Saccharin Derivatives May Kill Cancer Cells

Saccharin received a bad rap after studies in the 1970s linked consumption of large amounts of the artificial sweetener to bladder cancer in laboratory rats. Later, research revealed that these findings were not relevant to people. And in a complete turnabout, recent studies indicate that saccharin can actually kill human cancer cells. Now, researchers reporting in ACS’ Journal of Medicinal Chemistry have made artificial sweetener derivatives that show improved activity against two tumor-associated enzymes.

Saccharin, the oldest artificial sweetener, is 450 times sweeter than sugar. Recently, scientists showed that the substance binds to and inhibits an enzyme called carbonic anhydrase (CA) IX, which helps cancer cells survive in the acidic, oxygen-poor microenvironments of many tumors. In contrast, healthy cells make different –– but very similar –– versions of this enzyme called CA I and II. Saccharine and another artificial sweetener called acesulfame K can selectively bind to CA IX over CA I and II, making them possible anti-cancer drugs with minimal side effects. Alessio Nocentini, Claudiu Supuran and colleagues wondered whether they could make versions of the artificial sweeteners that show even more potent and selective inhibition of CA IX and another tumor-associated enzyme, CA XII.

The team designed and synthesized a series of 20 compounds that combined the structures of saccharin and acesulfame K and also added various chemical groups at specific locations. Some of these compounds showed greater potency and selectivity toward CA IX and XII than the original sweeteners. In addition, some killed lung, prostate or colon cancer cells grown in the lab but were not harmful to normal cells. These findings indicate that the widely used artificial sweeteners could be promising leads for the development of new anticancer drugs, the researchers say.

Source: American Chemical Society


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Timed Release of Turmeric Stops Cancer Cell Growth

Tina Hilding wrote . . . . . . . . .

A Washington State University research team has developed a drug delivery system using curcumin, the main ingredient in the spice turmeric, that successfully inhibits bone cancer cells while promoting growth of healthy bone cells.

The work could lead to better post‑operative treatments for people with osteosarcoma, the second most prevalent cause of cancer death in children.

The researchers, including Susmita Bose, Herman and Brita Lindholm Endowed Chair Professor in the School of Mechanical and Materials Engineering, and graduate student Naboneeta Sarkar, report on their work in the journal, ACS Applied Materials and Interfaces.

Young patients with bone cancer are often treated with high doses of chemotherapy before and after surgery, many of which have harmful side effects. Researchers would like to develop gentler treatment options, especially after surgery when patients are trying to recover from bone damage at the same time that they are taking harsh drugs to suppress tumor growth.

Turmeric has been used in cooking and as medicine for centuries in Asian countries, and its active ingredient, curcumin has been shown to have anti‑oxidant, anti‑inflammatory and bone‑building capabilities. It has also been shown to prevent various forms of cancers.

“I want people to know the beneficial effects of these natural compounds,” said Bose. “Natural biomolecules derived from these plant‑based products are inexpensive and a safer alternative to synthetic drugs.”

However, when taken orally as medicine, the compound can’t be absorbed well in the body. It is metabolized and eliminated too quickly.

In their study, the researchers used 3D printing to build support scaffolds out of calcium phosphate. While most implants are currently made of metal, such ceramic scaffolds, which are more like real bone, could someday be used as a graft material after bone cancer surgery. The researchers incorporated curcumin, encapsulated in a vesicle of fat molecules into the scaffolds, allowing for the gradual release of the chemical.

The researchers found that their system inhibited the growth of osteosarcoma cells by 96 percent after 11 days as compared to untreated samples. The system also promoted healthy bone cell growth.

“This study introduces a new era of integration – where modern 3D printing technology is coupled with the safe and effective use of alternative medicine, which may provide a better tool for bone tissue engineering,” said Bose.

Source: Washington State University


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3D Images of Cancer Cells in the Body

Medical physicists at Martin Luther University Halle-Wittenberg (MLU) have developed a new method that can generate detailed three-dimensional images of the body’s interior. This can be used to more closely investigate the development of cancer cells in the body. The research group presents its findings in “Communication Physics”, a journal published by the Nature Publishing Group.

Clinicians and scientists are in need of a better understanding of cancer cells and their properties in order to provide targeted cancer treatment. Individual cancer cells are often examined in test tubes before the findings are tested in living organisms. “Our aim is to visualise cancer cells inside the living body to find out how they function, how they spread and how they react to new therapies,” says medical physicist Professor Jan Laufer from MLU. He specialises in the field of photoacoustic imaging, a process that uses ultrasound waves generated by laser beams to produce high-resolution, three-dimensional images of the body’s interior.

“The problem is that tumour cells are transparent. This makes it difficult to use optical methods to examine tumours in the body,” explains Laufer whose research group has developed a new method to solve this problem: First the scientists introduce a specific gene into the genome of the cancer cells. “Once inside the cells, the gene produces a phytochrome protein, which originates from plants and bacteria. There it serves as a light sensor,” Laufer continues. In the next step, the researchers illuminate the tissue with short pulses of light at two different wavelengths using a laser. Inside the body, the light pulses are absorbed and converted into ultrasonic waves. These waves can then be measured outside the organism and two images of the body’s interior can be reconstructed based on this data. “The special feature of phytochrome proteins is that they alter their structure and thus also their absorption properties depending on the wavelength of the laser beams. This results in changes to the amplitude of the ultrasound waves that are generated in the tumour cells. None of the other tissue components, for example blood vessels, have this property – their signal remains constant,” Laufer says. By calculating the difference between the two images, a high-resolution, three-dimensional image of the tumour cells is created, which is free of the otherwise overwhelming background contrast.

