Writing today in ACS Medicinal Chemistry Letters, UF medicinal chemists describe how they took a generally lethal byproduct of marine cyanobacteria and made it more specifically toxic — to cancer cells.
When the scientists gave low doses of the compound to mice with a form of colon cancer, they found that it inhibited tumor growth without the overall poisonous effect of the natural product. Even at relatively high doses, the agent was effective and safe.
"Sometimes nature needs a helping human hand to further optimize these products of evolution to treat human diseases," said Hendrik Luesch, Ph.D., an associate professor of medicinal chemistry at UF's College of Pharmacy. "Based on what we learned about apratoxins' mechanism of action, we knew this compound class had great potential for use in anticancer therapies; however, the natural product itself is too toxic to become a therapeutic."
The researchers synthesized several apratoxin compounds that were similar to the original except for slight differences in composition, designing one that proved to be extremely potent against the cancer cells in cultures and in mice, but without the overwhelming toxicity.
The compound acts as a single agent to reduce levels of two types of proteins that are targeted by cancer research labs around the world — growth factors, and enzymes called tyrosine kinases, which act as receptors for the growth factors.
Known as apratoxin S4, the compound strips colon cancer cells of their ability to both secrete and use naturally occurring factors that fuel growth — something that Luesch, postdoctoral chemist Oi-Yen Chen, Ph.D., and assistant scientist Yanxia Liu, Ph.D., say is a powerful "one-two punch" against mushrooming populations of cancer cells.
The trio describes apratoxin's dual action for the first time in today's online publication, although Luesch presented early findings in May at the New York Academy of Sciences.
"This is an extremely interesting discovery that may have the potential to lead to a novel drug, but an extraordinary amount of additional research is needed before we will know. We can hope," said David J. Newman, D.Phil., chief of the National Cancer Institute's Natural Products Branch, who was not involved in the research. "Luesch has found a novel compound and a novel mechanism of action that stops the secretion of the receptor and the growth factor — as far as I am aware, this mechanism has only been shown in apratoxin at this time. If nothing else, he has shown us a new way to kill tumor cells and has revealed a new chemistry, and those are important steps."
Apratoxin is produced by cyanobacteria, microbes that have evolved toxins to fend off predators and cope with harsh conditions in a marine environment. Collectively known as blue-green algae — a misnomer because the single-celled organisms are not algae or members of the plant kingdom — a wide variety of cyanobacteria species exists in both sea and freshwater environments.
Like plants, cyanobacteria convert sunlight into energy through a process known as photosynthesis. But where plants exclusively use a green pigment called chlorophyll to capture light to make food, cyanobacteria also use a bluish pigment called phycocyanin.
In addition, cyanobacteria have the unique ability to use respiration as well as photosynthesis to acquire energy, making these organisms tiny chemical factories capable of producing many as-yet unidentified molecules that may be useful for health applications.
"Marine cyanobacteria produce a huge diversity of compounds," said Luesch, who is also a member of the UF Shands Cancer Center. "About half of anticancer drugs are based on natural products. All but a couple of them are derived from terrestrial organisms, yet more than 70 percent of the Earth is covered by oceans, which presumably contain a number of therapeutic molecules with potentially novel biological activities. When we studied the biological effects of apratoxin, we predicted it would be particularly useful against colon cancer if we could engineer it to be more selective."
Chen synthesized the apratoxins, while Liu carried out the biology and pharmacology experiments. More lab work is required before a drug based on apratoxin can be tested in patients with colon cancer, but Luesch believes apratoxin S4 is the first candidate to show the needed tumor selectivity, antitumor effects and potency to be effective. The UF Research Opportunity Fund and the Bankhead-Coley Cancer Research Program supported the study.
John Pastor | EurekAlert!
During HIV infection, antibody can block B cells from fighting pathogens
14.08.2018 | NIH/National Institute of Allergy and Infectious Diseases
First study on physical properties of giant cancer cells may inform new treatments
14.08.2018 | Brown University
Scientists develop first tool to use machine learning methods to compute flow around interactively designable 3D objects. Tool will be presented at this year’s prestigious SIGGRAPH conference.
When engineers or designers want to test the aerodynamic properties of the newly designed shape of a car, airplane, or other object, they would normally model...
Researchers from TU Graz and their industry partners have unveiled a world first: the prototype of a robot-controlled, high-speed combined charging system (CCS) for electric vehicles that enables series charging of cars in various parking positions.
Global demand for electric vehicles is forecast to rise sharply: by 2025, the number of new vehicle registrations is expected to reach 25 million per year....
Proteins must be folded correctly to fulfill their molecular functions in cells. Molecular assistants called chaperones help proteins exploit their inbuilt folding potential and reach the correct three-dimensional structure. Researchers at the Max Planck Institute of Biochemistry (MPIB) have demonstrated that actin, the most abundant protein in higher developed cells, does not have the inbuilt potential to fold and instead requires special assistance to fold into its active state. The chaperone TRiC uses a previously undescribed mechanism to perform actin folding. The study was recently published in the journal Cell.
Actin is the most abundant protein in highly developed cells and has diverse functions in processes like cell stabilization, cell division and muscle...
Scientists have discovered that the electrical resistance of a copper-oxide compound depends on the magnetic field in a very unusual way -- a finding that could help direct the search for materials that can perfectly conduct electricity at room temperatur
What happens when really powerful magnets--capable of producing magnetic fields nearly two million times stronger than Earth's--are applied to materials that...
The quality of materials often depends on the manufacturing process. In casting and welding, for example, the rate at which melts solidify and the resulting microstructure of the alloy is important. With metallic foams as well, it depends on exactly how the foaming process takes place. To understand these processes fully requires fast sensing capability. The fastest 3D tomographic images to date have now been achieved at the BESSY II X-ray source operated by the Helmholtz-Zentrum Berlin.
Dr. Francisco Garcia-Moreno and his team have designed a turntable that rotates ultra-stably about its axis at a constant rotational speed. This really depends...
08.08.2018 | Event News
27.07.2018 | Event News
25.07.2018 | Event News
14.08.2018 | Information Technology
14.08.2018 | Life Sciences
14.08.2018 | Life Sciences