New job for old drug: Cisplatin in ALS

Precluding clumping

The well-known and well-used anticancer drug cisplatin looks set to be the starting point for the development of new treatments for the incurable neurological disorder commonly known in the US as Lou Gehrig's disease and as motor neuron disease in the UK, but more formally as amyotrophic lateral sclerosis (ALS). On the basis of NMR spectroscopy and other studies, including X-ray absorption fine structure (EXAFS) measurements and synchrotron X-ray diffraction, new insights as to how the platinum-based compound might prevent the clumping of an enzyme associated with the disorder have been revealed.

ALS is usually associated with a rapid progression to weakness, muscle wasting, or atrophy, spasms, difficulty speaking, swallowing and problems breathing. The degeneration of upper and lower motor neurons gives rise to the symptoms but for about 95 percent of patients without a family history the cause of ALS is unknown. Claims that head trauma, military service, participation in contact sports, electric shock and exposure to toxic chemicals have not been examined rigorously and the etiology of the disorder remains a mystery.

Currently, there are limited options for sufferers. Disease management has healthcare providers endeavouring to keep patients and mobile and comfortable as possible while the drug riluzole (Rilutek from Sanofi-Aventis), which was approved in 2011 delays the need for ventilator assistance by up to five months at best. The drug works by selective inhibition of specific sodium channels associated with damaged neurons and so precludes the inadvertent stimulation that causes twitches, spasms and other involuntary movements. Unfortunately, symptoms for most patients develop to difficulty in swallowing and breathing problems and death within three to five years of diagnosis.

Now, Lucia Banci, Ivano Bertini and colleagues at the University of Florence, Italy, and at Fondazione Santa Lucia, and the University of Rome as well as Angela Trapananti of the CNR-IOM-OGG in Grenoble France, point out that sporadic ALS, the non-hereditary form of unknown etiology seems to arise coincident with clumping of the antioxidant enzyme human superoxide dismutase 1 enzyme. This enzyme binds copper and zinc ions and is known to be one of three SODs responsible for degrading free superoxide radicals in the body to molecular oxygen and hydrogen peroxide, which are then processed further by other enzymes. The enzyme thus protect cells from the harmful free radicals generated as by-products of respiration. The formation of clumps of the enzyme destroys its functionality exposing the unprotected cells to oxidative damage.

Cancer to ALS

The authors were already aware that cisplatin, cis-diamminedichloroplatinum(II), the chemotherapy agent that has been in use in areas such as testicular and ovarian cancer for several decades can latch on to a specific amino acid present in hSOD1, cysteine 111 (Cys111). The team hoped to determine whether cisplatin might have any effect on enzyme aggregation through a binding mechanism that precludes cluster formation. Indeed, in initial laboratory tests, the anticancer drug readily bonds to hSOD1 blocks aggregation and allows existing clusters to disintegrate freeing the individual enzymes once more. Intriguingly, the mode of action of cisplatin in cancer therapy is not yet fully understood.

The team further explains that cisplatin targets the sites that can form bonds between hSOD1 moieties once the enzyme loses its copper atom. This dis-aggregation mechanism does not, however, interfere with the normal functioning of the enzyme. The X-ray diffraction shows native hSOD1 and the cisplatin-bound counterpart to be essentially the same in terms of protein conformation and structure; cisplatin binding does not cause misfolding. Likewise, the NMR data show that in solution the enzyme's active site is unaffected by cisplatin binding.

"From this work it appears that cisplatin is a promising lead compound for the rational design of ALS treatments," the authors report in the Journal of the American Chemical Society. They point out that in their laboratory study cisplatin remains active in preventing enzyme aggregation for up to twelve months.