1. Natural Product Chemistry as a Source for Anti-Cancer Agents
Delaney Cheek, Levi Gates, Alex Harlan, Anne Hwang
Abstract
Our project consists of a literature-based review that analyzes the origins and importance of natural products and their use in cancer therapy. We found our information from primary sources like personal s and interviews as well as tertiary sources to find journal articles. Our goal was to find what it takes for a natural product to be a useful anti-cancer agent. After learning the history of natural products, we analyzed the process natural products go through the NCI, and evaluated products in current development as well as ones that are currently used today. We found that products are tested against the NCI60 cell line test, which is a broad test for common cancer types, and then are evaluated for their efficacy and selectivity by measures such as GI50, TGI, and LC50. More negative values of these results show highly potent compounds. Lastly we compared those results to an agent, OSW1, that is in development here at the University of Iowa as a viable anti-cancer agent and found that due to several limitations it has been simplified to a new compound, ZJ1, which is currently in preclinical trials.
Due to the high variability of structures that nature is capable of producing, natural product chemistry remains a useful source for discovery of compounds that have anti-cancer properties and can continue to be valuable in a rapidly growing field of emerging cancer therapies.
Discussion
The majority of knowledge pertaining to natural product use is derived from humans experimenting by trial and error on themselves. Palatability trials resulted in many untimely deaths in the search for disease treatments. However, along the way, a few of our brave experimenters avoided death and discovered some natural products that are even still used today. Acetylsalicylic acid, commonly known as aspirin, was derived from salicin, which came from the bark of a particular willow tree. Papaver somniferum L., was used in isolation of alkaloid products like morphine. Lastly, Digitalis Purpurea L., commonly known as foxglove, contains digitoxin which increases cardiac conduction.
Natural product chemistry, for a while, had a large role in the realm of developing new chemotherapy agents. However, while the role of natural products has decreased since immunotherapy has made its way into the scene, it still plays a very important part of anticancer drug development. Many solid organ tumor therapies are still based predominantly around chemotherapy agents. Many of these agents originated from natural products. Tamoxifen, an estrogen receptor modulator commonly found in breast cancer regimens is a prime example of one of these agents. Recently, at the University of Iowa, a natural product from the roots of Ornithogalum saundersiae, has been formulated into an chemotherapy agent called OSW-1.
The development of any drug is a long-term process. The main steps in anticancer drug development are divided into three main phases. These phases include discovery, preclinical and clinical development. Drugs are discovered and isolated from natural products by researchers in the pharmaceutical industry and other institutions. Techniques for isolating drug compounds from natural products include extraction and separation. For example, for extraction NCI uses a room temperature 1:1 v/v mixture of dichloromethane and methanol for percolation. (Beutler, 2009). In general, using heat for extraction of natural drug products is avoided. Heat can hinder biological screening, which is an important step in the drug development process. During the preclinical phase, the drug is obtained from the institutions and tested through human cell lines to determine whether or not the product is active against human malignancies. From “more than 600,000 compounds entered screening systems to select potential cancer agents” (Schwartsmann). The majority of the screen testing over the years has been processed through NCI.
Natural product chemotherapy development is happening right here at the University of Iowa. OSW1 is a natural product derived compound which has been worked on by Dr. Jin at the U of Iowa. OSW1 was isolated from the roots of Ornithogalum saundersiae, a plant found in Japan, due to the plant being used in herbal remedies for cancer for long periods of Japanese history. OSW1 was submitted to the NCI and ran through the NCI60 cell line test and tested very sensitive for many types of cancer, but most notably CNS, melanoma, and colon. It’s mechanism of action was also marked as unique and not like anything that has been discovered to date. It has been proposed that it inhibits Chaperone GRP78 which is a protein that guides the folding of other proteins and is highly overexpressed in cancer cells. Also, one of the most exciting things about OSW1 was, unlike many of the chemotherapy agents on the market today, OSW1 has the ability to kill dormant cancer cells. However, OSW1 also had several limitations. Firstly, the structure of OSW1 was very similar to glycosidase inhibitors (ie/ Digoxin) and although it’s MOA is very different it shares the same reason Digoxin is a poor medication for heart failure; a very narrow therapeutic index. Also the pKa of OSW1 is not close enough to physiological pH and therefore makes it hard to solubilize in blood. In response to the limitations of OSW1, the university of Iowa is working on a new compound called ZJ1 which includes a simplified structure of OSW1 and makes it more selectively potent. ZJ1 is currently in development with anti-cancer strategies like immunochemotherapy which harmonizes immunoglobulins and potent chemotherapy molecules to create a very targeted and very potent therapy to cancer cells. It will be interesting to see the results of the studies being done with ZJ1 in the future.
