Comments

1. #1 coturnix

   April 23, 2007

   Oooh, nice to have all the links in one place like this!

2. #2 mark

   April 23, 2007

   I’m certain that the intentions of Dr Michelakis are far more nobel

   That’s a fun misspelling.

   It’s also been interesting to me to see how cranks of many stripes latch onto this as proof that:
   1. The FDA is worse than Hitler
   2. Pharmaceutical companies hate cancer patients
   3. Doctors don’t want cures because they’d be out of business

   yada yada. It’s been a bit of a lightning rod for cranks this DCA stuff.

3. #3 Abel Pharmboy

   April 23, 2007

   Coturnix, putting the links altogether was Orac’s idea – I benefit more because he sends me more traffic than I do to him.

   Mark, I’m not sure if I really intended to misspell “nobel” but thanks for catching it. Your three points really capture the hysteria surrounding this whole story.

   The FDA is always in a no-win situation since they are responsible for both drug approval and withdrawal if safety becomes an issue. Their recent record has not been impressive and their relationship with Rx companies as “clients” via PDUFA creates conflicts of interest. Still, they do the best they can with using clinical trials of 1500-3000 patients to extrapolate safety and efficacy of drugs released to a diverse population of millions in far less controlled settings. I applaud anyone who chooses a career path at FDA.

   Pharmaceutical companies have done damage to themselves for sure, but only a creative, niche company will have the vision to sponsor a public-domain molecule like DCA.

   Oncologists (I know many of them and several blog here at Sb) would love for there to be a “cure” for cancer. Folks forget that oncologists are trained in surgery or internal medicine, so they’d still have plenty of work if a “cure” were ever found to the hundred or so diseases that we refer to singularly as cancer.

4. #4 coracle

   April 23, 2007

   However, it doesn’t help when he says things like:

   Dr Michelakis said: “One of the really exciting things about this compound is that it might be able to treat many different forms of cancer, because all forms of cancer suppress mitochondrial function.”

   He is concerned that, because DCA is a well-known substance – and has no patent – attracting drug company support for human trials might be a problem.

   Source:Cheap molecule may attack tumours (BBC)

   I can’t help thinking that if that quote hadn’t been used in media stories and made it to places like slashdot there wouldn’t be as much noise about it.

   Interestingly it’s not a direct quote, so perhaps it has been spun by journalists looking to make things a little more controversial.

5. #5 Willis

   April 23, 2007

   In order to give everyone a slightly better understanding of what is going on here, I will give you a summary of the apoptosis-inducing mechanism described by Michelakis, et al. I have previously posted a version of this on the dcasite. A very easy mistake to make is to think of dichloroacetate as somehow starving the cancer cell of energy or that it is “turning on” the mitochondria and they then induce apoptosis. This last mistake may be technically correct to the extent that cancer cell mitochondria were previously thought to be irreparably damaged, but it is an oversimplification. What the Alberta group has claimed to discover is a metabolic-electrical remodeling of certain cancers. My understanding of what this means is that they claim that the metabolic pathways of these cells have been altered from normal in such a way that they maintain their mitochondria in a hyperpolarized state (that is that the inside of the mitochondrial membrane is much more negative relative to the outside than would be the case in a normal cell), and that the hyperpolarized state of their mitochondria confers at least some of these cells’ apoptosis resistance. They cite evidence indicating that the vast majority of carcinomas exhibit hyperpolarized mitochondrial membrane potentials (the notable exceptions that the evidence appears to indicate do not have hyperpolarized mitochondrial membrane potentials are sarcoma, small cell lung cancer, large cell lung cancer, leukemia, and lymphoma). If they are correct about the metabolic-electrical remodeling, that is big news whether dichloroacetate works in humans or not. The “distinct”-ness – I would have said complete novelty – of this mechanism is why it is a big deal if they are correct.

   Here is a summary of the mechanism described by the Alberta group: (1) DCA inhibits pyruvate dehydrogenase kinase (PDK), the action of which is to inhibit pyruvate dehydrogenase (PDH); (2) inhibition of PDK leads to more PDH; (3) more PDH results in larger amounts of pyruvate being converted to acetyl-coA (essentially, the raw material of mitochondrial respiration); (4) the increased amounts of acetyl-coA enter the mitochondria where their oxidation results in the production of larger amounts of reactive oxygen species (ROS) (particularly H2O2); (5) the larger amounts of ROS damage Complex I of mitochondrial respiration; (6) the damage to Complex I results in inhibited efflux of H+ (a hydrogen atom without an electron, otherwise known as a proton; this is where the positive charge comes from); (7) because H+ is not being pumped out as quickly, the mitochondrial membrane potential becomes more positive, ultimately dissipating completely; (8) the mitochondrial transition pore (MTP), which Michelakis, et al. describe as voltage-sensitive, can now open, releasing pro-apoptotic factors and cytochrome c; (9) the cytochrome c and the increased ROS generated by the mitochondria activate Kv1.5 channels (a type of voltage-gated potassium ion channel) in the cell’s plasma membrane; (10) the activated potassium channels in the cell membrane allow increased efflux of potassium ions from the cell; and (11) the decreased intracellular concentration of potassium ions exerts a decreased inhibitory effect on caspases (which are essentially triggers for apoptosis). I have left out a few steps, but this, according to the Cancer Cell paper, is how dichloroacetate reverses the metabolic-electrical remodeling.

