ARCHIVE. By working through unexpected findings, researchers at Weill Cornell Medical College in Qatar (WCMC-Q) have moved closer to understanding a process that could contribute to more intelligent cancer therapies. The college’s Associate Dean for Research and Professor of Physiology and Biophysics, Dr. Khaled Machaca, is principal investigator on a project involving zinc and its role in cancerous cell division. While at first, the team suspected zinc to have an influence on a widely known cancer target, they were soon lead to a more profound effect of the mineral’s changed levels.
“So in science you want to do one of two things: you want to either prove your hypothesis, which seems smart and good … or you want to disprove it. And yet once you disprove your hypothesis you’ve learned something, so you’re really contributing new knowledge anyway. And that’s how science moves forward.”
In the case of cancer—marked by a dizzying range of causes and outcomes—hypotheses are more often stepping stones along an increasingly lit path to discover the mechanics of all the different types.
“One important thing when you think about cancer is that not all cancers are equal. Cancer is not a disease, it’s a class of diseases,” Dr. Machaca said.
Opportunity in the unexpected
For years, Dr. Machaca’s main line of research focused on how calcium affects oocyte (egg cell) development. Studying this led his team to recognize specific effects that metals have on cells at critical stages, including division, i.e. mitosis. Specifically, when they added chemical compounds known as chelators to bind (soak up) calcium, they noticed that, even when they reduced the type and amount of chelators, oocyte progress stopped.
“The chelators bind metals with a much higher affinity than calcium. So we used chelators specific for metals and we were able to block the pathway at much lower concentrations,” Dr. Machaca explained. “This told us that the requirement for oocyte maturation is not calcium but is some kind of metal. So we did some experiments and we found out that the target for this metal chelation is a protein called Cdc25c. That’s where the link to cancer came in.”
Long targeted by cancer researchers, Cdc25c is a protein required for regulation of cell division. Uncontrolled cell division underlies all cancers, so this target signifies a major gateway to cancer and its antidotes.
“We knew that, beyond requiring just any metals to function, Cdc25c required zinc specifically because we [in previous studies] purified the protein and observed how it worked with zinc. Knowing these things in the context of the oocyte, we wanted to translate these findings into cell division in the case of cancers.”
The experiments involved a cross study of cancer and normal cells exposed to chelating agents. The results of targeting zinc revealed an exciting new result and another bend in the road, again, away from what was suspected.
“So the very exciting new result is that we noticed, when we conducted the experiments at a certain concentration of this chelator, we can kill cancer cells but not normal cells, because cancer cells are more sensitive,” Dr. Machaca said. “Surprisingly, Cdc25c does not seem to be playing a role.”
Instead of interrupting the process of mitosis, Dr. Machaca explained, the effect of the chelator seemed to be killing the cancer cells on the spot, through a completely different mechanism than the one the team suspected when they were initially researching calcium and oocyte progress.
“When we chelate the metals, the cells just die. And the cool thing is that the sensitivity of the cancer cells is higher,” he said, “so we hope these new findings will help in the development of more targeted therapies.”
The team—consisting of Dr. Machaca, Dr. Hala Gali-Muhtasib, Professor at the American University of Beirut; Dr. Olga Boudker, Assistant Professor of Physiology and Biophysics at Weill Cornell Medical College, New York, and Maamoun Fatfat and Ghizlaine Bendriss, postdoctoral researchers at WCMC-Q—is now working with a QNRF National Priorities Research Program grant to highlight the exact mechanisms by which chelation of zinc leads to cancer cell death.
Dr. Machaca said that one hypothesis entails oxidative stress as the real killer of the cells when the metals that serve them are reduced through chelation. Such stress can be reduced when agents like vitamin E or C are added to the samples—in these cases, the team observed that the cells continue to live despite the chelation of metals.
The team has yet to identify the exact mechanisms at play, yet what they have found paves an information highway—among many—to more sophisticated cancer therapies.
Tying it all together
“Chemotherapy is a sledge hammer,” said Dr. Machaca. “Why do people lose hair when they are going through it? Because any dividing cell will be targeted and will die. Unfortunately, that’s the standard of care now. That is the best thing we have.
“You can ask ‘what is the difference with metal chelators—why are we interested in this?’ While it’s not a magic wand, it’s just one additional tool in your toolbox to approach cancer.”
Chelation is a method of treatment in various diseases that are linked to levels of metal in the body. Dr. Machaca is interested in researching the effects of approved drugs that people use to treat such diseases.
“So it would be really interesting to look at this and ask: ‘Are people taking those drugs less susceptible to cancer?’,” he said.
The body needs metals to survive, and Dr. Machaca explained that any drug at a high enough dosage would have negative effects. The trick would be to find just the right amount of chelating agent to stop the disease while not affecting the body’s natural processes.
“You’ll need to do clinical studies to this effect, to say what’s the dosage, what are the side effects and so on. These are all things we don’t know at this stage—we’re still figuring out how it all works. Once we know the mechanism a little better we will be able to publish those results.”
Zinc-dependent regulation of the cell cycle regulator Cdc25 as a potential anti-cancer target.