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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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« An Alzheimer's Update: Amyloid Lives? | Main | Bert Vogelstein on Cancer Drugs and Cancer Screening »

July 27, 2012

Antipsychotic Drugs Against Cancer?

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Posted by Derek

One of the hazards of medicinal chemistry - or should I say, one of the hazards of long experience in medicinal chemistry - is that you start to think that you know more than you do. Specifically, after a few years and a few projects, you've seen plenty of different compounds and their activities (or lack thereof). Human brains categorize things and seek patterns, so it's only natural that you develop a mental map of the chemical space you've encountered. Problem is, any such map has to be incomplete, grievously incomplete, and if you start making too many decisions based on it (rather than on actual data), you can miss out on some very useful things.

Here's a case in point: an assay against cancer stem cells, which have been a hot research area for some time now. It may well be that some classes of tumor are initiated and then driven by such cells, in which case killing them off or inactivating them would be a very good thing indeed. This was an interesting assay, because it included control stem cells to try to differentiate between compounds that would have an effect on the neoplasm-derived cells while leaving the normal ones alone.

And what did they find? Thioridiazine is what - an old-fashioned phenothiazine antipsychotic drug. For reasons unknown, it's active against these cancer stem cells. When the authors did follow-up screening, two other compounds of this class also showed up active: fluphenazine and prochlorperazine, so I'd certainly say that this is real.

And it appears that it might actually be the compounds' activity against dopamine receptors that drives this assay. The authors found that there's a range of dopamine receptor expression in such cells, and that this correlates with the activity of the phenothiazine compounds. That's quite interesting, but it complicates life quite a bit for running assays:

Our observations of differential DR expression between normal and neoplastic patient samples strongly suggest human CSCs are heterogeneous and drug targeting should be based on molecular pathways instead of surrogate phenotypic markers.

Working out molecular pathways is hard; a lot more progress might be made at this stage of the game by running phenotypic assays - but not if they're against a heterogeneous cell population. That way lies madness.

Interesting, the phenothiazines had been reported to show some anti-cancer effects, and schizophrenic patients receiving such drugs had been reported to show lower incidences of some forms of cancer. These latest observations might well be the link between all these things, and seem to represent the only tractable small-molecule approach (so far) targeting human cancer stem cells.

But you have to cast your net wide to find such things. Dopamine receptors aren't the most obvious thing to suspect here, and ancient antipsychotics aren't the most obvious chemical matter to screen. Drop your preconceptions at the door, is my advice.

Comments (22) + TrackBacks (0) | Category: Cancer | Drug Assays | The Central Nervous System


1. anon2 on July 27, 2012 8:41 AM writes...

Traditional approach of "screening" wins again.

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2. simpl on July 27, 2012 8:45 AM writes...

Are there any that don't cross the blood-brain barrier? Most of the side-effects seem to be in the brain, but the stem cells mentioned are in the blood.

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3. luysii on July 27, 2012 9:25 AM writes...

This sort of thing is just why developing drugs is so hard. Even when we think we know just what they're doing and why they're doing it, we don't.

Tricyclic antidepressants are another class of psychiatric drugs, well studied even down to their molecular interactions with their target proteins. One tricyclic ,Amitriptyline (Elavil) nonetheless may have a therapeutic effect in cystic fibrosis, by lowering lung ceramide (a second messenger) levels. Where does neurotransmitter reuptake (the classic action of the tricyclics) come into this? It doesn't and that's just the point.

For more details-- see

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4. NoDrugsNoJobs on July 27, 2012 9:38 AM writes...

#2 Simpl - Good idea! A challenge (and opportunity) is the fact that this class of drugs was optimized for CNS activity so the more well known ones probably all have pretty good penetration since they need to in order to work. a starting point might be to get a library of SAR analogues and screen both at the primary target as well as pk (including brain concentrations). Let's start a company!

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5. HTSguy on July 27, 2012 10:48 AM writes...

Oncology is not my field, but is anyone surprised by the extremely steep concentration:effect curves - they look to be all or nothing. In my experience, this is often a cause for caution.

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6. Anonymous on July 27, 2012 10:56 AM writes...

I'm not sure that testing only against homogeneous cell cultures is best. If tumors themselves aren't particularly homogeneous perhaps we should try testing against heterogeneous cultures. It would be exceedingly difficult to work out the mechanism of action of anything found, but I could easily imagine that interrupting processes between the different cell types within a tumor proving useful. That's something we probably wouldn't pick up on only testing homogeneous cultures.

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7. LittleGreenPills on July 27, 2012 11:09 AM writes...

Does a homogeneous cancer cell population even exist?

All of the studies that I have seen found that cancer cells are much more heterogeneous than thought, even when selecting for common pathways (ER positive breast cancer). You can observe this in vitro when high doses of your compound never quite kill all of the cells, and in the clinic when relapse occurs with the cancer no longer responding to the previous treatment.

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8. Anonymous on July 27, 2012 11:19 AM writes...

