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Annonaceous acetogenins for Cancer Date Written 2008
Author Joe Holmes Date Revised  

What are Annonaceous acetogenins?
Annonaceous acetogenins are powerful anticancer chemicals found in the Annonaceae family of trees (usually called Pawpaw,
Soursop, Custard-apple or Graviola trees). These chemicals are in high concentrations throughout the tree including the fruit (over 2% of the dry weight of the fruit is Annonaceous acetogenins see research # 3 below). The fruit is very tangy and delicious and eaten daily (anticancer chemicals and all) by many people in some parts of the world (it is the South American equivalent of Lemonade in the US). Annonaceous acetogenins are nontoxic (and tasty) and used medically in South America. For anyone that is wondering, yes this is the same Pawpaw that Baloo the bear in Walt ‘Disney’s animated movie “The Jungle book” sings about in the song “The Bare Necessities”.

A note to help avoid confusion.
To show how powerful Annonaceous acetogenins are against cancer, research is provided that compares them to the medical worlds super cancer killing (and toxic) chemotherapy Anthracycline type drugs (Doxorubicin and Adriamycin). Because the words “Adriamycin and Anthracyclines” (the toxic chemo drugs) and “Annonaceous acetogenins” (natural, safe and tasty) are unfamiliar to most people it is easy to confuse them when all the terms are used in the same research. The comparisons between the toxic chemo and safe and tasty terms will jump back and forth so please don’t confuse them. 

What are the Chemotherapy drugs that tasty Annonaceous acetogenins are being compared to?
 Doxorubicin and Adriamycin are toxic Anthracycline type drugs and are among the most effective cancer killing chemotherapy drugs used by Drs. Unfortunately they are also among the most toxic and are very destructive to your heart If the Drs. are trying to use them on you, kiss your heart goodbye. (see research #1 & 2)

How does the strength of the natural Pawpaw chemicals compare to the toxic Chemo drugs?
Anthracyclines are among the most powerful, effective and toxic chemotherapy drugs used on “Multiple Drug Resistant” (MDR) cancer (see research # 1 & 2) so Annonaceous acetogenins are commonly tested against Anthracyclines (see # 6--22 below). Most people find it hard to believe that Pawpaw can be so many times more effective than a FDA approved Chemo super drug, so medical research is provided to prove it. To get a feel of how much more powerful Pawpaw chemicals are than chemotherapy drugs, look at research summary #7, #17, #19 and #22.. (Notice this is even a very respected American medical research center saying this)

Will Annonaceous acetogenins kill all cancer?
 NO, Annonaceous acetogenins
work by various methods to block cancer cells from getting the ATP (energy) produced by Mitochondria that is needed by cancer for fast growth and or defense from chemotherapy and radiation (see # 4 & 5). Annonaceous acetogenins have little effect on slow growing and easy to kill cancer because the amount of ATP needed by these cancers is only a little more than needed by healthy cells. Also some energy dependant cancers can make enough energy without using the Mitochondria to survive. However many fast growing or Multiple Drug Resistant (MDR) cancers have high ATP needs and are dependant on Mitochondria. These cancers are hit extremely hard by Annonaceous acetogenins without affecting normal cells (see # 21). The effect of Annonaceous acetogenins on Mitochondria dependant cancer that is both fast growing and MDR is absolutely amazing!

Will Annonaceous acetogenins kill Prostate cancer?
 Several of these (like #6, 7, 12, 13, 14, 15 & 16) show the powerful effects of Pawpaw on human prostate cancer. However prostate cancer is always in a state of transformation, this means that even in a worst case aggressive and advanced prostate cancer there may be some cancer cells that are slow growing and not vulnerable to Pawpaw. There are other safe, legal, inexpensive, readily available and natural chemicals to kill these cells.

How else are Annonaceous acetogenins used?
 Very high doses of Annonaceous acetogenins are used to sedate patients and considered safe. It is used medically this way to replace the more expensive Valium. Also extremely large dosages produce vomiting and are used instead of Ipecac.

 Driving a car or operating machinery while on very high doses is as dangerous as taking Valium.

