ANTICANCER HERBSEric Yarnell, ND, RH(AHG)2015OncANP

SUMMARY OF ACTIONS

Mitotic DisruptorsProtein Translation

Inhibitor

PaclitaxelPodophyllotoxin

VinblastineVincristine

Harringtonine(omacetaxine)

Taxus brevifolia(Pacific yew)

Photo © 2015 E. Yarnell

Native rangeof

Taxusbrevifolia

“The Yew and People: Cultural Resources" in Pacific Yew: Draft

Environmental Impact Statement. U.S. Departments of Agriculture, Interior, and Health and Human

Services. January 1993.

Taxus baccata(European yew)Photo © 2015 E. Yarnell

arilseed

SPECIES COMMON NAME NATIVE HABITAT

T. BREVIFOLIA Pacific yew Pacific NW US/Canada

T. BACCATA European yew Europe, NW Africa, Iran, SW Asia

T. CUSPIDATA Japanese yew Japan, Korea, NE China

T. WALLICHIANA* = T. YUNNANENSIS Himalayan yew Afghanistan to Yunnan

(SW China)

T. CHINENSIS** Chinese yew W/Central China, N Vietnam

T. CANADENSIS Canada yew Eastern Canada

* CITES appendix II ** Endangered species

PACLITAXEL (TAXOL)

Synthetic derivatives: docetaxel, cabazitaxel

MICROBULE STABILIZATION

Ref: Jordan 2004

paclitaxel

{

normal{

polymerizedmicrobule

depolymerizingmicrobule

microbulenucleus

α-/β-tubulinheterodimers

POLITICS OF PACLITAXEL

Basically US gov’t (ie taxpayers) did most of the development and Bristol Meyers-Squibb (BMS) got 5 years of exclusive marketing with mega-profits, which we didn’t get much of (Oberlies 2004; Walsh 2002)

Generic name really should be taxol, but again BMS was allowed to use that and shifted generic to unwieldy paclitaxel

Very nice overview (never thought I’d say this) at http://en.wikipedia.org/wiki/Paclitaxel

“INACTIVE” TAXANES

Paclitaxel better absorbed from whole T. yunnanensis than in isolation in rats (Jin 2013).

“Inactive” taxanes enhance efficacy of paclitaxel in whole extracts (Ojima 1998).

paclitaxelpaclitaxel paclitaxel

resistance pump

other taxanescancer cell

CURCUMIN SYNERGY

Lin28

NFκB

+

paclitaxel resistance

curcuminHO OCH3

O O

H3CO OH

Zhou 2015;Dang 2015

Combination superior to either alone

in mouse models of colon cancer (Gao 2015),

breast cancer (Royt 2011; Kang 2009), and

cervical cancer (Sreekanth 2011)

MDR

Punfa 2014;Sandhu 2015

paclitaxel toxicity

Ototoxicity: Bucak 2015

Akt

+Bava 2011

Gut Pgp inhibitionby curcumin

increased taxolabsorption in mice

(Ganta 2010)

EGFR

paclitaxel+

Zhan2014

WHOLE PLANT USE

Needles over bark (for ecological reasons)

Tincture of fresh needles 1:3, 3–10 gtt tid

TAXOL-FORMING ENDOPHYTES

Taxomyces andreanae, endophytic fungus of T. brevifolia (Stierle 1993)

Ultimately not able to be commercially exploited; did not scale up (Staniek 2009)

Successful in vitro growth of Fusarium solani with taxol and precursor production (Chakravarthi 2013)

Paraconiothyrium variabile, endophytic fungus of T. baccata, (Somjaipeng 2015)

Perenniporia tephropora from T. chinensis (Wu 2013)

Pestalotiopsis species from T. cuspidata (Kumaran 2010)

Catharanthus roseus(Madagascar periwinkle)

Photo © 2013 D. Howell used with permission

Review (Yarnell 2005)

VINBLASTINE

Other major natural compound: vincristineSynthetic derivatives: vinorelbine, vindesine

MICROTUBLE DISRUPTION

polymerizedmicrobule

depolymerizingmicrobule

microbulenucleus

α-/β-tubulinheterodimers

vinblastine

Curcumin also inhibits microtubule formation;colchicine and podophyllotoxin

partly inhibit this while vinblastine doesn’t (Gupta 2006).

