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Adjunctive botanical therapy for glioblastoma.

Treat disease through diet by preference, refraining from the use of drugs; and if you find what is required in a single herb, do not resort to a compounded medicament.

~ Baha'u'llah, Baha'u'llah and the New Era, p. 106.

Introduction

Glioblastoma is a highly invasive brain tumor often arising from astrocytes, representing 15% of all brain tumors, and occurring more commonly in men than women, with median age of 55 years at time of diagnosis. Due to aggressiveness of glioblastoma, the median survival time of patients is less than 1 year even with treatment. These tumors grow quickly mainly because of their ability to form extensive blood supplies, a process known as angiogenesis. Conventional therapies, including debulking surgery, chemotherapy, Avastin to stunt angiogenesis temporarily, immunotherapy, and radiation therapy cause many devastating side effects, yet provide minimal change in survival rates. The addition of alternative therapeutics, such as the use of herbal extracts, and nutrition and diet therapy, plays an important role in reducing side effects from conventional therapies while optimizing their benefits, as well as improving quality of life and increasing survival time in patients fighting this devastating disease by optimizing immune function, reducing inflammation, and promoting healing and repair.

Diet Therapy

Current dietary focus for patients fighting any type of cancer must include cancer-fighting foods and nutrients. Diets high in raw organic vegetables and fruits and plant-based oils help regulate blood sugar, optimize detoxification and methylation, provide brain cells nutrients to heal and repair, and modulate cancer-promoting eicosanoids. Specifically, glioblastoma patients require a high-fat, low-carbohydrate diet, which Martuscello et al. showed to be as effective as a ketogenic diet in reducing brain tumor size. (1) Examples of plant-based fats include extra-virgin olive oil, coconut oil, avocado oil, and raw nuts and seeds. Animal protein should be kept to a low moderate amount (approximately 3-4 ounces per meal), as fats become the source of majority of caloric intake.

Omega-3 fatty acids, such as DHA and EPA found in fish oils, are essential lipids in brain cells and assist in brain repair post surgery, radiation, and chemotherapy. DHA and EPA specifically inhibit glioma tumor growth and invasion, reduce inflammation, and have been shown to increase survival rate in glioblastoma patients by 64% during a 2-year period over placebo. (2,3) A minimum of 3 grams of EPA/DHA supplementation is recommended.

Plant-Based Extracts

Plant-based extracts, such as bromelain derived from Ananas comosus, effectively block PGE2 pathways specifically in glioblastoma tumors. Glioblastoma depends on prostaglandin PGE2 pathways for growth, angiogenesis, pain, and immune dysregulation. Bromelain blocks PGE2 directly, thereby reducing angiogenesis, pain and tumor growth. (4) Gliomas grow through the processes of cell adhesion, migration and invasion into healthy brain cells. (5,6) Bromelain blocks cellular adhesion, migration, and invasion as well as preventing thrombosis, a common side effect of chemotherapy. A common dose for bromelain supplementation is 500 to 750 mg three times per day without food in patients with glioblastoma.

Boswellia serrata strongly inhibits 5-LOX pathway, another inflammatory pathway causing brain tumor growth and brain edema, in patients with glioblastoma. (8) Because of the high incidence of brain edema secondary to tumor growth and radiation therapy, Boswellia s. is a powerful herb to reduce edema without the side effects of commonly used steroid therapy. (9) Boeker and Winking showed the role of boswellic acids in reducing peritumoral edema by 30%. (7)

Curcumin, an extract of turmeric root, used since the ancient times in the East, is yet another powerful plant extract useful in the inhibition of tumor growth and more specifically in the inhibition of glioblastoma cancer stems cells. Curcumin acts on glioblastoma cells in several ways, proving its benefits as an adjunctive therapy in glioblastoma therapy. Curcumin suppresses antiapoptotic signals through activating cysteine proteases; it suppresses chemoresistant glioblastoma cells and acts synergistically with chemotherapy. (11) Furthermore, curcumin inhibits angiogenesis, thereby, acting as an anti-invasive, antiproliferative, and antimigratory agent. (10) Curcumin is especially useful with recurrent glioblastoma. Common oral dose of a highly bioavailable form is recommended to be 60 mg/kg per day. Intravenous dosing of curcumin may prove to be an even more powerful therapy for glioblastoma, though further research is needed.

Quercetin, a polyphenolic flavonoid found in multiple vegetables and fruit, is another plant extract that induces apoptosis in glioblastoma cells as well as sensitizing them to temozolomide and radiotherapy. (16) When quercetin is used in combination with temozolomide, the efficacy of the chemotherapy is increased by at least 65% than when temozolomide is used alone. (15) Quercetin has antimitotic effects through modulating protein kinase and lipid kinase pathways. Similar to vitamin C, at lower doses quercetin acts as an antioxidant, while at higher doses, it becomes a prooxidant.