   If the Alberta group is correct that the apoptosis-resistance of the majority of carcinomas is linked to the hyperpolarized mitochondrial membrane potential, that is much bigger news than you and Orac are giving it credit for. That is why I keep asking to hear from Orac on the science (no offense to you Abel). Dichloroacetate may or may not work in people the same way it does in rats, but if a/the major cause of apoptosis-resistance in carcinomas is the hyperpolarized mitochondrial membrane potential, that is still huge news. In fact, if they are correct on that, I think that would be one of the biggest cancer discoveries ever. As I have said before, I am not a conspiracy theorist; I think the problem is many of you have not appreciated just how “distinct” a description of carcinomas this paper offers.

6. #6 Mark

   April 23, 2007

   I don’t think anyone is saying this isn’t a neat paper. I think Abel and Orac are mostly just being skeptical of how expansive claims have been made from a single study.

   Your description of the mechanism is interesting. I’ll admit, I didn’t give the paper a super-thorough read since cancer isn’t really my field, so I thought it was more along the lines of creating the switch to aerobic respiration. Looking again at figure 1 I think you picked up on subtlety of their model that a lot of people haven’t talked about. Still, the description of it causing a switch, while simplistic, still seems accurate.

7. #7 Willis

   April 23, 2007

   I actually meant to mention that it would be like a switch, just not an on/off switch for the mitochondria. The switch is in normalizing the mitochondrial membrane potential, whether the mitochondria are respiration-functional or not. I know no one is pooh-poohing the paper itself – not any more at least – but I think that the focus on who thinks what about Big Pharma is pointless, just as pointless as the interminable ethical discussions.

8. #8 Abel Pharmboy

   April 24, 2007

   Willis, no offense taken. But since Orac hasn’t come by here’s my take. The Michelakis paper puts together several pieces that have been alluded to by others. For example, Chi Dang’s group at Hopkins was first to show that ectopic expression of PDK abrogates the ROS production that would normally trigger apoptosis – the Michelakis paper confirms this using DCA to inhibit PDK. What seems new to me is that the ROS-mediated increase in Kv1.5 efflux channels inhibits voltage-dependent calcium entry, suppressing NFAT and leading to an even greater increase in Kv1.5 expression and derepression of caspases. While most cytotoxic chemo drugs cause mitochondrial depolarization, the link between NFAT, Kv1.5, and PDK is the comprehensive contribution of this paper. So, inhibition of PDK or NFAT are useful strategies. But what remains to be seen are just how many human cancers have these abnormalities (most of the comparisons were done with cell lines).

   However, the other unique aspect of the paper was the examination of Kv1.5 expression and staging of 30 consecutive pts with non-small cell lung cancer – the higher the Kv1.5, the lower the stage. So, the potassium efflux channels need to be studied in other cancers as well.

9. #9 Orac

   April 24, 2007

   Actually, I have discussed the science ad nauseam, along with the bioethics implications. I remain puzzled just what exactly it is that Willis wants to know that I haven’t already discussed.

   In any case, I highly doubt that as a single agent DCA or any DCA-like drug will do much better than any other single agent. Tumors are amazingly skilled (it’s a figure of speech, all you ID advocates out there!) at evolving resistance to single agents.

10. #10 Orac

    April 24, 2007

    “I know no one is pooh-poohing the paper itself � not any more at least �”

    If you’re referring to me, I never pooh-poohed the paper. (I liked the paper and found its premise intriguing.) The hype surrounding the paper and the promotion of ill-advised self-experimentation, yes. The concept that this drug is some sort of “cure” when in fact its effects in animal models are not that much more impressive than any of a number of drugs that never showed efficacy in human trials, yes. The paper and its findings itself, no.

11. #11 Jean

    April 25, 2007

    I think you are right with DCA.

    But just think to 3-bromopyruvate.This molecule has completely eradicated advancer cancer in all animals tested.

    http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15465013&dopt=Citation
    But no clinical trial is planned.

    Do you think it’s normal,regarding cancer sufferers?
    (The main reason apparently is only because this compund is not patentable)….

12. #12 Abel Pharmboy

    April 25, 2007

    Jean, I wrote about 3-bromopyruvate earlier this month. It seems less promising than DCA because it also affects ATP generation by oxidative phosphorylation as well as glycolysis. Therefore, it is only active against tumor cells that are highly, highly glycolytic. DCA has a better chance of making it to clinic because of where it acts and, as Orac points out, will likely have to be combined with other agents to avoid rapid development of resistance.