VINCA ALKALOID RESISTANCEINHIBITORS

MDR1 = Pgp = ABCB1

Effluxfromcell

+ATP

MDR1 inhibitors (specific to vinca alkaloids):Fucoxanthin, canthaxathin (Eid 2012)

Rosmarinus officinalis, carnosic acid (Nabekura 2010)Cannabinoids (Holland 2006)

Curcumin (Attaoua 2015; Anuchapreeda 2002)Methoxyflavonoids of orange (Takanaga 2000)

WHOLE PLANT USE

Fresh flowering tops

Tincture 1:3, 1–2 ml tid

Watch for hypoglycemia (haven’t seen it but theoretically possible)

Cephalotaxus fortunei

(Japanese plum yew)

Photo © 2015 E. Yarnell

ALKALOIDS

Harringtonine Homoharringtonine(omacetaxine)FD

A approved

Oct 2

012

for resist

ant CML

HOMOHARRINGTONINE CLINICAL TRIALS

Chronic myelogenous leukemia, moderate (Li 2009)

Myelodysplastic syndrome (Wu 2009)

Acute myelogenous leukemia (Kantarjian 2015; Gu 2010)

Acute lymphoblastic leukemia

Acute promyelocytic leukemia, w/ all-trans retinoic acid (Wang 2015)

ADVERSE EFFECTS

Increases intestinal permeability, which may account for higher rates (>10%) of GI adverse effects (Watari 2015)

SYNERGIZERS

β-Elemene emulsion 400 mg qd with homoharringtonine and aclacinomycin more effective than without β-elemene in 120 pt w/ relapsed AML (Zheng 2014)

Crude extracts anticancer in vitro; some biflavones as well as alkaloids active in subfractions (Komoto 2015)

Matrine from Sophia spp synergistic in vitro (Han 2015)

Total saponins of Panax ginseng drive leukemic cells into cell cycle thus making them more susceptible to harringtonine (Gao 1999)

WHOLE PLANT USE

Dry seed

Tincture 1:3, 3–10 gtt tid

PODOPHYLLUM PELTATUM

Photo © 2015 E. Yarnell Photo © 2015 E. Yarnell

PODOPHYLLUM HEXANDRUM

Synonyms: P. emodi, Sinopodophyllum hexandrum

Common names: Himalayan mayapple, bantrapushi, ⿁鬼⺽⾅臼guǐ jiù

Grows in lower elevations of Himalayas

Endangered due to overharvesting (Nadeem 2000)

Photo © 2015 E. Yarnell

PODOPHYLLIN

Podophyllin

Crude resin Podophyllotoxin (P)Deoxy-P4’-Demethyl-Pα-Peltatinβ-Peltatin

Khaled 2013

ClinicalPodophyllin (10–25%)

+ tincture of benzoin

Photo © 2015 E. Yarnell

PODOPHYLLOTOXIN, PODOFILOX

Teniposide Etoposide

Gordaliza 2004

synthetic

synthetic

natural

MECHANISM OF ACTION: CANCER

Microtubulescan’t form

Cells stuck in metaphase

α-/β-tubulinheterodimers

P

P

Podophyllotoxinbinds tubulin

P

P

INDICATIONS

Genital warts, topical, 20–25%

CIN I and II topical 20% with vidabarine (Okamoto 1999)

Oral hairy leukoplakia 25% with acyclovir 5% (Moura 2010)

Cancer??

PODOPHYLLIN VS PODOPHYLLOTOXIN

Podophyllotoxin 0.5% at home more effective and cheaper than podophyllin 20% in office in head-to-head trial (Lacey 2003)

Weak arguments against podophyllin: batch-to-batch variability, possible greater toxicity (van Krogh 2001)

ETOPOSIDE AND TENIPOSIDE: MECHANISM OF ACTION

Topoisomerase II DNA

Topoisomerase II DNA

Topoisomerase II DNA

Form non-cleavable

complex

Form transient cleavable

complex

Separate

etoposideteniposide

WHOLE PLANT USE

High-ethanol (70%+) tincture of root (contains lignans)

1:3–1:5, 3–5 gtt tid, watch for catharsis

Low-ethanol (30%) tincture of root (no lignans)

1:3, 1–2 ml tid (as alterative)

Photo © 2015 E. Yarnell

Annona muricata (soursop, graviola)

ANNONACEOUS ACETOGENINS

Over 500 discovered in the Annonaceae family (McLaughlin 2008)

Multiple intriguing actions besides anticancer (antiparasitic, hypoglycemic, hepatoprotective, etc.) (Moghadamtousi 2015)