Resveratrol is another polyphenol naturally found in grapes, berries, and cacao. Like quercetin, resveratrol works synergistically with Temodar to optimize its antitumor activity and reverse Temodar-resistant glioblastoma cells. Resveratrol inhibits tumor growth, initiation, promotion, and progression and induces glioma cell differentiation. When used in conjunction with radiotherapy, resveratrol sensitizes glioma stem cells to radiation. (12)

Berberine, an alkaloid extract derived from plants such as Berberis aquifolium, Berberis vulgaris, Berberis aristata, Hydrastis canadensis and Coptis chinensis, provides further multidimensional support. Current research focuses on its blood sugar regulation properties as well as its benefits in the reestablishment of the microbiome. However, berberine also has been shown to have powerful potential in the adjunctive treatment of glioblastoma by inducing G1 cell arrest, sensitizing glioma cells to radiation, and inhibiting broad spectrum enzymes such as COX2, N-acetyltransferase, and topoisomerase. (17-19) The result is suppression of tumor growth and metastasis. Furthermore, berberine has a strong specificity for the nervous system, making it useful with neurological disorders. (20) Through modulating neurotransmitters and receptors in the brain while addressing inflammation and glioma cellular arrest, berberine is an ideal adjunct to any and all glioblastoma therapy.

Viral etiology, specifically cytomegalovirus and herpes simplex virus, have been implicated in glioblastoma. (13) Antiviral therapy is becoming a focus for glioblastoma therapy. Amongst these is an herbal bitter native to India, Andrographis paniculata, whose benefits are promising for glioblastoma patients. Its extract, andrographolide, inhibits cell proliferation and induces cell apoptosis in glioblastoma through inhibiting cancer cell signaling and causing G2/M cell phase arrest. (14)

Clinical Examples

A 28-year-old female with an inoperable lemon-size glioblastoma presented to our clinic. She received Fluorouracil (5FU) and Temodar and refused radiation. Using dietary modifications and herbal therapies orally and intravenously, the tumor shrank and became inactive within 11 months. She continued to lead a high quality of life throughout her treatment, while taking care of her 2-year-old daughter. She remains in remission.

A 62-year-old man with recurrent multiple brain tumors, diagnosed with glioblastoma, exhausted his conventional options. Six weeks within starting dietary and botanical therapy orally and intravenously, his tumor stabilized. Within 3 months, tumors began shrinking. He continues to be asymptomatic and lead a high quality of life.

A 58-year-old male with an inoperable glioblastoma, which had continued to grow despite Temodar chemotherapy, presented to our office. He instigated dietary and oral herbal medicine. His tumor shrank and disappeared within 1 year. He remained in remission for 7 years.

Conclusion

Glioblastoma is a difficult cancer to treat, and current conventional therapies have yet to offer results that increase survival rates and reduce recurrence and death rates. Botanical and dietary therapies provide a beneficial adjunct to conventional therapies optimizing quality of life, minimizing side effects from conventional therapies and reducing tumor size and activity. Further studies to substantiate the benefits of herbal and dietary medicine in the treatment of glioblastoma patients remain prudent.

Notes

(1.) Martuscello et al. A supplemented high-fat low-carbohydrate diet for the treatment of glioblastoma. Clin Cancer Res. 2015 Dec 2. pii:clincanres.0916.2015.

(2.) Spagnuolo et al. High fat diet and inflammation - modulation of haptoglobin level in rat brain. Front Cell Neurosci. 2015 Dec 15;9:479. doi:10.3389/fncel.2015.00479. eCollection 2015.

(3.) Gramaglia A, Loi GF, Mongioj V, Baronzio GF. Increased survival in brain metastatic patients treated with stereotactic radiotherapy, omega-3 fatty acids and bioflavonoids. Anticancer Res. 1999;19(6C):5583-5586.

(4.) Kelly GS. Bromelain: a literature review and discussion of its therapeutic applications. Alt Med Rev. 1996;l(4):243-257.

(5.) Tysnes BB, Maurer HR, Porwol T, et al. Bromelain extract from pineapple stem can control glioma invasion. Proceedings of the Society for Neuro-Oncology. 6th Annual Meeting. Neuro Oncol. 2001;3(4 no.234):324.

(6.) Tysnes BB, Maurer HR, Porwol T, et al. Bromelain reversibly inhibits the invasive properties of glioma cells. Neoplasia. 2001;3(6):469-479.

