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"text": "Paw Paw and Cancer: Annonaceous Acetogenins from Discovery to Commercial Products [p1.4.1]",
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"text": "Jerry L. McLaughlin [p1.5.1]",
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"text": "Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmaceutical Sciences, Purdue University, Heine Pharmacy Building, 575 Stadium Mall Drive, West Lafayette, Indiana 47904-2091"
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"text": "Received March 26, 2008"
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"text": "Extracts of paw paw (Asimina triloba, Annonaceae) are among the most potent of the 3500 species of higher plants screened for bioactive compounds in our laboratories at Purdue University. The paw paw is a small tree native to eastern North America; its edible fruits (sometimes referred to as “Indiana Bananas”) have nurtured mankind for centuries. Activity-directed fractionation of the paw paw extracts, using the brine shrimp lethality bioassay, led to the isolation and molecular characterization of over 50 unique annonaceous acetogenins. Fractionation of extracts from related species resulted in the identification of over 150 additional acetogenins. The annonaceous acetogenins are derivatives of long-chain ([p1.8.1] or[p1.8.2]) fatty acids. They are potent inhibitors of mitochondrial (complex I) as well as cytoplasmic (anaerobic) production of adenosine triphosphate (ATP) and the related nucleotides. The powerful cytotoxicity, in vivo antitumor, pesticidal, antimalarial, anthelmintic, piscicidal, antiviral, and antimicrobial effects indicated a myriad of potentially useful applications. Commercial development of these compounds uses natural mixtures of active components, incorporated into pesticidal, topical, and dietary supplement products. Successful applications and commercial products include a shampoo, highly effective in treating infestations of head lice, fleas, and ticks; a series of pesticidal sprays, which protects host plants against a diversity of pests; and an ointment for treatment of oral herpes (HSV-1) and other skin afflictions. The extract (in capsule form) enhances a mixture of natural anthelmintics. In addition, an encapsulated extract has been effectively used by certain cancer patients as a botanical supplement product.",
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"text": "The American Cancer Society estimates that some 10.5 million Americans have been diagnosed with cancer and that 34% of these patients will succumb to this disease within five years. About 1 444 920 new cancer cases were diagnosed and 559 650 victims died of cancer in 2007. More than 1500 Americans per day (approximately one per minute) die of cancer. With more attention being given recently to cancer prevention and early detection, the incidences of certain cancer types (stomach, colon, breast) have decreased in the past 18 years, but other cancer types (pancreas, ovary, leukemia) have stubbornly taken a consistent and heavy toll, year after year, since 1930. Cancer is now the second leading cause of death in the United States—exceeded only by heart disease—and accounts for one in every four deaths. American men have slightly less than a 1 in 2 lifetime risk of developing cancer; for women, the risk is a little more than 1 in 3. The U.S. National Institutes of Health (NIH) estimated overall costs for cancer in 2006 to be 206.3 billion.[p1.10.1] There is little doubt that cancer is a major health problem today; its immediate social significance supersedes those of infectious diseases, diabetes, drug abuse, crime, immigration, and, perhaps, even global warming.",
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"text": "As scientists, we are duty bound to help solve the problems of society. It has been my privilege to have known, personally, the discoverers of the anticancer effects of the vinca alkaloids, paclitaxel, camptothecin, homoharringtonine, and podophyllotoxin. As pharmacognosists and natural product chemists, we are experts at detecting, isolating, and characterizing useful molecules found in nature. The chemical diversity of higher plants continues to intrigue us. Certainly, many additional, novel, molecules that can specifically interrupt the biochemistry of cancer cells, alleviate suffering, and prolong life are awaiting discovery. Our past success in finding clinically useful antitumor botanicals, the promise of a host of new active natural compounds found from all natural sources in the past 25 years,[p1.11.1] and the diversity of natural compounds being reported in the scientific literature would certainly seem to justify research funding for the search for new antitumor botanicals. Unfortunately, the winds of good fortune for funding have been blowing in other directions. I feel fortunate, indeed, to have received 13 years of R01 support before the apparent “no grants for plants” era was initiated by some of the NIH study sections. What follows is a narrative of my successful results in a lifetime’s quest for new antitumor botanicals.",
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"text": "at detecting, isolating, and characterizing useful molecules found in nature. The chemical diversity of higher plants continues to intrigue us. Certainly, many additional, novel, molecules that can specifically interrupt the biochemistry of cancer cells, alleviate suffering, and prolong life are awaiting discovery. Our past success in finding clinically useful antitumor botanicals, the promise of a host of new active natural compounds found from all natural sources in the past 25 years,[p1.12.1] and the diversity of natural compounds being reported in the scientific literature would certainly seem to justify research funding for the search for new antitumor botanicals. Unfortunately, the winds of good fortune for funding have been blowing in other directions. I feel fortunate, indeed, to have received 13 years of R01 support before the apparent “no grants for plants” era was initiated by some of the NIH study sections. What follows is a narrative of my successful results in a lifetime’s quest for new antitumor botanicals.",
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"text": "As a young professor of pharmacognosy in 1971, I was lured away from the University of Washington to Purdue University to work with a growing, critical mass of young natural product enthusiasts that was being assembled by Varro E. (Tip) Tyler and Heinz G. Floss. My early work on the alkaloids of cacti had led to a few dozen new compounds,[p1.14.1] but such phytochemical work was considered “ho hum” by an NIH study section, and this project was soon abandoned. Fortunately, President Nixon had recently declared war on cancer, and new possibilities for funding from the United States National Cancer Institute (NCI) opened up. After receiving some start-up support for work on antitumor botanicals, from the fledgling Purdue Cancer Center, I joined forces with John M. Cassady and C.-J. Chang at Purdue; we soon were awarded two successive NCI plant antitumor contracts (1976–1982).",
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"text": "[p1.16.1] Adapted from the Varro E. (Tip) Tyler Award for Botanical Research address at the 48th Annual Meeting of the American Society of Pharmacognosy, July 14–18, 2007, Portland, ME.",
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"text": "[p1.17.1] To whom correspondence should be addressed. Present address: 2101 North 600 West, West Lafayette, IN 47906-8502. Tel and Fax: (765) 583-0023. E-mail: jerrymcl1014@aol.com.",
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"text": "[p1.18.1]Formerly at Nature's Sunshine Products, 1655 North Main St., Spanish Fork, UT 84660.",
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