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Understanding Lung Cancer

Natural Strategies in Collaborative Cancer Care

by John G.Connor, M.Ac., L.Ac.

edited by Barbara Connor, M.Ac., L.Ac.

April 6, 2011

 Table of Contents

·        Introduction

·        Natural Strategies in Collaborative Cancer Care

·        Examples of Natural Compounds Suppressive Against Lung Cancer

·        Examples of Natural Compounds Synergistic with Chemotherapeutic Agents Used in Lung Cancer

·        Examples of Natural Compounds that Target Growth Factors and Genes in Lung Cancer

·        Comprehensive Cancer Care Consultations

·        References

 

Introduction

Lung cancer is the leading cause of death among cancers worldwide and non-small cell lung cancer (NSCLC) comprises more than 80% of lung cancer cases.

 

Although very specific processes underlie malignant transformation, a large number of unspecific influences can initiate the disease including radiation, chemicals, viruses, inflammation, etc. Indeed, it appears that prolonged exposure to almost any provocative agent in the environment can potentially cause cancer. (Seyfried & Shelton 2010)

 

Individual studies estimate that as many as 69% of US cancer patients employ some type of complementary and alternative medicine, 76% of patients in a study of Midwestern cancer patients and 95% of radiation oncology patients in another study.  (Wargovich et al 2010)

 

Barbara and I feel that the emerging concept and practice of targeted therapies which have a high specificity toward tumor cells provides a broader therapeutic window with less toxicity than the current chemotherapeutic agents. They are also often useful in combination with cytotoxic chemotherapy or radiation to produce additive or synergistic anticancer activity because their toxicity profiles often do not overlap with traditional cytotoxic chemotherapy. Targeted therapies represent a new and promising approach to cancer therapy, one that is already leading to beneficial clinical effects. There are multiple types of targeted therapies available, including monoclonal antibodies, receptor tyrosine kinase inhibitors, and growth factor receptor inhibitors.

 

The wonderful thing about botanicals and nutritives is that they target many of the same growth factors, receptors and pathways as conventional drugs and chemos but in a gentler and less toxic way thereby allowing for decreased dosages in the more toxic chemos and drugs. One of the characteristics of plants is that they are pleiotrophic, i.e., they exert multiple effects. Therefore botanicals and herbs by their very nature not only enhance the effectiveness of chemos and drugs but they can reduce or eliminate many of their unwanted side effects.

 

There is an ever growing interest in treatment with natural compounds as an adjuvant cancer therapy along with conventional cancer therapy. (Virk-Baker et al 2010) For example the combination of a natural VEGF inhibitor along with lower doses of a pharmacological agent may prove helpful in reducing the unwanted side effects of chemotherapy. (Wargovich et al 2010)

 

Natural Strategies in Collaborative Cancer Care

 

The following is a list of natural strategies we employ and the issues we address in our approach to integrative cancer care:

 

·         Alkalinity and Acidosis in Cancer

·         Angiogenesis Blood Markers

·         Appendix of Cancer Pathways

·         Blood Tests for Cancer-Related Cachexia

·         Blood Tests that Detect Various Polymorphisms that Relate to the Metabolism or Detoxification of Chemotherapy

·         Blood Tests to Assess Hypercoagulation

·         Bone Building Protocol for Bone Related Cancer

·         Cancer and Sugar

·         Chemotherapy and Predictive Bio-markers

·         Copper Reduction Protocol

·         Counteracting Cancer Related Cachexia with Natural Compounds

·         Cytotoxic Herbs & Their Functions

·         Factors that Increase the Risk of Blood Clots and Thrombosis.

·         Glossary of Chemotherapeutic Drugs

·         Growth Factors and Genes Involved in Cancer

·         How Elevated Glucose and Insulin Promote Cancer

·         Immunotherapy - Activating the Immune System with Natural Compounds

·         Inflammatory Blood Markers

·         Inhibiting Angiogenesis with Natural Compounds

·         Managing the Side Effects of Chemotherapy with Natural Compounds

·         Markers for Assessing Bone Health

·         Natural Aromatase Inhibitors

·         Natural Compounds that Act as Biological Response Modifiers

·         Natural Compounds That Alleviate the Side Effects of Chemobrain

·         Natural Compounds that are Radiation Protective or Synergistic with Radiation Therapy

·         Natural Compounds that Downregulate HPV

·         Natural Compounds that Downregulate IGF and are Insulinotrophic, and Anti-cancer.