(7.) Boeker DK, Winking M. The role of boswellic acids in the therapy of malignant glioma. Deutsches Aerzteblatt. 1997;94:A1197-A1199.

(8.) Baba T, Chio CC, Black KL. The effect of 5-lipoxygenase inhibition on blood-brain barrier permeability in experimental brain tumors. J Neurosurg. 1992;77:403-406.

(9.) Streffer JR, Bitzer M, Schabet M, Dichgans J, Weller M. Response of radiochemotherapy-associated cerebral edema to a phytotherapeutic agent, H15. Neurology. 2001;56(9):1219-1221.

(10.) Sordillo et al. Curcumin for the treatment of glioblastoma. Anticancer Res. 2015 Dec;35(12):6373-6378.

(11.) Yin H et al. Curcumin sensitizes glioblastoma to temozolomide by simultaneously generating ROS and disrupting AKT/ mTOR signaling. Oncol Rep. 2014 Oct;32(4):1610-1616. doi:10.3892/or.2014.3342. Epub 2014 Jul 18.

(12.) Wang et al. Resveratrol, a potential radiation sensitizer for glioma stem cells both in vitro and in vivo. J Pharmacol Sci. 2015 Nov 10. pii:S1347-8613(15)00222-4. doi:10.1016/j. jphs.2015.11.001.

(13.) Chiocca EA, Aghi M, Fulci G. Glioblastoma viral therapy for glioblastoma. Cancer J. May/June 2003;9(3):167-179.

(14.) Li Y, Zhang P, Qiu F, et al. Inactivation of PI3K/Akt signaling mediates proliferation inhibition and G2/M phase arrest induced by andrographolide in human glioblastoma cells. Life Sci. 2012 Jun 27;90(25-26):962-967. doi:10.1016/j. Ifs.2012.04.044. Epub 2012 May 24.

(15.) Pozsgai E, Bellyei S, Cseh A, et al. Quercetin increases the efficacy of glioblastoma treatment compared to standard chemoradiotherapy by the suppression of PI-3-kinase-Akt pathway. Nutr Cancer. 2013;65(7):1059-1066. doi:10.1080/0 1635581.2013.810291. Epub 2013 Sep 13.

(16.) Jakubowicz-Gil J, Langner E, Bqdziul D, Wertel I, Rzeski W. Apoptosis induction in human glioblastoma multiforme T98G cells upon temozolomide and quercetin treatment. Tumour Biol. 2013 Aug;34(4):2367-2378. doi:10.1007/sl3277-0130785-0. Epub 2013 Apr 12.

(17.) Wang DY, Yeh CC, Lee JH, Hung CF, Chung JG. Berberine inhibited arylamine N-acetyltransferase activity and gene expression and DNA adduct formation in human malignant astrocytoma (G9T/VGH) and brain glioblastoma multiforms (GBM 8401) cells. Neurochem Res. 2002 Sep;27(9):883-889.

(18.) Yount G et al. Berberine sensitizes human glioma cells, but not normal glial cells, to ionizing radiation in vitro. J Exp Ther Oncol. 2004 Jul;4(2):137-143.

(19.) Eom KS et al. Berberine induces G1 arrest and apoptosis in human glioblastoma T98G cells through mitochondrial/ caspases pathway. Biol Pharm Bull. 2008 Apr;31(4):558-562.

(20.) Jiang W, Li S, Li X. Therapeutic potential of berberine against neurodegenerative diseases. Sci China Life Sci. 2015 Jun;58(6):564-569. doi:10.1007/sll427-015-4829-0. Epub 2015 Mar 6. Review. .

by Nooshin K. Darvish, ND, FICT

Nooshin K. Darvish, ND, FICT, is a licensed naturopathic physician, fellow in integrative cancer therapies, and Lyme-literate physician. She is one of the very few physicians who completed a two-year medical residency in naturopathic family medicine at Bastyr University. For over 20 years, she has specialized in diagnosing and treating chronic diseases including Lyme disease, cancer, and neurological disorders, using an integrative and noninvasive approach. Dr. Darvish blends the best of Western, Eastern, natural, bioenergy, functional, and anti-aging medicines to diagnose and create effective evidence-based individualized treatment plans. She trains medical and naturopathic doctors nationally and internationally in integrative and holistic medicine. She is the founder and medical director of Holistique Medical Center in Bellevue, Washington. For more info, please visit www.DrDarvish.com or e-mail info@DrDarvish.com.
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Author:Darvish, Nooshin K.
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Date:Aug 1, 2016
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