Methods
To find the history of natural products we searched large literature databases like web of science, PubMed,
google scholar, and embase. We used terms like “natural products”, “chemotherapy”, “cytotoxicity”, “anti
neoplastic agent” and “nature”. We read many papers that outlined the history of natural products and
incorporated them into our project. We read the National Cancer Institute (NCI) website to learn the way the
institute discovers new anticancer agents. We investigated the website to understand and define the steps of
natural product development. To get the data regarding current clinical trials of natural anticancer agents, we
put the trade name of the natural drug in the search box and cancer. To get some more detailed information
regarding clinical trials and anticancer drug information, we contacted to natural products branch of DTP in
NCI. To learn about naturally derived chemotherapy drugs, we interviewed natural product researchers at the
University of Iowa who are developing anti cancer drugs.
Figure 1. All new approved drugs 1981−2014; n = Figure 2. All anticancer drugs 1981−2014; n = 174.
*Natural products include natural products per se, derivatives, pharmacophore, or mimics of natural products
Source: Newman DJ, Cragg GM. Natural Products as Sources of New Drugs from 1981 to J Nat Prod. 2016
Results
History and Overview
With cancer being such a terminal prognosis, it has called for extensive research in the subject, and science has turned to nature to find answers. It also called for the development of institutions like the NCI which helps streamline the discovery process in an attempt to expedite it.
Process of Drug Discovery
Discovery
Pre-Clinical
Acquisition
Screening
Production/Formulation
Toxicology Evaluation
Clinical
Phase I Studies
Phase II Studies
Phase III Studies
Comparison of Chemotherapy Drugs
There are many compounds in which the NCI has deemed to have cytotoxicity to cancer cells. There are also many mechanisms of action that are unknown in the way that they kill cancer cells. In our comparison of chemotherapy drugs we looked at two locally researched drugs, OSW1 researched by Dr. Jin here at the University of Iowa.
Conclusion
Natural product chemistry was the foundation in which anti cancer drugs, like pacitaxil, tamoxifen, topetcan, and many other small molecule chemotherapies were developed. It led to institutions like the NCI being created to help expedite the selection, identification, and discovery process. Even with new discoveries like immunochemotherapy, natural product chemistry and small molecule anticancer drugs can still play a role in chemotherapies for cancer patients. In the past 100 years, cancer has become a focal point of popular attention and with that comes discoveries of anti cancer agents with for a long time most of them were naturally derived.
References
Mayer Am, et al. The odyssey of marine pharmaceuticals: a current pipeline perspective. Trends Pharmacol Sci Jun;31(6):
Cragg GM, Pezzuto Jm. Natural Products as a Vital Source for the Discovery of Cancer Chemotherapeutic and Chemopreventive Agents. Med Princ Pract. 2016;25 Suppl 2:41-59.
Alejandro M.S. Mayer et al. The odyssey of marine pharmaceuticals: a current pipeline perspective. Trends pharmacol Sci Jun;31(6):
Newman DJ, Cragg GM. Natural Products as Sources of New Drugs from 1981 to J Nat Prod Mar 25; 79(3):
Ke Hu, Xinsheng Yao. Methyl protogracillin (NSC ): the spectrum of cytotoxicity against 60 human cancer cell lines in the National Cancer Institute's anticancer drug screen panel. Anti-Cancer Drugs 2001 Jul;12(6):541-7.
Schwartsmann, G., Winograd, B., & Pinedo, H. M. (1988). The Main Steps in Development of Anticancer Agents, 12, 301–313.