Journal of Neuro-Oncology

Publisher: Springer Science+Business Media B.V., Formerly Kluwer Academic Publishers B.V.

ISSN: 0167-594X (Paper) 1573-7373 (Online)

DOI: 10.1023/A:1006387010528

Issue: Volume 46, Number 2 Date: January 2000 Pages: 97 - 103

Boswellic Acids Inhibit Glioma Growth: A New Treatment Option?

M. Winking1, S. Sarikaya1 , A. Rahmanian1, A. Jödicke1 and D.-K. Böker1

(1) Neurosurgical Clinic, Justus-Liebig University Giessen , Giessen , Germany

 

Abstract Conventional malignant glioma therapy (surgery, radiation therapy and chemotherapy) does not yield satisfying results. The prognosis of the glioma patient depends more on the histological grading of the tumor and patient''s age than on the therapy. Especially the adjuvant chemotherapy failed to date to influence survival time in glioma patients significantly. To improve results in malignant glioma therapy additional therapeutic regimes are necessary.

In an earlier study we were able to show a significant reduction on perifocal edema by an extract from gum resin (EGR) accompanied with a clinical improvement in patients with malignant glioma. Also a decrease of urinary LTE4-excretion as a metabolite of leukotriene synthesis in brain tumors was observed. Furthermore we had found a proliferation inhibiting activity of the extract form EGR, the boswellic acids in cell cultures.

The purpose of this experimental study was to elucidate the effects of the boswellic acids, which are constituents of an extract from gum resin on tumor growth in vivo. Female wistar rats weighing 200–250g were treated with the drug 14 days after inoculation of C6 tumor cells into their right caudate nucleus and randomization into 4 groups. The treatment groups received different dosages and were compared to a control group without any additional treatment. Survival time of the rats in the highest dosage group (3 × 240mg/kg body weight) was more than twice as long as in the control group (P < 0.05).

In a second experiment the inhibition of tumor cell proliferation was examined. The C6 tumor cells were implanted into the caudate nucleus. Drug treatment was started immediately after implantation and stopped after 14 days. The animals were sacrificed and the brains were examined microscopically. Comparing low and high dosage of EGR treatment a significant difference in tumor volume was detected (P < 0.05). The proportion of apoptotic tumor cells in animals with high dose treatment was significantly larger than in the low dose (treatment) group (P < 0.05).

These data demonstrate an influence of EGR in rat glioma growth and might represent a new therapeutic option on glioma treatment in man in future. Further experimental work on human gliomas is needed to definitively answer this question.

boswellic acids - glioma - chemotherapy

 

 

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[xvi] Clin Exp Metastasis. 2003;20(4):375-83.

Triterpenoids from Glycine max decrease invasiveness and induce

caspase-mediated cell death in human SNB19 glioma cells.

 

Yanamandra N, Berhow MA, Konduri S, Dinh DH, Olivero WC, Nicolson GL,

Rao JS.

 

Division of Cancer Biology, Department of Biomedical and Therapeutic

Sciences, University of Illinois College of Medicine at Peoria , Peoria ,

Illinois 61605, USA .

 

In recent years there has been an increasing interest in compounds

present in foods that may prevent or slow the progression of chronic

illnesses, such as cardiovascular disease, osteoporosis and cancer.

Saponins have been reported to have important time-dependent anti-cancer

properties. We have used a highly purified and characterized saponin

fraction containing the soyasapogenol B glycosides (the 'B group'

saponins) from soybeans (Glycine max L.) to demonstrate a reduction in

SNB 19 human glioblastoma cell invasion (45% decrease compared to

untreated cells) in vitro in a Matrigel invasion assay. We have also

demonstrated that triterpenoid saponin induces apopotosis and affects

mictochondiral function. Dose-dependent loss of mitochondrial

trans-membrane potential in SNB 19 cells occurred with treatment, along

with release of cytochrome c, processing of caspase-9, and -3 and

specific cleavage of poly ADP-ribose polymerase (PARP), a substrate of

caspase-3. The results suggest that the saponin fraction induces

apoptosis in SNB19 human glioblastoma cells by stimulating cytochrome-c

release and subsequent activation of a caspase cascade. Our observations

clearly demonstrate the pro-apoptotic and anti-invasive activities of

the soyasapogenol B glycosides from soybeans.

 

PMID: 12856725 [PubMed - indexed for MEDLINE]

 

 


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