Benefits of Calendula Officinalis After Radiation Therapy Treatments

Radiation therapy kills tumor cells, yet has acute side effects that may include: dermatitis, diarrhea, dry mouth, fatigue, hair loss, immune suppression, incontinence, mucositis, nausea, shortness of breath and sexual problems. The slide presentation below summarizes clinical and non-clinical studies on Calendula studied in laboratories around the world, and its' benefits on protecting the skin from the harmful effects of radiation therapy.

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Slide 1. The Benefits of Calendula Officinalis on Protecting the Skin from the Harmful Effects of Radiation Kevin Leach Ph.D. DABT

Slide 2. Radiation Therapy is an important modality in cancer treatment • Approximately 50% of all cancer patients receive radiation therapy Delaney G, Jacob S, Featherstone C, Barton M. The role of radiotherapy in cancer treatment: estimating optimal utilization from a review of evidence-based clinical guidelines. Cancer. 2005;104:1129-1137 Begg AC, Stewart FA, Vens C. Strategies to improve radiotherapy with targeted drugs. Nat Rev Cancer. 2011;11:239-253 • Radiation contributes to approximately 40% of the total therapeutic value of the entire course of cancer treatments Barnett GC, West CM, Dunning AM, Elliott RM, Coles CE, Pharoah PD, Burnet NG. Normal tissue reactions to radiotherapy: towards tailoring treatment dose by genotype. Nat Rev Cancer. 2009;9:134-142 Multiple Treatment Modalities Surgery Immunotherapy Chemotherapy Radiation Multiple Treatment Modalities.

Slide 3. Radiation Therapy Kills Tumor Cells Leads to the death of tumor cells Acute Molecular Effects of Radiation Cell Damage and Death • DNA breaks • Oxidative damage to cellular components • Lipid peroxidation • Protein malfunction Inflammation • Gene expression of pro-inflammatory genes • Secretion of pro-inflammatory proteins • Immune cell activation Acute Tissue Side Effects

Slide 4. Radiation Therapy has acute side effects • Dermatitis • Fatigue • Dry mouth • Nausea • Diarrhea • Shortness of breath • Incontinence • Sexual problems • Immune suppression • Hair loss • Mucositis.

Slide 5. Radiation Dermatitis Grade 1 • Erythema • Dry desquamation • Swelling • Pigment changes • Hair loss • Scaling Grade 2 • Brisk erythema • Focal sloughing • Moist desquamation • Pain • High chance of infection Grade 3 • Extensive moist desquamation outside of skin folds Grade 4 • Ulcerations • Hemorrhage • Skin ulceration • Skin necrosis • 95% of patients who receive radiation therapy experience radiation dermatitis • 23% experience Grade 2 or higher • Grade 3 or higher is associated with discontinuation of therapy McQuestion M. Semin Oncol Nurs. 2011; 27e1-17 Salvo N. et al. Curr Oncol. 2010; 17;94-112 Severity Scoring of Radiation Dermatitis.

Slide 6. Calendula has been studied in laboratories around the world • The individual components and/or the extract of calendula have been tested for activity against • Oxidants • Inflammation • Microbial growth • Cellular proliferation • Pain • Water loss from the skin • Wound healing • Protection from the sun • Radiation dermatitis.

Slide 7. Calendula Extract Has A Complex Mixture of Phytochemicals Calendula Tocopherols They include: • Flavinoids • Carotenoids • Tocopherols • Sesquiterpenes • Coumarins • Andersen F.A. Et al. 2010. Int. J. Tox. 29 (suppl 4) 221S-243S.

Slide 8. Studies Demonstrate the Activities of Calendula Extract Calendula Anti- inflammatory.

Slide 9. Radiation reacts with water inside the cell to form oxygen radicals • Oxygen radicals cause- • DNA damage • Protein disfunction • Lipid membrane damage • Activate the inflammation machinery in the cell Oxidants and Radiation Dermatitis Reactive Oxygen Species DNA Damage Cell DeathLipid Peroxidation Cell Leakage Protein disfunction Inflammation Loss of Water Radiation Therapy.

Slide 10. Radiation induced Oxidants Tocopherols Coumarins Flavinoids Carotenoids Non-Clinical Studies Show Calendula Extract Components Scavenge Radiation Induced Oxidants • Nimse S.B. and Pal D. RSC ADV, 2015, 5, 27986-28006.

Slide 11. Anti-Oxidant Activity Non-Clinical Studies Show Calendula Extract Components Block the Cellular Effects of Oxidants ROS DNA Damage Cell DeathLipid Peroxidation Cell Leakage Protein Oxidation Inflammation Loss of Water Calendula extract components block the harmful effects of oxidants • Cordova CA. et al. Redox Rep. 2002; 7(2):95-102 • Abdel-Azlem SH. Et al. Cytotechnology May 2014, Vol 66(3) 457-470 • Fonseca YM et al. J. Ethnopharmacol. 2010, 127:596- 601.

Slide 12. Inflammation and Radiation Dermatitis Radiation induced oxidants leads to activation of inflammatory pathways in the irradiated pathway • Activates inflammatory cell signaling pathways • Cytokines, NFkB, p38 MAPK • Increased activity of enzymes that mediate inflammation • Cyclooxygenase, Prostaglandin synthase • Leading to • Edema • Erythema • Pain Oxidative Stress Expression of inflammatory genes Gene activating factors Activates Ras Raf Mek1/2 MAPK Cell Signaling Events IL-1b TNFa PGES MMP1 COX.