 This is a part of the diet of millions of people and it took some digging to find any problems. However high consumption of Annonaceous acetogenins for several decades can interfere with brain ATP needs in some people and cause a type of Parkinson’s disease (see# 23). This is very rare even with heavy long-term usage so several months usage to kill cancer is very safe.

Are Annonaceous acetogenins available?
 Yes but no single Annonaceae tree has all types so it takes a combination. Annona muricata (sometimes called Amazon Pawpaw or Graviola) and Asimina triloba (commonly called American Pawpaw) are readily available and between them should contain all of the Annonaceous acetogenins tested in # 6—22 below.

Why isn’t Annonaceous acetogenins FDA approved in the US?

The research below needs commentary and explanations added to make it more understandable but the demand for information is so high and available help is so limited that finishing this completely must wait until more help is available.

 There is no way to represent the research on artemisinin with just the 25 research summaries included below but to someone that understands what the big words and numbers mean its obvious Artemisinin is a powerful and safe cancer killer.

Things of interest have been underlined in the research below while important information is in bold and the most important information is in Bold and underlined.

1: Europace. 2005 May;7(3):227-30.
Doxorubicin-induced second degree and complete atrioventricular block.
Kilickap S, Akgul E, Aksoy S, Aytemir K, Barista I.
Hacettepe University Oncology Institute, Medical Oncology Department, Hacettepe
University Faculty of Medicine, Cardiology Department Sihhiye, 06100 Ankara, Turkey.

Doxorubicin is one of the most effective chemotherapeutic agents used in the treatment of malignancies. Cardiotoxicity is the most important dose-limiting toxicity of doxorubicin. Although cardiomyopathy is the most well known side effect of doxorubicin, it usually occurs many years after the treatment and relates to cumulative doxorubicin dosage. Another form of doxorubicin cardiotoxicity is arrhythmia which may occur at any time and after any dosage. However, doxorubicin-induced arrhythmia is rarely a life-threatening side effect. In this report, we present a case in which there were doxorubicin-induced life-threatening arrhythmias.
PMID: 15878560 [PubMed - in process]
2: Paediatr Drugs. 2005;7(2):67-76. Anthracycline-induced cardiotoxicity in children with cancer : strategies for prevention and management.
Iarussi D, Indolfi P, Casale F, Martino V, Di Tullio MT, Calabro R.
Cattedra di Cardiologia, Dipartimento di Scienze Cardiotoraciche e Respiratorie, Seconda Universita di Napoli, Naples, Italy.

The fact that anthracyclines are cardiotoxic seriously narrows their therapeutic index in cancer therapy. The cardiotoxic risk increases with the cumulative dose and may lead to congestive heart failure (CHF) and dilated cardiomyopathy in adults and in children. The prevention of anthracycline-induced cardiotoxicity is particularly important in children who can be expected to survive for decades after being cured of their malignancy. Attempts to reduce anthracycline cardiotoxicity have been directed towards: (i) decreasing myocardial concentrations of anthracyclines and their metabolites by dose limitation and schedule modification; (ii) developing less cardio-toxic analogs; and (iii) concurrently administering cardioprotective agents to attenuate the effects of anthracyclines on the heart. As regards schedule modification, avoidance of anthracycline peak levels may reduce the pathologic and clinical cardiotoxicity, although this has not always been observed. The analogs of doxorubicin, such as idarubicin and epirubicin, have similar cardiotoxicity to that of doxorubicin when given in amounts of equivalent myelotoxicity. Liposomal anthracyclines are a new class of agents that may permit more specific organ targeting, thereby producing less systemic and cardiac toxicity, but more studies are required to assess the advantages, if any, of these preparations over classical anthracyclines. The cardioprotective agent, dexrazoxane, an iron chelator, is highly effective and provides short-term cardioprotection to most patients receiving even the most intensive doxorubicin-containing regimens. Its long-term benefits remain to be determined. In addition, data remain insufficient to make specific recommendations regarding current use of dexrazoxane in children.It is thought that subtle abnormalities, related to anthracycline treatment in childhood, can develop into more permanent myocardial disease resulting in cardiomyopathy, which may progress to CHF. As regards the therapy of patients with anthracycline cardiotoxicity, two different situations have, therefore, to be considered: (i) if the patient presents with cardiac abnormalities, such as a reduction in fractional shortening at echocardiogram, without cardiac symptoms; and (ii) if the patient has CHF.In the presence of CHF, recovery with digitalis-diuretic therapy alone seldom occurs, and in patients who have refractory hemodynamic decompensation, heart transplantation is indicated. In patients with CHF, therapy with ACE inhibitors induces improvement in left ventricular structure and function, but this improvement is transient. Randomized clinical trials are, therefore, necessary to determine the effects of ACE inhibitors in mild-to-moderate left ventricular dysfunction.The beneficial effects of beta-adrenoceptor antagonists (beta-blockers) on cardiac function in heart failure due to anthracyclines seem comparable with those observed in other forms of heart failure with systolic dysfunction. Many drugs are available to treat children with CHF due to anthracycline treatment, but they are only palliative.
PMID: 15871628 [PubMed - in process]

