Paw Paw and Cancer
Cancer is quickly becoming the leading cause of death in most developed nations with diagnoses occurring at a younger age and at more advanced stages. Although conventional therapies tend to offer some rate of local control and cure, additional interventions to optimise response rates are continuously sought. Naturopathic and Integrative therapies are gaining popularity and are increasingly being implemented despite a paucity of supporting data.
Asimina Triloba is commonly known as Paw Paw and grows in the northeastern part of the United States of America. It was first discovered as a potent inhibitor of agricultural pests and in nature, it is found to be ingested by the zebra swallowtail butterflies as protection from predators. It’s in vitro anti-cancer and cytotoxic activity has been studied for almost fifty years. The pioneer of this discovery is namely Jerry McLaughlin who after an NCI grant of 20 years and extensive work at Purdue University intentionally obtaining and studying over 3500 species of higher plants isolated 350 new cytotoxic compounds (McLaughlin 1999) of which the annonaceous acetogenins were the most potent leads.
The biologically active component of Asimina triloba are the annonaceous acetogenins isolated from the bark, twigs and fruit of the Paw Paw tree. The acetogenins are found to be the most potent of all the annonaceous components. Chemically they are derivatives of long chain fatty acids and biologically, they exhibit their behavior through the depletion of ATP levels by inhibiting complex 1 of mitochondria and inhibiting the NADH oxidase of plasma membranes of tumor cells (Coothankandaswamy et al 2010). They are also shown to deplete the other DNA bases used as the building blocks of DNA for tumor cell replication and proliferation (S. Fotopoulos et al unpublished). They have also been found to block multi-drug resistance mechanisms restoring the sensitivity of cancer cells to chemotherapy by blocking the ATP required for the multi-drug resistance cell membrane pump to function (Oberlies et al 1997 and Johnson et al 1999) (McLaughlin 2008.)
The acetogenins are preferentially taken up by cancer cells over normal cells as the energy demands of cancer cells are much larger than normal cells as well as the high levels of NADH oxidase which provides the binding center for the acetogenins. In this way the acetogenins are thought to exert their effect preferentially on tumor cells than normal cells.
In vivo mouse studies using ovarian cancer cell lines show an effectiveness of tumor cytotoxicity approaching that of cisplatin with less adverse effects as measured by weight stability (Life Sciences Journal 1993). Multiple other in vitro (Nam 2021 and 2018) and mouse studies have shown effectiveness against cancer cell lines and one study showed some effect on prevention, increasing the time to cancer development in mouse models but not in the incidence or multiplicity of cancer development (Cuendet et al 2008).
No trials have suggested any serious adverse reactions to date; however, one in vivo study has shown neurotoxicity in mice (Potts 2011) at doses above which are used in a clinical setting. There has also been one case report (Kaas et al 2020) describing an 80-year-old man who developed Parkinsonian symptoms from high amounts of paw paw fruit consumption over a 5-to-10-year period. The other limiting side effect is emesis which defines the higher limit of dose. Unpublished clinical case studies describe a tolerated dose up to 6 capsules per day equating to 51mg per day.
Trials are currently underway to determine both the safety and efficacy of adding this as a complement to a conventional care plan. As always, working with a practitioner with expertise in this area is recommended.
References
"Paw Paw and Cancer: From Discovery to Clinical Trials" http://www.pawpawresearch.com/visual.html
Coothankandaswamy V, Liu Y, Mao SC, Morgan JB, Mahdi F, Jekabsons MB, Nagle DG, Zhou YD. The alternative medicine pawpaw and its acetogenin constituents suppress tumor angiogenesis via the HIF-1/VEGF pathway. J Nat Prod. 2010 May 28;73(5):956-61. doi: 10.1021/np100228d. PMID: 20423107; PMCID: PMC2890309.
Oberlies, N. H.; Chang, C.-J.; McLaughlin, J. L. J. Med. Chem. 1997, 40, 2102–2106.
McLaughlin JL. Paw paw and cancer: annonaceous acetogenins from discovery to commercial products. J Nat Prod. 2008 Jul;71(7):1311-21. doi: 10.1021/np800191t. Epub 2008 Jul 4. PMID: 18598079.
Potts LF, Luzzio FA, Smith SC, Hetman M, Champy P, Litvan I. Annonacin in Asimina triloba fruit: implication for neurotoxicity. Neurotoxicology. 2012 Jan;33(1):53-8. doi: 10.1016/j.neuro.2011.10.009. Epub 2011 Nov 23. PMID: 22130466.
Nam JS, Park SY, Lee SO, Lee HJ, Jang HL, Rhee YH. The growth-inhibitory effects of pawpaw (Asimina triloba [L.] Dunal) roots, twigs, leaves, and fruit against human gastric (AGS) and cervical (HeLa) cancer cells and their anti-inflammatory activities. Mol Biol Rep. 2021 Mar;48(3):2173-2181. doi: 10.1007/s11033-021-06226-y. Epub 2021 Feb 25. PMID: 33630206.
Nam JS, Park SY, Lee HJ, Lee SO, Jang HL, Rhee YH. Correlation Between Acetogenin Content and Antiproliferative Activity of Pawpaw (Asimina triloba [L.] Dunal) Fruit Pulp Grown in Korea. J Food Sci. 2018 May;83(5):1430-1435. doi: 10.1111/1750-3841.14144. Epub 2018 Apr 16. PMID: 29660776.
Cuendet, Muriel & Oteham, Carol & Moon, Richard & Keller, William & Peaden, Paul & Pezzuto, John. (2008). Dietary Administration of Asimina triloba.(Paw Paw) Extract Increases Tumor Latency in N.-Methyl-N.-nitrosourea-Treated Rats*. Pharmaceutical Biology. 46. 3-7. 10.1080/13880200701729497.
Kaas B, Hillis AE, Pantelyat A. Progressive supranuclear palsy and pawpaw. Neurol Clin Pract. 2020 Apr;10(2):e17-e18. doi: 10.1212/CPJ.0000000000000704. PMID: 32309040; PMCID: PMC7156197.