·         Natural Compounds that Enhance the Effectiveness of Paclitaxel

·         Natural Compounds that Enhance the Effectiveness of Platinums

·         Natural Compounds that Inhibit Multi Drug Resistance

·         Natural Compounds that Lower Homocysteine

·         Natural Compounds that Protect against Bone Cancer

·         Natural Compounds that Protect against the Side Effects of Doxorubicin

·         Natural Compounds that Reduce the Side Effects of Carboplatin

·         Natural Compounds that Reduce the Side Effects of Paclitaxel

·         Natural Compounds that Reduce the Side Effects of Platinol (Cisplatin)

·         Natural Compounds that Reduce the Side Effects of Platinum Drugs

·         Natural Compounds that Synergize with Doxorubicin (Anthracyclines)

·         Natural Compounds that Target Growth Factors and Genes Involved in Cancer

·         Natural Compounds which Hasten Recovery from Surgery

·         Neuropathy and Cancer Pain Management

·         Nutritional Support for Glutathione and Optimal Liver Detoxification

·         Radiation and Cancer

·         Reducing Inflammation with Natural Compounds

·         Suppressing Hypercoagulation with Natural Compounds

·         Surgery and Cancer

·         Teas and Soups which Alleviate the Side Effects of Chemo and What to Eat During Chemo

·         Tissue Pathology Reports

·         Understanding the Mechanism behind Bone Metastasis

 

Examples of Natural Compounds Suppressive Against Lung Cancer

 

1.       Andrographis - Andrographolide, a diterpenoid lactone isolated from a traditional herbal medicine Andrographis paniculata, is known to have the potential to be developed as a chemotherapeutic agent. In order to understand the anti-cancer properties of andrographolide, we examined its effect on migration and invasion in human NSCLC A549 cells. The results of wound-healing assay and in vitro transwell assay revealed that andrographolide inhibited dose-dependently the migration and invasion of A549 cells under non-cytotoxic concentrations. (Lee et al 2010)

 

2.       Emodin – is a tyrosine kinase inhibitor, a natural anthraquinone, which exhibits anti-cancer effects in lung cancer.  (Chen et al 2009)

 

3.       Essential Fatty Acids (EPA & DHA) – Skeletal muscle depletion is associated with reduced plasma (n-3) fatty acids in non-small cell lung cancer patients. (Murphy et al 2010)

 

4.       Ginseng - Treatment with red ginseng significantly inhibited both lung tumor multiplicity and tumor load. Our results demonstrated that red ginseng was a potent chemopreventive agent for the prevention of lung tumorigenesis in A/J mice. (Yan et al 2006)

 

5.       Glucocorticoids - Among the more than 50 different agents tested, several groups of chemicals have shown significant efficacy against mouse lung tumor development, including glucocorticoids and isothiocyanates. Glucocorticoids have proven to be successful during the progression stage of tumor development, whereas isothiocyanates have proven particularly effective in blocking carcinogenesis. (Yan et al 2006)

 

6.       Green Tea - EGCG is thought be the most active component in Polyphenon E, but it has to be with other tea catechins to show chemopreventive activity on lung tumorigenesis in aerosolized form. The aerosol delivery of Polyphenon E is an effective method of chemoprevention, which could be considered for further studies in animal models as well as clinical trials. (Fu et al 2009)

 

7.       Isothiocyanates  - Among the more than 50 different agents tested, several groups of chemicals have shown significant efficacy against mouse lung tumor development, including glucocorticoids and isothiocyanates. Glucocorticoids have proven to be successful during the progression stage of tumor development, whereas isothiocyanates have proven particularly effective in blocking carcinogenesis. (Yan et al 2006)

 