3: J Econ Entomol. 1992 Dec;85(6):2353-6.
Evaluation of various parts of the paw paw tree, Asimina triloba (Annonaceae), as commercial sources of the pesticidal annonaceous acetogenins.
Ratnayake S, Rupprecht JK, Potter WM, McLaughlin JL.
Department of Medicinal Chemistry and Pharmacognosy, School of Pharmacy and
Pharmacal Sciences, Purdue University, West Lafayette, IN 47907.

Various plant parts of the paw paw tree (Asimina triloba Dunal, Annonaceae) were extracted and partitioned to concentrate the mixture of acetogenins into a standardized pesticidal extract (F005). A bioassay with brine shrimp larvae (Artemia salina Leach) was used to determine the relative potencies of the various extracts. The small twigs (0-0.5 cm diameter) yielded the most potent extract (LC50 = 0.04 ppm); the stem wood (LC50 = 4.9 ppm) and leaves (LC50 = 53.7 ppm) yielded the poorest activities. The unripe fruits, seeds, root wood, root bark, and stem bark were notably potent and, generally, yielded > 2% of their dry weight as F005. The smaller diameter stems were more potent than the larger stems. We conclude that, by pollarding the trees, the entire twigs and small branches of paw paw could be processed to produce a potent acetogenin mixture; this biomass could be made available in quantities needed for commercialization of the pesticidal product and could be renewable through regrowth from the parent trunk and larger branches.
PMID: 1464691 [PubMed - indexed for MEDLINE]
4: J Nat Prod. 1999 Mar;62(3):504-40.
Annonaceous acetogenins: recent progress.
Alali FQ, Liu XX, McLaughlin JL.
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, Indiana 47907, USA.

The Annonaceous acetogenins are promising new antitumor and pesticidal agents that are found only in the plant family Annonaceae. Chemically, they are derivatives of long-chain fatty acids. Biologically, they exhibit their potent bioactivities through depletion of ATP levels via inhibiting complex I of mitochondria and inhibiting the NADH oxidase of plasma membranes of tumor cells. Thus, they thwart ATP-driven resistance mechanisms. This review presents the progress made in the chemistry, biology, and development of these compounds since December 1995.
Publication Types:    Review
PMID: 10096871 [PubMed - indexed for MEDLINE]
5: Cancer Lett. 1997 May 1;115(1):73-9.
The Annonaceous acetogenin bullatacin is cytotoxic against multidrug-resistant human mammary adenocarcinoma cells.
Oberlies NH, Croy VL, Harrison ML, McLaughlin JL.
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, IN 47907-1333, USA.

Cytotoxic effects of the Annonaceous acetogenin, bullatacin, were studied inmultidrug-resistant (MDR) human mammary adenocarcinoma (MCF-7/Adr) cells vs. theparental non-resistant wild type (MCF-7/wt) cells. Bullatacin was effectivelycytotoxic to the MCF-7/Adr cells while it was more cytostatic to the MCF-7/wt cells. ATP depletion is the mode of action of the Annonaceous acetogenins, and these agents offer a special advantage in the chemotherapeutic treatment of MDR tumors that have ATP-dependent mechanisms.
PMID: 9097981 [PubMed - indexed for MEDLINE]
6: J Nat Prod. 2005 Feb;68(2):194-7.
Asimitrin and 4-hydroxytrilobin, new bioactive annonaceous acetogenins from the
seeds of Asimina triloba possessing a bis-tetrahydrofuran ring.
Kim EJ, Suh KM, Kim DH, Jung EJ, Seo CS, Son JK, Woo MH, McLaughlin JL.
Narcotic & Neuropharmacological Drug Division, Drug Evaluation Department, Korea Food and Drug Administration, Seoul 122-020, Korea.