O

O

O

(H2C)11

HOH

HO

H

OH

HO

annonacin A

ANTICANCER ACTIONS: PRECLINICAL

EXTRACT MODEL EFFECT REFERENCE

LEAVES, ETHYL ACETATE

Lung cancer cells, in vitro

Apoptosis (mitochondrial), cell cycle arrest in G1

Moghadamtousi 2014

LEAVES, ETHANOL

Colon cancer cells, in vitro

Aberrant crypt foci formation reduced

Eggadi 2014; Moghadamtousi 2015

LEAVES, ETHANOL

Chronic myeloid leukemia cells, in vitro Apoptosis Ezirim 2013

LEAVES, ETHANOL Breast cancer, mice Prevention of DMBA

carcinogenesis Minari 2014

CASE STUDY66-yr-old woman with ER/PR+, EGFR-, pT2N1M0 (stage IIb) breast cancer (Hansra 2014)

Initial therapy: lumpectomy, adjuvant anthracycline and paclitaxel, adjuvant radiation

Biopsy-proven lung metastasis 3 yr later; progressed despite hormonal therapy and multiple rounds of chemo (liver mets developed)

Started capecitabine 2.5 g po qd (2 wk on/1 wk off) + 10-12 soursop leaves boiled 5-7 min daily

CEA, CA 15-3 and CA 27-29 markers all fell dramatically

Stopped soursop and all tumor markers rose (still on capecitabine); PET = worse mets

Restarted soursop, all tumor markers fell again, PET showed stable disease (still stable 5 yr later)

PARKINSON’S DISEASE

High intake of fruit associated with atypical Parkinson’s disease (Caparros-Lefebvre 1999; Lannuzel 2002)

Chamorro people of Guam: Lytico-Bodig disease (ALS, dementia, Parkinsonism), see Island of the Colorblind by Sacks (he proposed it was cycad nut toxicity biomagnified by flying fox bats)

Have to eat 1 fruit per day for 1 yr to be at risk (Champy 2005)

Annonaceous acetogenins are implicated; doses in leaves as medicine far below fruit as food

WHOLE LEAF USE

Dry leaf tincture 1:2–1:3, 1–3 ml tid

Dry leaf infusion: 1–2 g leaf, steep 15 min, strain, drink 1 cup tid

PROSTATE CANCER CASE STUDY

68-yr-old man with stage IV prostate cancer, CKD stage 3, obesity (mild), metabolic syndrome, hypertension

Initial biopsy (2006): Gleason 3+4 in 3 of 6 cores, tPSA 7.26 ng/ml, PAP 3.61 ng/ml in 2010

Initial bone scans (2007) x2: left hemipelvis infiltrated, ruled out Paget’s dz of bone

Lots of back and hip pain, but history of bus driving (many hours sitting) and improves with stretching, heat, etc.

PR CA CASE TREATMENTS

Low carb, organic meat, high veggie diet

Modified citrus pectin 5 g bid

Artemisinin 300 mg tid every other week

Vitamin D3 5,000 IU qd

Fish oil

Power Immune product (patient’s choice)

All followed intermittently

HERBAL FORMULAHERB PERCENT RATIONALE

WITHANIA SOMNIFERUM T 0.13 Adaptogen, calmingURTICA DIOICA SEED T 0.1 Nephroprotective

CRATAEGUS MONOGYNA LEAF, FLOWER G 0.1 Hypotensive, CV tonicCATHARANTHUS ROSEUS HERB T 0.09 Anticancer

TAXUS BREVIFOLIA LEAF T 0.05 AnticancerCEPHALOTAXUS FORTUNEI SEED T 0.05 AnticancerPHYTOLACCA AMERICANA ROOT T 0.05 Lymphagogue, anticancer

AMMI VISNAGA FRUIT T 0.15 Prostate spasmolyticPISCIDIA PISCIPULA BARK T 0.12 Prostate spasmolytic

MIRABILIS MULTIFLORUM ROOT T 0.08 Appetite suppressantVISCUM ALBUM T 0.08 Hypotensive

Sig 1 tsp tid

FOLLOW-UP

Bone scan 2015: stable disease (still unlikely to be Paget’s)

tPSA: rising (9/15 up to 13 ng/ml, stable since 4/15), PSADT 10 yr, PSAV 0.6 ng/ml/yr

eGFR: went from 42 ml/min to 58 over duration of treatment

Feeling well, hip/back pain fluctuates but never severe

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