8.       Milk Thistle (Silibinin) - Silibinin inhibits human nonsmall cell lung cancer cell growth through cell-cycle arrest by modulating expression and function of key cell-cycle regulators. (Mateen et al 2010)

 

9.       Ocimum sanctum (Holy Basil) – induces apoptosis in A549 lung cancer cells and suppresses the in vivo growth of Lewis lung carcinoma cells. (Magesh et al 2009)

 

10.   Pomegranate juice - Oral consumption of pomegranate fruit extract inhibits growth and progression of primary lung tumors in mice. (Khan et al 2007)

 

11.   Pterostilbene inhibits lung cancer through induction of apoptosis. (Schneider et al 2010)

 

12.   Resveratrol – can induce apoptosis in multidrug-resistant human NSCLC SPC-A-1/CDDP cells by down-regulating the expression of survivin. (Zhao et al 2010) Bakuchiol, an analogue of resveratrol exhibited anti-tumor effects on human lung adenocarinoma A 549 cells. (Chen et al 2010)  In another study resveratrol inhibited HO-1 and subsequently MMP-9 and MMP-2 expression in lung cancer cells. The inhibitory effects of resveratrol on MMP expression and invasion of lung cancer cells are, in part, associated with the HO-1-mediated NF-kappaB pathway. (Liu et al 2010)

 

13.   Vitamin D has important protective effects against lung cancer. These results indicate that there is potential for the use of calcitriol (Vitamin D, 1,25-dihydroxycholecalciferol) as a chemopreventive agent against the development of lung cancer. (Menezes et al 2008) Although there was no overall association between vitamin D and lung cancer risk, women and young participants with a higher level of vitamin D were observed to have a lower lung cancer risk. (Kilkinnen et al 2008)

 

Examples of Natural Compounds Synergistic with Chemotherapeutic Agents Used in Lung Cancer

 

1.       Astragalus - Astragalus-based Chinese herbal medicine may increase effectiveness of platinum-based chemotherapy when combined with chemotherapy in NSCLC. (McCulloch et al 2006)

 

2.       Curcumin – In a laboratory study, vinorelbine alone caused 37.9% cell death in NSCLC cells.  However when pretreated with cur cumin 24 hours prior to vinorelbine, the cell death rose to 61.3%, dramatically increasing the treatment effect of vinorelbine (Sen, Sharma et al 2005)

 

3.       Emodin –Emodin enhances the cytotoxicity induced by gefitinib in two NSCLC cell lines. (Chen et al 2009)

 

4.       Panax Ginseng - Ginsenoside Rg3 exhibited an inhibitory effect when combined with gemcitabine on angiogenesis and growth of lung cancer in mice. (Liu et al 2009)

 

Examples of Natural Compounds that Target Growth Factors and Genes in Lung Cancer

 

EGFR – epidermal growth factor receptor - Activating mutations in the epidermal growth factor receptor (EGFR) are associated with enhanced response to EGFR tyrosine kinase inhibitors in non-small cell lung cancer (NSCLC), whereas KRAS mutations translate into poor patient outcomes. (Mack et al 2009) EGF stimulates urokinase-type plasminogen activator expression, which in turn promotes angiogenesis.

 

Examples of Natural compounds shown to block EGF receptor activation and its downstream effectors include:

1.     Curcumin

  1. Cysteine (un-denatured whey protein concentrate)
  2. Genistein

 

HIF-1α – (Hypoxia-inducible factor-1)

HIF-1α -plays a key role in tumor angiogenesis by regulating the expression of angiogenic factors including VEGF.  HIF-1alpha over expression is associated with increased vascularization, drug resistance, and poor diagnosis. The PI3K/Akt/mTOR/p70S6K pathway is implicated in the regulation of HIF-1alpha expression at the translational level. (Jung et al 2010)

Overwhelming evidence indicates hypoxia promotes tumor growth, progression, and resistance to therapies. Recent studies on the hypoxia-inducible factors (HIF), have corroborated further the essential role of hypoxia in tumor growth and progression. Both HIF-1α and HIF-2α are overexpressed frequently in human cancers. (Yoo et al 2011)

Tumour resistance against radiation- and chemo- therapy is facilitated by oxygenation reduction at tumour areas. HIF-1alpha regulated genes are mostly responsible for this type of resistance. (Said et al 2010) Targeting HIF-1 can suppress tumor angiogenesis and improves the effectiveness of other angiogenic targets, chemotherapy and radiation therapy.