 Bioactivity-directed fractionation of the seeds of Asimina triloba resulted in the isolation of asimitrin (1) and 4-hydroxytrilobin (2). Compound 1 represents an adjacent ring-hydroxylated bis-tetrahydrofuran (THF) acetogenin. Compound 2 has an adjacent bis-THF ring with two flanking hydroxyl groups and a alpha,beta-unsaturated gamma-lact one with a 4-hydroxyl group. Compounds 1 and 2 showed cytotoxic selectivity, with 100-10,000 times the potency of adriamycin against prostate adenocarcinoma (PC-3) and colon adenocarcinoma (HT-29) cell lines.
PMID: 15730242 [PubMed - indexed for MEDLINE]
7: J Nat Prod. 1996 Feb;59(2):97-9.
Squamotacin: an annonaceous acetogenin with cytotoxic selectivity for the human prostate tumor cell line (PC-3).
Hopp DC, Zeng L, Gu Z, McLaughlin JL.
Department of Medicinal Chemistry and Pharmacognosy, Purdue University, West Lafayette, Indiana 47907-1333, USA.

The bark extracts of Annona squamosa yielded a new bioactive acetogenin, squamotacin (1), and the known compound, molvizarin (2), which is new to this species. Compound 1 is identical to the potent acetogenin, bullatacin (3), except that the adjacent bistetrahydrofuran (THF) rings and their flanking hydroxyls are shifted two carbons toward the gamma-lactone ring. Compound 1 showed cytotoxic selectively for the human prostate tumor cell line (PC-3), with a potency of over 100 million times that of Adriamycin.
Publication Types:     Research Support, U.S. Gov't, P.H.S.
PMID: 8991957
8: Yakugaku Zasshi. 2004 Oct;124(10):673-81.
[Systematic synthesis of antitumor annonaceous acetogenins]
[Article in Japanese]
Kojima N. Graduate School of Pharmaceutical Sciences, Osaka University, Suite, Osaka 565-0871, Japan.

Systematic synthesis of mono- and bis-THF ring cores, synthetic intermediates of antitumor annonaceous acetogenins, has been achieved by asymmetric alkynylation and subsequent stereodivergent THF ring formatio Systematic synthesis of mono- and bis-THF ring cores, synthetic intermediates of antitumor annonaceous acetogenins, has been achieved by asymmetric alkynylation and subsequent stereodivergent THF ring formation as key steps. The asymmetric alkynylation of alpha-oxyaldehyde and alpha-tetrahydrofuranic aldehyde with (S)-3-butyne-1,2-diol derivatives gave good yield with very high diastereoselectivity. These adducts were converted into mono- and bis-THF cores via two kinds of one-pot THF ring formation, respectively. In addition, the total synthesis of murisolin, which shows cytotoxic activity against human tumor cell lines with potency from 10(5) to 10(6) times that of adriamycin, was also achieved.
Publication Types: Review    Review, Tutorial
PMID: 15467275 [PubMed - indexed for MEDLINE]

9: Life Sci. 2002 Feb 1;70(11):1259-69.
Involvement of caspase-3 activation in squamocin-induced apoptosis in leukemia cell line HL-60.
Zhu XF, Liu ZC, Xie BF, Li ZM, Feng GK, Xie HH, Wu SJ, Yang RZ, Wei XY, Zeng YX.
Cancer Institute, Cancer Center, Sun Yat-sen University of Medical Sciences, Guangzhou, China.

