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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

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March 27, 2014

Dichloroacetic Acid, In a New Form

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Posted by Derek

Remember dichloroacetic acid? In 2007, there was a stir about it as a cancer therapy, and on internet forums you still see it referenced as a "cancer cure" that no drug company will touch because it's unpatentable/doesn't have to be taken forever/too cheap/not evil enough, etc.

The people spreading that stuff around don't know how to use PubMed, because a look through the literature will show that DCA is still an active area of research (in some cases, involving people who've taken it on their own). Interestingly, PubMed also makes it apparent that the rest of the literature on the compound is in its role as a water pollutant. But the problem with it as a drug is that it has poor pharmacokinetics. Its site of action is the mitochondrion, but it doesn't do a very good job of getting there (as one would expect from a small molecular weight carboxylic acid, especially one that's as ionized as this one is at body pH).

So here's an attempt to do something about that. The authors, from the University of Georgia, tether several DCA molecules to a scaffold that should do a better job of targeting mitochondria. They go as far as cellular data to prove the point, but there's nothing in vivo (I'm not sure what would happen in that case, but it would seem worth finding out).

This, one should note, is a new molecule, and one that was perfectly capable of being patented - it has novelty, and it apparently has more utility for its stated purpose. Every time you hear about how Evil Pharma won't work on X, or Y, or Z, because "they can't patent it", keep in mind that we here at Evil Pharma know a lot of ways to patent things. Part of what makes us so darn evil, you know.

Comments (18) + TrackBacks (0) | Category: Cancer


1. Algirdas on March 27, 2014 7:38 AM writes...

A fun side note on journal publishing business, a perennial favourite round these parts:

If you click on Derek's link to a Pubmed entry, you'll see that the article has an associated erratum. While Springer charges $40 to see the article itself, shockingly, they provide access to erratum free of charge. Erratum contains the following:

Erratum to: J Bioenerg Biomembr (2012)
DOI 10.1007/s10863-012-9496-2

A separate analysis of the same patient was previously presented in a Case Report by Dana F. Flavin: “Non-Hodgkin’s Lymphoma Reversal with Dichloroacetate,” Journal of Oncology, vol. 2010, Article ID 414726, 4 pages, 2010. doi: 10.1155/2010/414726

This erratum appears right after the original article itself.

So: someone writes a manuscript that is a clear duplication of an existing literature; this must have been pointed out during the peer review; the editor accepts the article nevertheless, but appends and "erratum" on the next page. The publisher still charges $40 to see the duplication. Nice business model, if you can get it...

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2. Yossarian on March 27, 2014 8:22 AM writes...

See: Mitaplatin, a potent fusion of cisplatin and the orphan drug dichloroacetate.

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3. 3BP on March 27, 2014 8:29 AM writes...

It appears that you've overlooked a wealth of literature around a related anti-cancer agent, 3-bromo pyruvate (3BP), principally from the Pedersen lab, There’s plenty of in vivo data around this compound (within link above), including limited clinical data in the context of the “Warburg effect”. Furthermore, the mono-carboxylate transporter 1 (MCT1) appears to sensitize cancer cells to 3BP (active) uptake. Elevated MCT1 has been proposed as a biomarker for enhanced 3BP specificity and efficacy

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4. smith john smith on March 27, 2014 8:59 AM writes...

Yossarian, how does the cisplatin get DCA to the mitochondria??

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5. Dee on March 27, 2014 9:05 AM writes...

I may be wrong here, but dont e.g. figures 5A and C with two completely flat ECAR/OCR curves for "Mito-DCA" very much suggest that this is primarly a very effective mitochondrial toxin?

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6. Yossarian on March 27, 2014 9:14 AM writes...

smith john smith:

See Figure 1. After crossing the plasma membrane, mitaplatin becomes reduced to release of the active drugs cisplatin and DCA.

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7. smith john smith on March 27, 2014 9:35 AM writes...

with due respect yossarian, how does getting DCA into the cytoplasm deliver it into the mitochondrial matrix? would love to know . . . . thousands of things get into the cytoplasm but never get into the mitochondria.

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8. fourtytwo on March 27, 2014 9:48 AM writes...

"Part of what makes us so darn evil, you know."

I hope that when you finished typing this you laughed manically whilst stroking your white cat.

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9. Carl 'SAI' Mitchell on March 27, 2014 10:37 AM writes...

Pharma companies aren't any more evil than most other large corporations. It's mostly just an aspect of being a publicly owned company, all the shareholders want to make a profit, and while all of them can be good people and want to help others they'll likely differ on how they want to help others. Since they'll have conflict on benevolent actions but support each other on making a profit, companies focus much more strongly on making a profit. Not to mention that not everyone is good.
Pharma companies just happen to deal with things that can save people's lives, and if they make too much of a profit they get seen as extra evil. If they stop researching new antibiotics because they haven't found a new one in decades, well, that's evil. Etc.

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10. David Young MD on March 27, 2014 11:21 AM writes...