Tumor hypoxia is known to activate angiogenesis, anaerobic glycolysis, invasion and metastasis. (Lu et al 2010)

The therapeutic efficacy of silibinin in lung tumor growth inhibition and regression by antiangiogenic mechanisms seem to be mediated by decreased tumor-associated macrophages and cytokines, inhibition of hypoxia-inducible factor-1 alpha, NF-kappaB, and STAT-3 activation, and up-regulation of the angiogenic inhibitors, Ang-2 and Tie-2. (Tyagi et al 2009)

Examples of Natural Compounds that Target HIF-1α

  1. Apigenin – in lung cancer cells (Liu et al 2005) Flavonoids comprise a large group of naturally occurring low molecular weight substances that are present in fruits, vegetables, nuts, seeds, and the stems, leaves, flowers, bark, and roots of most plants, as well as tea, coffee, and wine. The average Western diet is estimated to contain approximately 23 mg/day of quercetin, kaempferol, myricetin, apigenin, and luteolin. (Fotsis et al 1997)
  2. Resveratrol – inhibits Hypoxia-Inducible Factor-1 (HIF-1) and VEGF (Vascular Endothelial Growth Factor). (Zhang et al 2005) Resveratrol down-regulates the expression of HIF-1 alpha in nasopharyngeal cancer cells. (Quan et al 2009) Resveratrol inhibits HIF-1 alpha in colon cancer cells.  (Wu et al 2008) it inhibits HIF-1 alpha in ovarian cancer cells. (Park et al 2007) and it inhibits HIF-1 alpha in cervical cancer cells. (Tang et al 2007)
  3. Silibinin (Silymarin)/Milk Thistle - inhibits HIF-1 alpha expression in cervical cancer and hepatoma cells (Garcia-Maceira & Mateo 2009) in prostate cancer cells (Jung et al 2009)

 

MMP 2 & 9 – are involved in basement membrane degradation.  For the tumor to form it has to break down the extra-cellular matrix.  This allows new branches to form from an existing blood vessel. They are particularly upregulated in bone metastasis.

 

Multivariate statistical methods then identified a panel of six biomarkers (tumour necrosis factor-α, CYFRA 21-1, interleukin-1ra, matrix metalloproteinase-2, monocyte chemotactic protein-1 and sE-selectin) as being the most efficacious for diagnosing early stage NSCLC. (Farlow et al 2010)

 

Cell line mobility was strongly inhibited and the enzymatic activity of MMP-2 decreased following culture with the rhubarb serum metabolite in human lung adenocarcinoma A549 cells. (Shia et al 2010)

 

CYP ω-hydroxylase promotes tumor angiogenesis and metastasis by upregulation of VEGF and MMP-9 via PI3 K and ERK1/2 signaling in human NSCLC cells. (Yu et al 2010)

 

Examples of Natural Compounds that Down Regulate MMP 2 & 9

  1. Eugenol – in cloves, basil and cinnamon – downregulates MMPs. (Manikandan et al 2010)
  2. Ganoderma lucidum – reduces MMP-9 expression. (Weng et al 2008)
  3. Ginger – regulates MMP-9 (Weng et al 2010)
  4. Vitamin D3 – reduced the expression of MMP-2 and MMP-9 in metastatic lung carcinoma. (Nakagawa et al 2005)

 

Survivin - is a dual function protein. It inhibits the apoptosis of cells by inhibiting caspases, and also promotes cell growth by stabilizing microtubules during mitosis. Over-expression of survivin has been demonstrated to induce drug-resistance to various chemo-therapeutic agents such as cisplatin (DNA damaging agent) and paclitaxel (microtubule stabilizer) in cancers. (Cheung et al 2009) Inflammatory breast cancer often over-expresses survivin.