Annonaceous acetogenins have potent antitumor effect in vitro and in vivo. Squamocin is one of the annonaceous acetogenins and has been reported to have antiproliferative effect on cancer cells. Our results from this study showed that squamocin inhibited proliferation of HL-60 cells with IC50 value of 0.17 microg/ml and induced apoptosis of HL-60 cells. Investigation of the mechanism of squamocin-induced apoptosis revealed that treatment of HL-60 cells with squamocin resulted in extensive nuclear condensation. DNA fragmentation, cleavage of the death substrate poly (ADP-ribose) polymerase (PARP) and induction of caspase-3 activity. Pretreatment of HL-60 cells with caspase-3 specific inhibitor DEVD-CHO prevented squamocin-induced DNA fragmentation, PARP cleavage and cell death. The expression levels of protein bcl-2, bax have no change in response to squamocin treatment in HL-60 cells, whereas stress-activated protein kinase (SAPK/JNK) was activated after treatment with squamocin in HL-60 cells. These results suggest that apoptosis of HL-60 cells induced by squamocin requires caspase-3 activation and is related to SAPK activation.
PMID: 11883704 [PubMed - indexed for MEDLINE]
10: Arch Pharm Res. 2001 Aug;24(4):300-6.
Annomocherin, annonacin and annomontacin: a novel and two known bioactive mono-tetrahydrofuran annonaceous acetogenins from Annona cherimolia seeds.
Kim DH, Son JK, Woo MH.
Department of Pharmacy, College of Pharmacy, Catholic University of Daegu, Gyeongsan, Korea.

A novel and two known bioactive mono-tetrahydrofuran (THF) annonaceous acetogenins, annomocherin (1), annonacin (2) and annomontacin (3), have been isolated from the fractionated ethanolic extracts of the seeds of Annona cherimolia, guided by the brine shrimp lethality test (BST). Their structures were elucidated on the basis of spectroscopic and chemical methods. All compounds have a relative stereochemistry of threo/trans/threo for the mono-THF ring with two flanking hydroxyls. Compound 1 has a double bond at C-23/24 of aliphatic chain. Compound 1 was isolated from natural sources for the first time, and was named annomocherin. Two known Compounds 2 and 3 which have never been isolated from this species before, were obtained. Compound 1 exhibited potent and selective cytotoxicities against the breast carcinoma (MCF-7) and kidney carcinoma (A-498) cell lines with 100 to 1,000 times the potency of adriamycin. In brine shrimp lethality test (BST), 1-3 exhibited cytotoxicity.
PMID: 11534761 [PubMed - indexed for MEDLINE]

11: Yao Xue Xue Bao. 1997 Apr;32(4):286-93.
[Studies on new cytotoxic annonaceous acetogenins from Uvaria grandiflora and absolute configurations]
[Article in Chinese]
Pan XP, Yu DQ. Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050.

Two new cytotoxic annonaceous acetogenins, named uvarigrin(1) and uvarigrandin A(3), were obtained from the roots of Uvaria grandiflora Roxb(Annonaceae). Based on X-ray analysis and Mosher's methodology, the overall absolute configuration of 1 was established as 15S, 17R, 18R, 21R, 22R, 36S. The absolute configuration of 3 was also resolved by Mosher's methodology. The relative configuration of the previously reported uvarigranin (2) was revised. Compound 1 showed cytotoxicity against HCT-8, Bel7402 and A2780 human tumor cell lines at ED50 levels of 0.15, 0.21 and 0.41, respectively.
PMID: 11499032 [PubMed - indexed for MEDLINE]

12: J Nat Prod. 2001 Apr;64(4):502-6.
Annomolin and annocherimolin, new cytotoxic annonaceous acetogenins from Annona cherimolia seeds.
Kim DH, Ma ES, Suk KD, Son JK, Lee JS, Woo MH.
Department of Pharmacy, College of Pharmacy, Catholic University of Daegu, Gyeongsan, 712-702, Korea.

