Reading Reaction Journal # 3

Arsenic anticancer target revealed

Researchers from China and France believe they have uncovered the molecular mechanism by which arsenic trioxide kills certain cancer cells. Arsenic is a poisonous metalloid that has been used in Chinese medicine for centuries to treat illnesses such as psoriasis and syphilis. More recently it has been shown to be effective against acute promyelocytic leukaemia (APL), a cancer of the blood.

However, the role that arsenic plays in the sequence of reactions leading to the death of the cancer cells has not been clear. Now, Xiao-Wei Zhang, from the Shanghai Institute of Hematology, and colleagues believe they have pinpointed the key target of the arsenic compound, although a detailed mechanism of action has still to be established.

It has been known for some time that in APL a genetic mutation results in the production of a rogue 'fusion protein' called PML-RAR which is vital to the survival of the cancer cells. Arsenic trioxide triggers a cellular protein called SUMO to 'tag' the fusion protein, earmarking it for destruction. The destruction of the protein leads to the death of the cancer cell, but until now, how As₂O₃ achieves this had remained a mystery.

The new research has shown that when As₂O₃ is added to cell extracts containing the fusion protein, the protein becomes insoluble and that the arsenic is associated with the insoluble fraction. The team then isolated a particular region of the PML protein called a zinc finger and showed that arsenic binds to this region, which is rich in cysteine residues. The researchers say that the binding of arsenic to this region causes several protein molecules to join together as an oligomer through cross-linking and conformational changes. The altered protein is then bound by SUMO, resulting in the protein aggregate's subsequent degradation. Team member Xiao-Jing Yan believes that knowing the target protein of the arsenic could allow better treatments to be devised in tandem with other drugs that also hit the same protein.

Arsenic trioxide has been used in medicine for centuries, but only now are the mysteries of how it kills cancer being solved © Science

'These exciting observations suggest that arsenic may be acting directly on the PML-RAR fusion protein to enhance its SUMO modification and thus provide the trigger for its destruction,' says Ron Hay of the University of Dundee in the UK, who has studied the role of SUMO in arsenic-induced degradation of PML.

'However the precise mechanism that allows arsenic to substitute for the zinc already bound to PML and how this brings about increased SUMO modification remains to be determined,' Hay continues. 'Clearly this will be a hot topic for future research and may reveal how arsenic, which binds to many proteins, has this remarkably specific activity on PML-RAR.'

References
Hadlington, S. (2010, April 08). Arsenic anticancer target revealed. Chemistry world.Retrieved April 26, 2010. From: http://www.rsc.org/chemistryworld/News/2010/April/08041002.asp

Vocabulary
Molecular: the smallest unit into which a substance can be divided without chemical change, usually a group of two or more atoms
Arsenic: a very poisonous substance, used to kill rats (= animals like mice, but larger) and harmful insects
Metalloid: a chemical element with some of the properties of a metal and some of a non-metal, for example silicon and arsenic
Sequence: a series of related things or events, or the order in which they follow each other
Pinpointed: to find out or say the exact position in space or time of something
Destruction: when something is destroyed
Cysteine: an amino acid containing sulfur that is found in most proteins; oxidizes on exposure to air to form cystine
Modification: a change to something, usually to improve it
Degradation: when the beauty or quality of something is destroyed or spoilt
Cellular: made of small parts
Zinc: a bluish white metal that is used in making other metals or for covering other metals to protect them
In tandem: If two pieces of equipment, people, etc. are working in tandem, they are working together, especially well or closely

Summary
China and France’s researchers have found that molecular mechanism from arsenic trioxide can kill certain cancer cells. Arsenic is a poisonous metalloid, but Chinese medicine has used it for centuries to cure illnesses; that is why people research arsenic’s efficacy. Recently, researchers have discovered it can be fight APL. However, they still do not understand which arsenic leads to the death of cancer cells. Arsenic trioxide triggers a cellular protein, and then we know the destruction of the protein results in the death of cancer; however we still do not know how As2O3 did this. Scientists have uncovered a particular region of PML protein that arsenic binds to this region, which is rich in cystic residues. Scientists also consider arsenic may act directly on the PML-RAR fusion protein and thus provide the trigger for its destruction. The precise mechanism still needs to be determined, but in the future arsenic will be a hot topic.

Reaction
Arsenic is a poisonous metalloid, and Chinese medicine just uses it to treat some illnesses, which are visible on the skin. Now Scientists want to know why the destruction of the protein leads to the death of the cancer cell, and how As2O3 achieves this, but it is still a mystery now. In my memories, the mechanism of arsenic endostain is the same as moss, which has poison. “When As2O3 is added to cell extracts containing the fusion protein, the protein becomes insoluble and the arsenic is associated with the insoluble fraction.” This is very important information for the human because we can make sure how to make drugs to treat people who have APL. I never tried arsenic because it is so dangerous. However, when I finished reading the article, I have an idea that I want to become the person who treat people’s illness with arsenic.