A few years ago, The Daily Mail boldly asked “Could arsenic be a miracle cure for cancer? Scientists say it had astonishing results when added to a leukemia drug”. It’s worth pointing out that even in the subheading bullet points the Mail Online immediately downplayed their excitement a little, de-escalating from arsenic being a potential “miracle cure” to the claim that it “makes chemotherapy more effective”.
The Mail Online wasn’t the only one to cover this story. Medical News Today headlined “Poison or cure? Arsenic can help treat cancer, study finds” while Science Daily said “Arsenic in combination with an existing drug could combat cancer – An ancient medicine shows new promise” and Harvard Magazine asked “Is Arsenic a Key Ingredient in the Battle Against Cancer?”. So, the Mail Online seem to be in good company in reporting this apparently exciting news.
New use for a traditional medicine?
One thing all of these stories had in common was the detailing of arsenic in traditional Chinese medicine. Harvard Magazine quoted study author Kun Ping Lu:
“In Chinese traditional medicine, “Arsenic has been used for thousands of years,” said Lu. “Its oxidized form is the active ingredient” for a concoction the Chinese called “magic bullet,” which was used to treat a specific kind of leukemia, APL”.
Arsenic, in fact, has been claimed to treat a whole range of diseases throughout history – in Ancient Greek times it was used to treat ulcers and in Chinese Traditional Medicine it’s been used for over 2000 years. Arsenic was once added to Indian Ayurvedic herbal remedies and when Paracelsus, an Italian Professor of Medicine from the 1500s was skeptical of the old methods of balancing humours to treat disease, he introduced arsenic as an alternative. Paracelsus, in fact, stumbled across a genuine therapeutic action of arsenic in its ability to treat syphilis – an indication for which arsenic was used well into the 20th Century until antibiotics came along.
But arsenic has not only been a persistent element in traditional medicine, it has also been used to treat cancer – first, to treat chronic myeloid leukaemia in the 1930s and later to treat acute promyelocytic leukaemia (APL). Arsenic trioxide (ATO) has been used to treat APL since its approval in 1995.
The study
The study the Mail Online et al. referenced was summarised in Nature Communications in an article titled “Arsenic targets Pin1 and cooperates with retinoic acid to inhibit cancer-driving pathways and tumor-initiating cells”. The study is apparently based on three things:
- A protein called Pin1 is important in cancer
- Arsenic trioxide (ATO) is a treatment for cancer
- All-trans-retinoic acid (ATRA) inhibits Pin1
A good introduction to any peer-reviewed article will use scientific literature to convince you that the question the researchers have asked is a valid one and set their work within the context of what is known in the field. At first glance, this article is particularly industrious in the effort to convince the reader on the three areas above. They strongly stress that “Pin1 is a critical “driver” and a unique drug target in cancer. Pin1 is hyperactivated in most human cancers and correlates with poor clinical outcome”.
ATO and leukaemia
ATO has been approved for use in a certain kind of leukaemia called acute promyelocytic leukaemia (APL) for many years and is successfully used in combination with ATRA in patients with APL. There are very few alternative treatments for this form of leukaemia and ATO combined with ATRA has low toxicity.
The underlying mechanism of this treatment is down to the existence of a protein called PML-RARα which causes APL. PML-RARα doesn’t exist in normal conditions however patients with APL have a genetic mutation which produces this fusion of the genes for two individual proteins PML and RARα – this generates the fusion protein, PML-RARα. It doesn’t really matter what PML-RARα does, only that it drives APL and it doesn’t exist outside of disease. Studies have shown that ATO binds to the PML part of this fusion protein and degrades it.
The chemical structure of Pin1 is shown with ATO (I) sitting within in apparent binding pocket on the protein. This image is adapted from the paper.
ATO and Pin1
But the authors of this study were interested in the effect of arsenic on a completely different protein – Pin1.
They don’t really explain why they thought arsenic might remove Pin1 in cancer cells. They used a technique to identify ATRA as a drug of interest, but it seems like they only looked at ATO because it’s already used in combination with ATRA.
In their study the authors find that treating cancer cells with arsenic in the lab reduces the levels of Pin1. They also show that ATO and ATRA combined, reduce cancer cell growth and reduce tumour size in mice. And they go some way towards explaining the mechanism behind these interactions and discounting alternative explanations for their findings.
In many ways, it’s a solid paper.
So why am I skeptical?
There are a few reasons, though, to be wary of the findings in this paper and the way it has been presented. Firstly, it’s the particularly hyped up nature of the story – arsenic has been used to treat leukaemia since the mid-1990s, this isn’t really news. But it does make me wonder if there’s a particular reason this article might be so strongly endorsed.
The authors also don’t really explain why they picked arsenic in the first place other than they’re interested in ATRA and Pin1… In fact they’re very, very interested in Pin1.
They argue “that Pin1 is a critical “driver” and a unique drug target in cancer” – which is particularly interesting because as a cancer researcher with a PhD in cancer cell biology, I’ve never even heard of this protein. They reference three papers to support their claim but two of them are from the group’s own lab – the final paper they reference, an article titled “Pin1 in cancer” is from a separate source. This unrelated (and therefore, unbiased to some degree) article argues that Pin1 is hyperactivated in around 10% of all cancers. That number is pretty high, but it is certainly not enough to say that Pin1 is a “critical driver” in “most human cancers”.
So why are the authors so keen on Pin1? The suggestion that it’s a “unique drug target” might give us a clue.
At the end of the article is the heading “Competing interests” under which is stated “K.P.L. and X.Z.Z. are inventors of Pin1 technology, which was licensed by BIDMC to Pinteon Therapeutics. Both Dr. Lu and Dr. Zhou own equity in, and consult for, Pinteon. Their interests were reviewed and are managed by BIDMC in accordance with its conflict of interest policy. The remaining authors declare no competing interests.”
Pinteon Therapeutics is a “private venture backed biotechnology company focused on the discovery and development of breakthrough therapeutics targeting Pin1” and we can therefore assume that this company will make money from the generation of Pin1 inhibitors that can be used to treat cancer.
Of course, Pin1 inhibition might well make for an interesting cancer target – there’s no disputing that – but its promise might well be overstated both in this article and in the media coverage of the article.
Me? I’m suspending judgement until we see more compelling evidence.