Two new cytotoxic annonaceous acetogenins, annomolin (1) and annocherimolin (2), were isolated from an ethanolic extract of the seeds of Annona cherimolia. Annomolin has a mono-THF ring with one flanking hydroxyl and possesses a 1,2-diol at C-7/8 of the aliphatic chain. Annocherimolin has a mono-THF ring with two flanking hydroxyls and possesses a double bond at C-21/22. Their structures were elucidated by spectral data and chemical derivatization. Compound 1 showed cytotoxic selectivity for the human prostate tumor cell line (PC-3), with a potency of over 10,000 times that of adriamycin. Compound 2 showed cytotoxic potencies about 10,000 times those of adriamycin in the breast (MCF-7) and colon (HT-29) cancer cell lines.
PMID: 11325235 [PubMed - indexed for MEDLINE]

13: J Nat Prod. 2000 Nov;63(11):1503-6.
Asitrocin, (2,4)-cis- and trans-asitrocinones: novel bioactive mono-tetrahydrofuran acetogenins from Asimina triloba seeds.
Kim EJ, Tian F, Woo MH.
Division of Antibiotics, Department of Drug Evaluation, Korea Food and Drug Administration, Seoul, 122-020, Korea.

Asitrocin (1) and the mixture of (2,4)-cis- and trans-asitrocinones (2 and 3), new bioactive Annonaceous acetogenins, were isolated from the seeds of Asimina triloba by activity-directed fractionation using the brine shrimp lethality test. Asitrocin and the mixture of (2,4)-cis- and trans-asitrocinones have a configuration of erythro/trans/threo from C-15 to C-20, the mono-THF moiety with two flanking hydroxyl groups. The structures were determined by spectroscopic methods. These acetogenins showed potent bioactivities in the brine shrimp lethality test (BST) and among six human solid tumor cell lines with notable selectivity for the prostate (PC-3) and the pancreatic (MIA PaCa-2) cell lines at 10-100 times the potency of adriamycin.
PMID: 11087592 [PubMed - indexed for MEDLINE]

14: Arch Pharm Res. 1999 Oct;22(5):524-8.
cis-Annonacin and (2,4)-cis-and trans-isoannonacins: cytotoxic monotetrahydrofuran annonaceous acetogenins from the seeds of Annona cherimolia.
Woo MH, Chung SO, Kim DH.
Department of Pharmacy, College of Pharmacy, Catholic University of Taegu-Hyosung, Kyongsan, Korea.

cis-Annonacin (1) and the mixture of (2,4)-cis-and trans-isoannonacins (2 and 3), three known mono-tetrahydrofuran annonaceous acetogenins, have been isolated from the seeds of Annona cherimolia by the use of the brine shrimp lethality test (BST) for bioactivity directed fractionation. Their structures were elucidated based on spectroscopic and chemical methods. 1 showed potent cytotoxicities in the brine shrimp lethality test (BST) and among six human solid tumor cell lines with notable selectivity for the pancreatic cell line (PaCa-2) at about 1,000 times the potency of adriamycin. The mixture of 2 and 3 is over 10,000 times cytotoxic as adriamycin in the pancreatic cell line (PaCa-2). All of the compounds are about 10 to 100 times as cytotoxic as adriamycin in the prostate cell line (PC-3).
PMID: 10549583 [PubMed - indexed for MEDLINE]

15: J Nat Prod. 1999 Jun;62(6):848-52.
Two novel acetogenins, annoglaxin and 27-hydroxybullatacin, from Annona glabra.
Liu XX, Pilarinou E, McLaughlin JL.
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, Indiana 47907, USA.

Two new bioactive Annonaceous acetogenins, annoglaxin (1) and 27-hydroxybullatacin (2), have been isolated from the fractionated ethanolic extracts of the leaves of Annona glabra, directing the fractionation with the brine shrimp lethality test (BST). The structures of 1 and 2 were elucidated on the basis of spectroscopic and chemical methods, and the absolute stereochemistries were determined by the advanced Mosher ester method. 1 presents unusual features of an OH at C-8 and a carbonyl at C-12 and, while less potent than 2, shows interesting selectivity for the human breast carcinoma (MCF-7) cell line. Compound 2 was at least 100 000 times more potent than adriamycin against the human kidney carcinoma (A-498), prostate carcinoma (PC-3), and pancreatic carcinoma (PACA-2) cell lines in our panel of six human solid tumor cell lines.
PMID: 10395501 [PubMed - indexed for MEDLINE]

16: Phytochemistry. 1999 Mar;50(6):1033-40.
Asitrilobins A and B: cytotoxic mono-THF annonaceous acetogenins from the seeds of Asimina triloba.


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