 

Downregulation of survivin plays a pivotal role in gefitinib-induced apoptosis in EGFR mutation-positive NSCLC cells. (Okamoto et al 2010)

 

Examples of Natural Compounds that Inhibit Survivin

  1. Green tea extract /EGCG (Int. J. Concol 2007)
  2. Quercetin - Quercetin-induced apoptosis might be associated with a decrease in mutant P53 and Survivin proteins. (Ma et al 2006)

                                                

Comprehensive Cancer Care Consultations

 

Barbara & I have been working in the integrative oncology setting for many years and have been collaborating closely with Donald Yance for 6 years.  We are graduates of both his Level One and Level Two Professional Clinical Trainings - Fundamentals of the ETMS (Eclectic Triphasic Medical System) and Advanced Clinical Applications of the ETMS in Cancer Therapies.

 

Our cancer protocols are designed to work synergistically with targeted individualized medical treatment plans and emphasize the practice of healthy medicine aimed at the root source of ill-health.  Our primary focus is to build your immune system, enhance your vitality, and to bring about harmony and balance throughout your body.  The botanicals and nutrients will target a multitude of cancer pathways generally and specifically in each case.

 

Using chemo-sensitivity screening and tumor marker testing we will be identifying what are the most appropriate chemos or drugs to use which will have the greatest impact on the cancer and at the same time have the least negative impact on your health. If you need to undergo chemotherapy or radiation we will provide you with specific protocols to help alleviate the side effects as well as specific protocols to help enhance the effects of the chemos.

 

If you are interested in finding out more about how we work or if you would like to set up a phone consult please phone us at 919-309-7753 or email us at johnandbarbaraconnor@me.com.

 

References

 

1.       Bagchi, Debasis & Harry G. Preuss, Phytopharmaceuticals in Cancer Chemoprevention, CRC Press, Boca Raton, 2005

 

2.       Beckett, Geoffrey, Simon Walker, Peter Rae & Peter Ashby, Lecture Notes – Clinical Biochemistry, 8th edition, Wiley-Blackwell, Oxford,  2010

 

3.       Boik, John, Natural Compounds in Cancer Therapy, Oregon Medical Press, Princeton, MN, 2001

 

4.       Boik, John, Cancer & Natural Medicine, A Textbook of Basic Science and Clinical Research, Oregon Medical Press, Princeton, MN, 1996

 

5.       Chernecky, Cynthia C, and Barbara J. Berger, Laboratory Tests and Diagnostic Procedures, Saunders, St. Louis, 2008

 

6.       Davis, Cindy D, Nancy Emenaker and John Milner, “Cellular Proliferation, Apoptosis and Angiogenesis: Molecular Targets for Nutritional Preemption of Cancer, Seminars in Oncology, Vol 37, No. 3, June 2010, pp 243-257

 

7.       Gullet, Norleena P, Ruhul Arnin, Soley Bayraktar, et al, “Cancer Prevention With Natural Compounds”, Seminars in Oncology, Vol 37, No 3, June 2010, pp 258-281

 

8.       Heber, David, Editor-in –Chief, Nutritional Oncology, Second Edition, Academic Press, London, 2006

 

9.       McKenna, Dennis J., PhD,  Kenneth Hones & Kerry Hughes, Botanical Medicines, The Desk Reference for Major Herbal Supplements, Second Edition, The Haworth Herbal Press, New York, 2002

 

10.   Neal, Michael J., Medical Pharmacology at a Glance, Sixth edition, Wiley-Blackwell, Oxford, 2009

 

11.   Stargrove, Mitchell, Jonathan Treasure & Dwight L. McKee, Herb, Nutrient, and Drug Interactions, Mosby Elsevier, St. Louis,  2008

 

12.   Weiss, Rudolf, MD & Volker Fintelmann, MF, Herbal Medicine, Thieme, New York, 2000

 

13.   Yance, Donald, “Donald Yance’s Eclectic Triphasic Medical System (ETMS): An Integrative Wholistic Approach to Treating and Preventing Cancer”, (Monograph) 2010

 

14.   Yance, Donald, Herbal Medicine, Healing & Cancer, Keats Publishing, Lincolnwood (Chicago) IL, 1999

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