The development of Halle’s medical physicists can be applied to a wide range of applications in the preclinical research and the life sciences. In addition to cancer research, the method can be used to observe cellular and genetic processes in living organisms.

Source: Martin-Luther-University

Researchers Reveal a Key Mechanism for Cancer Metastasis

Cancer metastasis, the migration of cells from a primary tumor to form distant tumors in the body, can be triggered by a chronic leakage of DNA within tumor cells, according to a team led by Weill Cornell Medicine and Memorial Sloan Kettering Cancer Center researchers.

How metastasis occurs has been one of the central mysteries of cancer biology. The findings, published in Nature, appear to have partly solved this mystery. The authors traced the complex chain of events that results from chromosomal instability – a widespread feature of cancer cells in which DNA is copied incorrectly every time these cells divide, resulting in daughter cells with unequal DNA content. Using models of breast and lung cancer, the investigators found that chromosomal instability leads to changes in the cells that drive metastasis.

“We showed that chromosomal instability can cause a leakage of DNA from the nuclei of cancer cells, leading to a chronic inflammatory response within the cells—and the cells essentially can hijack that response to enable themselves to spread to distant organs,” said study co-lead author Dr. Samuel Bakhoum, a Holman research fellow at Weill Cornell Medicine and a senior resident in radiation oncology at Memorial Sloan Kettering Cancer Center. Dr. Bakhoum conducted the study in collaboration with co-lead author Bryan Ngo, a student in the Weill Cornell Graduate School of Medical Sciences.

The discovery is principally a basic science advance, but should also have long-range implications for cancer drug development.

“Metastasis causes 90 percent of cancer deaths, and this work opens up new possibilities for therapeutically targeting it,” said senior author Dr. Lewis Cantley, the Meyer Director of the Sandra and Edward Meyer Cancer Center and a professor of cancer biology in medicine at Weill Cornell Medicine.

Prior studies have linked chromosomal instability to metastasis, although the reason for the link hasn’t been clear. “Our starting hypothesis was that chromosomal instability generates a lot of genetically different tumor cells, and that a Darwinian selection process promotes the survival of the cells that are capable of spreading and forming distant tumors,” Dr. Bakhoum said.

When he injected chromosomally unstable tumor cells into mice, he indeed found that they were many times more likely to spread and form new tumors than tumor cells in which chromosomal instability was suppressed. That was true even though both sets of tumor cells started out genetically identical, with the same abnormal numbers of chromosomes, suggesting that chromosomal instability itself was a driver of metastasis.

The researchers examined gene activity in these two sets of tumor cells. They found that those with high chromosomal instability had abnormally elevated activity stemming from more than 1,500 genes—particularly in ones involved in inflammation and the response of the immune system to viral infections. “These were cancer cells cultured in a dish, not in the presence of any immune cells,” Dr. Bakhoum said. “We were very surprised by that and wondered what could be driving this inflammatory reaction.”

Recent studies by other laboratories offered some clues: Chromosomes in unstable tumor cells can sometimes leak out of the cell nucleus where they normally reside. These mis-located chromosomes encapsulate themselves to form “micronuclei” in the fluid, or cytosol, in the main part of the cell outside of the main nucleus. However, micronuclei tend to rupture eventually, releasing naked DNA into the cytosol.

Cells interpret DNA in the cytosol as a sign of an infecting virus, which typically releases its DNA in the cytoplasm when it first attacks a cell. Human cells have evolved to fight this type of viral infection by sensing naked cytosolic DNA using a molecular machine called the cGAS-STING pathway. Once activated, this pathway triggers an inflammatory antiviral program.

Dr. Bakhoum and colleagues examined their chromosomally unstable tumor cells, and found that they did indeed have plenty of cytosolic DNA—and showed evidence of chronic activation of the anti-viral cGAS-STING proteins. Lowering cGAS-STING levels reduced inflammation and prevented the ability of otherwise aggressive tumor cells to metastasize when injected into mice.

In an ordinary cell, an antiviral response stimulated by DNA leakage from the nucleus would soon bring about the cell’s death. The researchers found, however, that tumor cells have succeeded in suppressing the lethal elements of the cGAS-STING response. At the same time, they use other parts of the response to enable themselves to detach from the tumor and become mobile within the body.

“They start acting as if they were certain kinds of immune cells, which are normally activated by infection,” Dr. Bakhoum said. “In response, they move to the site of infection or injury in the body very quickly. By doing so, cancer cells engage in some form of lethal immune mimicry.”

The researchers estimate, based on recent studies of metastatic tumor properties, that about half of human metastases originate this way. They are currently investigating strategies for blocking the process.

It might not be feasible to target chromosomal instability itself, since tumor cells are inherently prone to that, Dr. Bakhoum said. However, he noted, “chromosomally unstable tumor cells, with their cytosolic DNA, are basically full of their own poison.” Undoing their ability to suppress normal and lethal antiviral response to cytosolic DNA would, in principle, kill these aggressive cancer cells swiftly, with minimal effects on other cells.

“One of our next steps is to understand better how these cells alter the normal response and how we can restore it,” Dr. Bakhoum said.

Source: Weill Cornell Medicine


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