5.4 Anticancer effect
There is evidence that cisplatin induces cells to undergo apoptosis (programmed cell death).
This occurs because the cell recognises the damaged DNA and triggers the mechanisms that signal the cell to die.
This self-destruct mechanism is present in all cells and is part of the organism’s way of destroying cells that might be harmful to itself.
See Box 2 for information on cell death and DNA repair systems.
Box 2 DNA repair systems and cytotoxicity: why do cells die?
Damage is constantly caused to cells and DNA by normal metabolism and by external factors such as UV radiation, smoking, chemicals, and so on. Sometimes this leads to the damaged cell swelling and then bursting – a form of cell death known as necrosis. DNA is continually checked for ‘errors’ in its sequence by various proteins.
If there is a large amount of damage, enzymes come into play that trigger the death of a cell by apoptosis or programmed death. If the damage is not too great, the checking proteins activate enzymes to eradicate the errors and perform a ‘repair’ by excising the damaged part and reconstituting the sequence. Indeed, it is the existence of these DNA repair systems that is believed to lead to resistance to cisplatin in certain cancers. On the other hand, studies have shown that repair-deficient mutant cells are much more sensitive to cisplatin.
Professor Lippard talks you through the effect of cisplatin on the autorepair mechanisms in the following video. You’ll also see the gel electrophoresis technique being used to separate DNA fragments.
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What type of protein is thought to bind to cisplatin-modified DNA, preventing access by repair proteins?
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High-mobility-group (HMG) proteins.
So in general, cisplatin appears to inhibit repair in mutant cells, leading to cell death. The difficult question to be answered is how do Pt 1,2-intrastrand cross-links inhibit repair?
One hypothesis is that the binding of HMG protein HMGB1 with the 1,2-intrastrand cisplatin–DNA complex shields the DNA from intracellular repair, leading to apoptosis. This binding occurs by means of HMG inserting a phenyl group protruding from its backbone into the notch created when cisplatin forms a complex with DNA.
This also increases the bend in the DNA even more to about 60–90°, facilitating the binding of a signalling protein called P53 which triggers a cascade of events leading to cell death. However, there is equally compelling evidence suggesting that HMGB1 can cause these changes even in the absence of cisplatin-induced lesions. So it is clear that these complex mechanisms still remain an area where much research is required.
Figure 23 shows schematically how these mechanisms are thought to operate.
OpenLearn - Metals in medicine
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