Radical Life and Death
Radicals are always suspicious - even in normal and degenerated cells. Locking them away instead of using their radicalism could prove to be a mistake. Gray areas are everywhere, to the chagrin of simplifiers and stereotyped thinkers - and unfortunately also of all optimistic black-and-white painters in medicine and cell biology. The gray usually comes up punctually when they simplify a darn complicated detail of life in a pleasant way, divide all the processes involved into good, bad, harmful and he althy and believe they have understood their interaction. The next step towards even greater accuracy then reliably brings back imponderables and confirms that all previous ideas were a bit too simplistic. A current example from cancer research is now provided by Peng Huang from the University of Texas and his colleagues.
Your subject was a quirk of degenerated tissue in the body that was clearly labeled "evil": Cancer cells often contain significantly larger amounts of reactive oxygen species (ROS). These appear as a fundamental evil and a self-reinforcing damaging mechanism at the same time. On the one hand, the aggressive respiratory chain defects are suspected of promoting the development of cancer in general. It has been proven that this happens, for example, in mitochondria with slight genetic defects, which supply faulty respiratory enzymes, are responsible for more ROS and are found more frequently in prostate cancer patients than in he althy people.
On the other hand, more ROS stimulate growth in cancer cells that are already proliferating – and the cells apparently further intensify this process by producing more radicals. In short, if anything really deserves its reputation as a villain, it's ROS and the associated oxidative stress in cells. It's no wonder that many combatants of the disease aim to prevent the formation of radicals or to meddle with those that have already formed.
So far, so clear and unambiguous. Just too clear to be true, as Huang's team didn't realize first. For example, several of the promising drugs currently being tested against tumors work through an initially unintended side effect, which at first glance seems to be the opposite of a useful strategy: they do not reduce the oxidative stress of the cells, they increase it. Apparently, a high ROS concentration is not only advantageous for tumor cells.
Huang and Co were interested – maybe drugs that specifically increase the amount of ROS in cancer cells could kill the tumors? The researchers tested the idea with the chemical PEITC, which was already on the menu for cancer preventives: the beta- Phenyl ethyl- I sot hioc yanat, which is found in cruciferous vegetables. Paradoxically, it was initially thought to be an antioxidant that works on tumor cells by blocking ROS - under the Huang team's close scrutiny, it should now simply prove the opposite.
PEITC was tested in a cell line that had been genetically engineered to chronically increase levels of oxidative stress. To do this, the scientists selectively switched on one of two known oncogenes, Ras and Bcr-Abl, and thus set the oxidase enzymes of mitochondria into a radical waste-producing tumble. As with tumor cells, the increase in ROS then led to an increased rate of cell division. Collateral damage caused by oxidative stress can only just be limited by the cells if they simultaneously run all antioxidant protection mechanisms at full speed - and Huang and colleagues have now bowled the PEITC precisely into the gears of this overheating protection program.
The researchers discovered that the substance blocks two crucial signals at the same time: Firstly, it intercepts the glutathione molecule GSH, which transmits the cell command for increased antioxidant activity; on the other hand, it inhibits the GPX receptor, which normally accepts this GSH signal in order to drive the antioxidant machine. With PEITC, therefore, no increased antioxidant efforts - and that has consequences for the modified test cells: the constantly boosted oxidative stress increases to an extent that is no longer controllable, the cell overreacts and dies. The researchers immediately demonstrated that this also works with real tumor cells. And apparently also in the living object: mice with cancer survived longer when they were treated with appropriate amounts of PEITC.
Only the cardinal question remains – doesn't switching off the anti-oxidation protective mechanism also damage normal cells? To put it another way: is the use of PEITC only fatal for tumor cells, but not for the rest of the body? This seems to have been the case in the researchers' experiment: control cells without increased ROS concentrations did not need their antioxidant program as urgently and could tolerate its blockade by PEITC.
Finally a new way to also "target highly malignant cells with increased oxidative stress that are resistant to conventional cancer drugs", as Huang thinks? Worth at least the pre-clinical and any subsequent clinical testing that the researcher now sees fit. The hope remains that only a few gray side effects will mix with the clarity that has just been achieved.