Plant Spotlight Series Strawberry and Palbociclib- Side by Side Comparison

February 2020 (Series # A006)

Strawberry

● Produced from the plant F ragaria ananassa. ● Strawberry identified key ingredients are ○ Anthocyanins - Pelargonidin-3-glucoside, -3-glucoside. ○ Flavonols - , , . ○ Ellagitannins - Ellagic Acid.

Palbociclib

● Oral drug, kinase inhibitor targeting CDK4 and CDK6. Approved for breast cancer.

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Plant Spotlight Series : Strawberry and Palbociclib- Side by Side Comparison

Strawberry (Fisetin) Palbociclib

Marketed by Generic, and available as a Dietary Pfizer Inc Supplement

Biological Targets Number of targets including Cyclin-dependent kinase 4 (C DK4) Cyclin-dependent kinase 4 (C DK4) ; and Cyclin-dependent kinase 6 Cyclin-dependent kinase 6 (C DK6) ; (C DK6) , key kinases for cell cycle Cyclin-dependent kinase 2 (C DK2) ; progression and cell proliferation. Cyclin-dependent kinase 1 (C DK1) ; (P albociclib Prescribing Cyclin-dependent-like kinase 5 information) (C DK5) ; Cyclin-dependent kinase 5 activator 1 (C DK5R1) ; G2/mitotic-specific cyclin-B1 (C CNB1) ; G2/mitotic-specific cyclin-B2 (C CNB2) ; G2/mitotic-specific cyclin-B3 (C CNB3) ; Glycogen synthase kinase-3 alpha (G SK3A) ; Glycogen synthase kinase-3 beta (G SK3B) ; Arachidonate 12-lipoxygenase (A LOX12) ; Arachidonate 15-lipoxygenase (A LOX15) ; Casein kinase II subunit alpha (C SNK2A1) ; Casein kinase II subunit alpha' (C SNK2A2) ; Casein kinase II subunit beta (C SNK2B) (L u X et al, J Nutr., 2005; Lu H et al, J Med Chem., 2005; Lee J et al, Bioorg Med Chem Lett., 2007; Golub AG et al, Bioorg Med Chem., 2013; Yokoyama T et al, J Med Chem., 2015)

Pathways Targeted Proliferation, Arachidonic acid Proliferation, G1S Cell Cycle Metabolism, PI3K-AKT Signaling, TP53 Signaling, Apoptosis

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Plant Spotlight Series : Strawberry and Palbociclib- Side by Side Comparison

Clinical Dosing Daily dose of 100 mg is used in a 125 mg once daily taken with food clinical trial (F arsad-Naeimi A et al, for 21 days followed by 7 days off Food Funct., 2018) . treatment (P albociclib Prescribing information) .

Approved by FDA for Not approved as a therapeutic agent For the treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer in combination with an aromatase inhibitor as initial endocrine-based therapy in postmenopausal women or in men; or in combination with fulvestrant in patients with disease progression following endocrine therapy (P albociclib Prescribing information) .

Off-Label Use for Orally, strawberries are used for GI - tract mucous membrane inflammation, diarrhea, intestinal sluggishness, liver disease, jaundice, upper and lower respiratory tract mucous membrane inflammation, gout, arthritis, nervous tension, kidney ailments involving gravel and stones, diuretic, supportive for heart and circulatory ailments, fever, night sweats, blood purification, for stimulating metabolism, anemia, as a tonic, for inhibiting menstruation, and supporting weight loss. Topically, strawberries are used as a compress for rashes.

Impact in Breast Cancer Proliferation G1S Cell Cycle Proliferation G1S Cell Cycle

Inhibitor Inhibitor Inhibitor Inhibitor

G2M Cell PI3K-AKT G2M Cell PI3K-AKT Cycle Signaling Cycle Signaling

Inhibitor Inhibitor No effect No effect

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Plant Spotlight Series : Strawberry and Palbociclib- Side by Side Comparison