#1 Keeping in mind of course (as many already know that some low-grade non-hodgkins lymphomas regress on their own without any treatment, opening up the possibility of some drug getting a good rap because of the coincidence of the taking of the drug and the regression of the nodes. Then again, a low grade lymphoma might be the most "sensitive" of all cancers in terms of responding to even very weak cytotoxic meds. Getting a low grade lymphoma to regress is much, much easier than getting a meaningful anticancer effect in gastric cancer, pancreas cancer, non-small cell lung cancer.

The new drug, made of tethered DCA molecules might be more likely to penetrate into the cell and do its work. Now watch out for side effects, which are likely to happen if tethered DCA is able to penetrate and do stuff. And those side effects may be quite serious ones at that.

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11. Paul Brookes on March 27, 2014 12:35 PM writes...

Regarding patentability, the method they used for mito' targeting here is the triphenylphosphonium cation, which has been widely exploited (and patented) by Mike Murphy's group. A pharma spin off (Antipodean Pharma) has the IP on this class of molecules fairly well locked up AFAIK, so whatever you attach to TPP+ for mito' targeting is pretty much a non-starter unless you want to license that IP.

WRT DCA, it was explored some time ago in clinical trials for patients with inherited mitochondrial disease (e.g. NCT00004493). The thinking was that by activating PDH it would simply shove more carbon in the TCA cycle instead of to lactate. Nothing came of it, and I recall hearing of some side effects but can't recall what they were.

The scary thing is they needed to use it at concentrations in the high uM range, which is super-high for TPP-conjugates. Most of these types of molecule (e.g. Mito-Q) are effective in the nanomolar range, and get toxic at higher doses. If you assume a 1000x mito' enrichment (not unusual for these drugs), then 150 uM outside would equate to 150 mM in the mito' matrix, which is pretty frickin' high!

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12. kona coffee on March 28, 2014 9:39 AM writes...

Hmm is anyone else encountering problems with the pictures on this blog
loading? I'm trying to figure out if its a problem on my end or if it's
the blog. Any suggestions would be greatly appreciated.

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13. Robb on March 28, 2014 11:52 AM writes...

In response to a friend posting the "DCA cancer cure" story I looked into the history. It turns out that the meme was started by a DCA researcher in Canada who suggested it as a cancer therapy then launched a public appeal soliciting donations to run a small trial because pharma wasn't interested in an unpatentsble drug.

The researcher must have learned some evil, because a quick search of the us patent office's database shows he does in fact hold a patent on the use of DCA as a cancer therapy.

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14. Anonymous on March 28, 2014 4:29 PM writes...

Just as a small aside, low potency doesn't mean much at all during in vitro screening IMO. Many, many chemotherapies that are used only have observed IC50 values in the high uM to mM range when tested in panels of cancer cell lines, yet for some reason they still work clinically. The idea that you need nanomolar potent compounds is highly misleading, and the dogma that you should immediately throw away compounds after in vitro screening due to low potency is increasingly proving to be dubious rationale. If we listened to the dogma that nanomolar potencies are needed to make drugs that work in the clinic, we would have thrown away virtually all alkylating and hormonal disrupting agents that are used in hospitals to treat cancer patients everyday.

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15. anony-mous on March 29, 2014 8:53 AM writes...

@3. 3BP - I have followed the Pedersen Lab's work on 3-bromopyruvate for some time. While fascinating, dosing "even" cancer patients with such a hot alkylating agent may well lead to a situation where the "cure" is worse than the disease....

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16. Anonymous on March 29, 2014 11:07 PM writes...

3BP is an alkylating agent with lots of off target effects. For terrible forms of cancer like pancreatic, I could see it as a last line of defense. Also, look up KEGG charts. All glycolytic inhibitors are NOT the same. The are some very, very, very interesting branches off of glycolysis that are heavily involved in cancer signaling cascades. A molecule like 3BP works further down stream in glycolysis. The MAIN target which is most disease modifying in my opinion would be hexokinase. Why has there been such little effort at finding HK inhibitors? 2DG has QT prolongation problems, it isn't viable.

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17. anony-mous on March 31, 2014 5:52 AM writes...

@13 / 15 - It is is claimed that the main target of 3BP is hexokinase (as you state later) - the only "targets" upstream of HK are the glucose transporters - so your premise seems flawed. I suspect HK inhibitors have been less aggressively prosecuted as folk don't want to induce diabetes....not to mention RBC lysis / anemia (they're dependent on glycolysis, as are select other cells in man).

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18. fluorogrol on March 31, 2014 10:22 AM writes...


"So: someone writes a manuscript that is a clear duplication of an existing literature; this must have been pointed out during the peer review; the editor accepts the article nevertheless, but appends and "erratum" on the next page. The publisher still charges $40 to see the duplication. Nice business model, if you can get it..."

How do you know it was pointed out during peer review?

Yes, the erratum appeared immediately after the paper in the issue, but that was the June 2013 issue and the duplicated paper had been online since Dec 2012 (see web publication date in PubMed).

The mostly likely scenario is that the reviewers missed the duplication, so it was accepted and published online, and at some point during the first half of 2013 the duplication was pointed out to the journal.

I agree it's a bit much to charge for access to an article you know to be duplicated, but at least the erratum is free (see

What is particularly poor in this case is that if you go directly to the article's abstract page (e.g., via the DOI), there is nothing to indicate the existence of the erratum.

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