VITAMIN C HALTS GROWTH OF AGGRESSIVE FORM OF COLORECTAL CANCER

High levels of vitamin C kill certain kinds of colorectal cancers in cell cultures and mice, according to a new study from Weill Cornell Medicine investigators. The findings suggest that scientists could one day harness vitamin C to develop targeted treatments.Colorectal cancer is the third most-common cancer diagnosed in the United States, with about 93,090 new cases each year. Around half of those cases harbor mutations in the KRAS and BRAF genes; these forms of the disease are more aggressive and don't respond well to current therapies or chemotherapy.

In a study, published Nov. 5 in Science, a team of researchers from Weill Cornell Medicine, Cold Spring Harbor Laboratory, Tufts Medical Center, Harvard Medical School and The Johns Hopkins Kimmel Cancer Center found that high doses of vitamin C—roughly equivalent to the levels found in 300 oranges—impaired the growth of KRAS mutant and BRAF mutant colorectal tumors in cultured cells and mice. The findings could lead to the development of new treatments and provide critical insights into who would most benefit from them.

"Our findings provide a mechanistic rationale for exploring the therapeutic use of vitamin C to treat colorectal cancers that carry KRAS or BRAF mutations," said senior author Dr. Lewis Cantley, the Meyer Director of the Sandra and Edward Meyer Cancer Center and the Margaret and Herman Sokol Professor in Oncology Research at Weill Cornell Medicine.

The conventional wisdom is that vitamin C improves health in part because it can act as an antioxidant, preventing or delaying some types of cell damage. However, Dr. Cantley and his colleagues discovered that the opposite was true in regards to high-dose vitamin C's therapeutic effects for the KRAS and BRAF forms of colorectal cancer—they occur as a result of inducing oxidation in these cancer cells.

In an oxygen-rich environment such as human arteries, a fraction of vitamin C, also called ascorbic acid, becomes oxidized and is transformed into a new compound called dehydroascorbic acid (DHA). Scientists have known for some time that a specific membrane protein, known as glucose transporter GLUT1, enables both glucose and DHA to enter cells—an activity not afforded to ascorbic acid. But it was less clear what DHA does once inside the cells.

In the study, investigators show that DHA acts like a Trojan horse. Once inside, natural antioxidants inside the cancer cell attempt to convert the DHA back to ascorbic acid; in the process, these antioxidants are depleted and the cell dies from oxidative stress.

"While many normal cells also express GLUT1, KRAS-mutant and BRAF-mutant cancer cells typically have much higher levels since they require a high rate of glucose uptake in order to survive and grow," Dr. Cantley said. "Also, KRAS and BRAF mutant cells produce more reactive oxygen species than normal cells and therefore need more antioxidants in order to survive. This combination of characteristics makes these cancer cells far more vulnerable to DHA than normal cells or other types of cancer cells."

Although Dr. Cantley cautioned that these results need to be evaluated in the setting of a human clinical trial, the pre-clinical findings may offer a promising new treatment strategy for the KRAS or BRAF forms of the disease, perhaps as part of a combination therapy. The investigators say their study could lead to the development of new biomarkers that could help physicians determine who would most benefit from treatment. These insights may also have implications for other hard-to-treat cancers that express high levels of GLUT1 transporter, such as renal cell carcinoma, bladder cancer and pancreatic cancer.

Vitamin C has multiple effects on cellular functions in addition to its anti- or pro-oxidant functions, so it will be important to study the effects of high-dose vitamin C on normal and immune cells, said lead author Dr. Jihye Yun, a postdoctoral fellow in Dr. Cantley's lab.

Further study is unquestionably expected to grow our comprehension of these procedures. Be that as it may, now that we know the instruments, we can use the information shrewdly to get the coveted impacts," she said. 

"This is not a treatment that you would need to meander into indiscriminately without information of what is happening in your tumor," Dr. Cantley included. 

Dosing proposals additionally should be resolved. Helpful advantage would likely require intravenous infusions, as oral measurements are not assimilated effectively in the digestive tract to accomplish the high serum centralization of vitamin C expected to make harmfulness these malignancy cells. Late stage I clinical trials led on people to test danger have demonstrated that intravenous implantation of vitamin C at measurements that changed over to comparable levels of serum as the Cantley mice trials had great security profiles. 

"Our trust is that our study will move mainstream researchers to investigate this sheltered and modest regular atom and fortify both fundamental and clinical examination seeing vitamin C as a disease treatment," Dr. Yun said.

LIGHTS TO STEER THE HEART

We rely on upon electrical waves to direct the musicality of our pulse. At the point when those signs go amiss, the outcome is a possibly deadly arrhythmia. Presently, a group of analysts from Oxford and Stony Stream colleges has figured out how to accurately control these waves - utilizing light. Both cardiovascular cells in the heart and neurons in the mind impart by electrical signs, and these messages of correspondence travel quick from cell to cell as 'excitation waves'. Interestingly, such waves are additionally found in a scope of different procedures in nature, from compound responses to yeast and single adaptable cells.

For heart patients there are at present two alternatives to hold these waves within proper limits: electrical gadgets (pacemakers or defibrillators) or medications (eg beta blockers). Then again, these techniques are moderately unrefined: they can stop or begin waves yet can't give fine control over the wave rate and bearing. This is similar to having the capacity to begin or stop a vessel yet without the capacity to direct it. In this way, the examination group set out to discover approaches to guide the excitation waves, getting instruments from the creating field of optogenetics, which so far has been utilized basically as a part of cerebrum science.

Dr Gil Bub, from Oxford University explained: 'When there is scar tissue in the heart or fibrosis, this can cause part of the wave to slow down. That can cause re-entrant waves which spiral back around the tissue, causing the heart to beat much too quickly, which can be fatal. If we can control these spirals, we could prevent that.

'Optogenetics uses genetic modification to alter cells so that they can be activated by light. Until now, it has mainly been used to activate individual cells or to trigger excitation waves in tissue. We wanted to use it to very precisely control the activity of millions of cells.'


A protein called channelrhodopsin was delivered to heart cells using gene therapy techniques so that they could be controlled by light. Then, using a computer-controlled light projector, the team was able to control the speed of the cardiac waves, their direction and even the orientation of spirals in real time - something that never been shown for waves in a living system before.

In the short term, the ability to provide fine control means that researchers are able to carry out experiments at a level of detail previously only available using computer models. They can now compare those models to experiments with real cells, potentially improving our understanding of how the heart works. The research can also be applied to the physics of such waves in other processes. In the long run, it might be possible to develop precise treatments for heart conditions.

Dr Emilia Entcheva, from Stony Brook University, said: 'The level of precision is reminiscent of what one can do in a computer model, except here it was done in real heart cells, in real time.

'Precise control of the direction, speed and shape of such excitation waves would mean unprecedented direct control of organ-level function, in the heart or brain, without having to focus on manipulating each cell individually. This ideal therapy has remained in the realm of science fiction until now.'

The team stresses that there are significant hurdles before this could offer new treatments - a key issue is being able to alter the heart to be light-sensitised and being able to get the light to desired locations. However, as gene therapy moves into the clinic and with miniaturization of optical devices, use of this all-optical technology may become possible. In the meantime, the research enables scientists to look into the physics behind many biological processes, including those in our own brains and hearts.