Pros and Cons of Differential Impact Pros Pros in Cancer Indications Fisetin inhibits CDK4/6 which cause Palbociclib is an inhibitor of CDK4 G1S cell cycle arrest and subsequent and CDK6. CDK4/6 are decrease in proliferation of cancer downstream of estrogen signaling cells (L u X et al, J Nutr., 2005) . pathway and along with CCND1 Since Fisetin also inhibits CDK1 and they lead to proliferation. CDK2, Fisetin can also cause G2M Inhibiting CDK4/6 by Palbociclib, arrest and subsequent apoptosis in reduces proliferation of ER breast cancer cells. Loss of RB1 will positive breast cancer cells. not limit the effect of Fisetin. Fisetin Palbociclib is cytostatic and causes can also enhance certain cancer cells to undergo chemotherapeutic drugs like senescence. cisplatin, 5-fluorouracil, Cyclophosphamide response. (S mith Cons ML et al, J Cell Biochem., 2016) . Palbociclib effect is limited to RB1 Inhibition of Casein kinase by Fisetin wild-type status. If RB1 is deleted can cause upregulation of tumor or mutated, Palbociclib will not suppressor PTEN and TP53. PTEN show therapeutic effect. upregulation causes inhibition of Similarly, if CDK1 or CDK2 is PI3K-AKT signaling. PI3K-AKT constitutively activated, signaling is dominant in breast Palbociclib’s effect will be limited. cancer (L i J et al, Front Pharmacol., Palbociclib can antagonize certain 2018) . chemotherapeutic drug effects like gemcitabine, Docetaxel, Cons Trifluridine, Mercaptopurine etc Since GSK3B is an endogenous (W itkiewicz AK et al, Cell Rep., inhibitor of beta-catenin signaling, 2018) . Fisetin mediated inhibition of GSK3B may cause this signaling upregulated. High beta-catenin signaling can limit Fisetin response.

Demonstrated Response In a cohort of 37 colorectal cancer Overall Response Rate (Complete patients, Fisetin supplementation and Partial Response) and was given to 18 patients while 19 Progression Free Survival (PFS) patients received placebo. Patients in (P albociclib Prescribing the Fisetin group had reduced information) : inflammatory factors (IL-8 and In patients with ER-positive, hs-CRP) and MMPs (MMP7 and HER2-negative advanced or MMP9) compared to placebo metastatic breast cancer, (F arsad-Naeimi A et al, Food Funct., Palbociclib with Letrozole (n=444) 2018) . showed 55.3% objective response In a clinical trial of 75 patients with rate in comparison to 44.4% Esophagus dysplasia (precursor of response rate with Letrozole alone esophageal squamous cell (n=222). Median PFS was 24.8 carcinoma), 60 g/d strawberry months in Palbociclib and extract was given to 38 Subjects. In Letrozole arm vs 14.5 months in 29 of evaluated 36 patients (80.6%), Letrozole arm (Table 8). there was a decrease in histological In patients with HR-positive, grade of dysplasia. This dose also HER2-negative advanced or

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Plant Spotlight Series : Strawberry and Palbociclib- Side by Side Comparison

decreased inflammatory biomarkers metastatic breast cancer, like iNOS, COX2, NFkB, and RPS6 by Palbociclib with Fulvestrant 60-80% (C hen T et al, Cancer Prev (n=347) showed 24.6% objective Res (Phila)., 2012) . response rate in comparison to Intake of Rosaceae family fruits 10.9% response rate with (apples, peaches, nectarines, plums, Fulvestrant alone (n=174). Median pears and strawberries) is shown to PFS was 9.5 months in Palbociclib be associated with significant and Fulvestrant arm vs 4.6 months reduced risk of Esophageal Cancer in Fulvestrant arm (Table 9). (F reedman ND et al, Int J Cancer., 2007) . Intake of Rosaceae family fruits (apples, peaches, nectarines, plums, pears and strawberries) is shown to be associated with significant reduced risk of Head and Neck Cancer (F reedman ND et al, Int J Cancer., 2008) . -rich Strawberry Extract (PRSE) is shown to significantly reduce highly invasive breast cancer tumor growth in a breast cancer xenograft (A matori S et al, Sci Rep., 2016) .

Toxicity No recorded data about toxicity Neutropenia, Infections, Leukopenia, Fatigue, Nausea, Alopecia, Stomatitis, Diarrhea, Anemia, Rash, Asthenia, Thrombocytopenia, Vomiting, Decreased appetite, Dry skin, Pyrexia, and Dysgeusia. (P albociclib Prescribing infor- mation)

Available format and doses Capsule (100 mg and other dosages) Capsules: 125 mg, 100 mg, and 75 mg

Cost $0.41/- (1x100 mg capsule) $619.36/- (1X125 mg) (s wansonvitamins) (D rugs.com)

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Plant Spotlight Series : Strawberry and Palbociclib- Side by Side Comparison

Disclaimer

● These statements have not been evaluated by the Food and Drug Administration. This analysis is not intended to diagnose, treat, cure, or prevent any disease. ● This website/document is provided for informational purposes only and is not intended as a substitute for the advice provided by your physician or other healthcare professional. ● You should not use the information on this website/document for diagnosing or treating a health problem or disease, prescribing any medication or other treatment, or discontinuing any medication or treatment recommended by your healthcare provider.

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