I remember that phenothiazine derivatives have been identified as weak antiandrogens (Bisson et al., PNAS, 2007).

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9. NoDrugsNoJobs on July 27, 2012 11:19 AM writes...

Ha, a little googling and cancer is cured! To your fine point #2 Simpl, there are peripheral dopamine antagonists such as Domperidone, etc. It would be interesting to see if they have anticancer effects on the stem cell population.

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10. simpl on July 27, 2012 12:20 PM writes...

@9. NoDrugsNoJobs - Thanks for the lead.
I'm also thinking that thioridazine was taken off the market for agranulocytosis occuring after prolonged use. This may be another way of saying that it removes some healthy stem cells too.

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11. Cellbio on July 27, 2012 12:28 PM writes...


I thought one of the curves has that too steep look that worries me too, others look OK. However, fairly high doses which worries me. Screened millions of wells in phenotypic assays, found screening at 10 uM to be useless with all the noise that came out as hits and had the table top drop curves that did not look like a target interaction.

Also found that purified cell populations were not better for screening or subsequent analysis.

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12. MoMo on July 27, 2012 1:00 PM writes...

Ye Gods! More of the same! These compounds mangle membranes like nobody's business and have been the subject of several companies who have been erased by the sands of time.

Check out CombinatoRxs patents for a brief glimpse at their activity.

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13. Skeptical on July 27, 2012 1:14 PM writes...

These tricyclic amphipathic cations such as the phenothiazines show up all the time to be a new uM lead for target X. Some believe these effects are due to non-specific interactions with membranes (altering the membrane biophysics/dislodging a protein). They just insert into the phospholipid bilater. These effects probably are not related to a discreet target interaction. Check out Carfagna and Muhoberac, 1993, Mol Pharm. This is not a new idea.

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14. Skeptical on July 27, 2012 1:14 PM writes...

These tricyclic amphipathic cations such as the phenothiazines show up all the time to be a new uM lead for target X. Some believe these effects are due to non-specific interactions with membranes (altering the membrane biophysics/dislodging a protein). They just insert into the phospholipid bilater. These effects probably are not related to a discreet target interaction. Check out Carfagna and Muhoberac, 1993, Mol Pharm. This is not a new idea.

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15. milkshake on July 27, 2012 2:37 PM writes...

One simple way to remove the CNS permeability would be to use the Certizine carboxylic acid sidechain trick

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16. NoDrugsNoJobs on July 27, 2012 3:55 PM writes...

It seems the various effects in different cell lines would point away from a non-specific effect.

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17. xmedkmst on July 27, 2012 4:15 PM writes...

This brings back bad memories of screening campaigns gone bad. It seems that with a few phenothiazines and a couple of different rhodanines you can get screening results that will warm any biologist's heart. They get the MBA guys all heated up and then the chemists are on the hook to provide a timeline to the clinic.

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18. Pharmaheretic on July 27, 2012 5:00 PM writes...

"Pfizer has one of the largest marketing budgets in the world. One can only imagine how much they spend on consultants to strategically develop their online marketing campaigns. The email from our tipster read, in its entirety: "Our friends at Pfizer offer a fine product called Rimadyl. In order to market this product to vet clinics and canine lovers everywhere, they suggest you visit their website"

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19. Mutatis Mutandis on July 27, 2012 5:32 PM writes...

There is no such thing as a homogeneous cell population, even if cells are genetically identical, if only because of signalling states and cell cycle. The more relevant, the more inhomogeneous. But the technologies to measure single cells and separate them into populations do exist: High content screening and flow cytometry. Not for millions of wells, but on a scale to help figure out MoA or guide LO, yes.
Bulk molecular measurements on cells are always tricky. If you measure increases of protein A and B in a Well, that does not prove that there is any Cell in which both A and B are increased.

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20. Ethan Perlstein (@eperlste) on July 27, 2012 7:26 PM writes...

A friend forwarded me this paper a month or two ago. I'm not convinced that the effect is DR-dependent, rather I think this could be membrane-based polypharmacology at work -- again!

Derek blogged about my lab's paper on Zoloft accumulation in yeast back in May, and a recent Neuron paper from Teja Gromer's lab shows antipsychotic drug accumulation in synaptic vesicles, in accordance with the weak base model first proposed by Rapoport & Sulzer in the mid-90s.

Cationic amphipaths strike again!

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21. Kaleberg on July 28, 2012 11:12 PM writes...

This note reminded me that I had seen an article some years back saying that schizophrenics had lower cancer rates due to various gene expression effects. I can't remember where I saw this, but a quick search got me a 2007 Science News article, Why People With Schizophrenia Have Lower Rates Of Cancer: New Clues. (

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22. David Borhani on July 29, 2012 7:56 PM writes...

Dose-response curves look very steep, probably even too steep for action via a DR dimer (see, e.g., ). Others have commented on this, I see. Ideas on what else may be going on, other than "polypharmacology"?

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