Slide 13. Anti- Inflammatory Activity Studies Show That Calendula Extracts Stop Inflammation Block Edema Inhibit inflammatory signaling pathways Inhibit inflammatory enzymes.

Slide 14. Blocks Edema Faradiol esters are sesquiterpenes present in abundance in Calendula Officianalis • Faradiol myristic ester • Faradiol palmitic ester Calendula Extract Components Stop Inflammation Calendula Component Potency Faradiol myristic ester IC45=240mg/cm2 Faradiol palmitic ester IC45=240mg/cm2 In Experiments - Calendula extract components block induced edema in mice • Della Loggia R. Et al. 1994. Planta Med. 60; 516-520 • Zitterl-Eglseer K. Et al. 1997. J. Ethnopharmacology. 57; 139-145.

Slide 15. Reduces Molecular Markers of Inflammation Calendula Extracts Stop Inflammation • Coumarins are found in abundance in Calendula Officianalis • Esculetin • Scopoletin • 7-hydroxy coumarin • P Coumaric acid In experiments of inflammation - calendula extract components reduce markers of inflammatory signaling Calendula component NFkB nuclear localization p38 MAPK phosphorylation Nitric oxide levels TNFa levels IL-1b levels PGE2 levels MMP1 levels Scopoletin Esculetin 7-HC P-CA • Zhao Y. Et al. 2016. Med Chem 6:5 327-330 • Chen T. Et al. 2015 Free Radical Research; 49(12); 1459-1468 • Nascimento MVPdS Et al. 2016. Immunopharmacology and Immunotoxicology; Vol 38, No.5, 344-352 • Sim MO Et al. 2015 Nutrition Research and Practice. 9(4):364- 369.

Slide 16. Blocks Activation of Inflammatory Enzymes Calendula Extracts Stop Inflammation • Flavinoids are found in abundance in Calendula Officianalis • Quercetin • Isorhamnetin In studies - Calendula extract components inhibit COX2 and PGES enzymes which play a role in inflammation-erythema and collagen breakdown following injury to the skin COX2 PGESROS ErythemaInflammation Collagen Breakdown Pain Quercetin Quercetin Isorhamnetin Isorhamnetin • Li Y. Et al. 2016. Nutrients. 8, 167; 1-14 • Han X. Et al. 2015. Biomol Ther 23(4), 357-366.

Slide 17. Radiation Therapy and Skin Infections • Skin infections are common in patients with radiation dermatitis • Altoparlak U. etal. The Eurasian Journal of Medicine 2011 Dec 43(3) 177-181 • Infection can exacerbate dermatitis and delays healing • Hill A. etal. Am J Clin Oncol. 2004 Aug 27(4) 381-3 Wet Desquamation Dry Desquamation.

Slide 18. Anti- Microbial Activity Non-Clinical Studies Show That Calendula Extracts Kill Microbes Bacteria • Bacillus subtillis • Staphylococcus aureus • Escherichia coli • Klebsiella pneumoniae Yeast • Candida albicans • Candida monosa Fungus • Neurospora Crossa • Efstratiou E. etal. Complement Ther Clin Pract 2012 Aug18(3) 173-6) • Janssen AM etal. 1986. Pharmaceutisch Weekblad Scientificd Edition. Vol 8. 289-292 • Iauk L etal. 2003. Phytotherapy Res. 17:599-604 • Kalvatchev Z etal. 1997. Biomed Pharmacother. 51; 176-180 Calendula stopped growth or killed.

Slide 19. Radiation Dermatitis is a type of wound • Calendula extract has been shown experimentally to accelerate wound healing Wet Desquamation.

Slide 20. Wound Healing Non-Clinical Studies Show That Calendula accelerates wound healing Increased local angiogenesis • New blood vessels bring growth factors to stimulate repair and immune cells to clear debris Increased epithelialization • Fibroblasts proliferate to create the new skin over the wound Wound closure times decreased • Naeini AT. Et al. 2012. Comp Clin Pathol; 21: 253.

Slide 21. Radiation Therapy Leads to Impaired Barrier Function and Dry Skin • Skin dryness can be measured clinically by Transepidermal Water Loss (TEWL) • In clinical studies of patients receiving radiation therapy - TEWL increases were predictive of radiation dermatitis severity and duration • Schmuth M. etal. Arch Dermatol Vol 137 Aug 2001 p1019-1023 • Due to the known effects of radiation therapy on the skin, clinical guidelines stress the need to hydrate the skin during radiation therapy Wet Desquamation Dry Desquamation.

Slide 22. Hydrating Activity Clinical Studies Show that Calendula Hydrates Skin • Calendula hydrates skin • A clinical study showed that the skin hydration increased as with calendula application to skin Calendula • Provides moisture to skin cells • Akhtar N. Acta Polonicae Pharm-Drug Research Vol 68 No5 p693-701, 2011.

Slide 23. Calendula Containing Products for Damaged Skin • My Girls™ Skin Care cream • My Guys™ Skin Care cream • Calendula extracts have been used for skin ailments since antiquity and it is acknowledged as a traditional medicine by the European Medical Agency • Currently there are several topical products for skin conditions available over the counter that include calendula.