Anti-diarrhoea drug drives cancer cells to cell death
aktuelles.uni-frankfurt.de
aktuelles.uni-frankfurt.de
1. Loperamide is not unique. I don't know why these researchers have singled it out. Is it because they heard there's an opioid that doesn't get you high? It only avoids getting you high because it doesn't get into the brain. IF you deliver it to the brain to treat a brain tumor, it will get you high.
2. Patients with GBM already get a shit-ton of opioids for pain, which do cross the blood-brain barrier. Is there any reason at all to imagine that this opioid, using the same mechanism as other opioids, if delivered the area other opioids already reach, will have a different outcome?
3. I don't understand why identifying that loperamide causes cell death via ATF4 is even worth publishing. "Opioid that causes cell death uses same mechanism as other opioids that induce cell death"? Maybe I'm missing something here?
4. This was published in Autophagy. Which is another way of saying it wasn't novel enough to be published anywhere anyone reads. Which is why this is a university press release, and not a discussion by anyone else.
Edit: I don't mean this in a gatekeeping way, I honestly was just curious to hear an example of how this happens. Do people outside tech have someone in tech mention the site to them? Do they browse and just read the fraction of articles that aren't about something software related?
2. Many people have areas of interest outside of their profession.
(3 minutes of searching got me Con Kolivas, and "ck" sounds familiar so that might be him.)
edit: now I see heavyset_go has commented about the same.
I got to HN itself ... I don't know how. I delete my account about once a year to try and limit my breadcrumb trail, so I can't really look backwards and say how long I've been here, or what may have gotten me here. IIRC, it was probably due to chasing articles on startups/entrepreneurship, as I seem to think that was over-represented in my early HN reading. But it's probably been about a decade, so take that with a grain of salt.
I can't speak for the original poster but I think HN users are attracted to complexity and raw truth. Medicine and programming have a lot in common in that regard.
An example is the discovery and isolation of insulin [0]. Banting barely convinced somebody to give him lab space for 2 measly months. He then experimented with tying off the ducts of dog pancreases or removing the pancreases altogether. He realized he could keep a severely diabetic dog alive with injections from another dog's pancreatic juices. There was some drama around the subsequent purification of insulin and the Nobel Prize.
The full story almost sounds like software hacking and startup drama.
[0] https://www.sciencehistory.org/historical-profile/frederick-...
People do get high on immodium [0]. With huge doses, but still.
0: https://www.forbes.com/sites/robertglatter/2018/01/31/fda-cr...
This is wild. I had no idea! How does one even discover that?
I always worried about the diarrhea problem that would justify such a purchase, but I guess this explains it.
Question for you - is this "brain damage" that I often hear results from taking a particular drug the result of intentful downregulation of certain neuronal receptors (e.g., meth -> too much dopamine in synapse -> downregulate dopamine receptors), or is the drug actually killing brain cells/neurotoxic?
1. E.g., cocaine as a strong vasoconstrictor can directly cause cerebral ischemia, causing hypoxic damage to the brain. Acute hypoxic damage is relatively uncommon, but atrophy due to chronic hypoxia is more common. Because the bulk of atrophy in chronic coke users is in some of the most hypoxia-sensitive areas of the brain, it might be the primary mechanism of damage.
2. Opioids can do the same via respiratory depression, even though blood flow to the brain is not impaired. Chronic opioid abusers tend to dose themselves into respiratory depression - and post-mortems show their brains to have ischemic neural damage.
3. Seizures are intrinsically neurotoxic. Damage from other sources (such as above) predisposes to seizure, which can have effects on the remainder of the brain.
4. We generally suspect there is more cell death than downregulation of neuronal receptors. When we look at the basal ganglia of chronic drug users (the dopaminergic neurons involved in the 'reward' circuit), we find atrophy, suggesting actual neuronal loss.
4b. What type of regulatory (e.g., down regulation) change occurs depends on the drug. Some drugs imitate an existing signal (e.g., opioids), so downregulation would be the homeostatic response. Coke and ecstasy stimulate dopamine release and serotonin release respectively, so we can expect a downregulation in receptors, but we may also see an upregulation in the transmitting cell in response to increased "release this signal" demands. Even that depends on the drug in question - amphetamine prompts dopamine release, so the releasing cell runs low and may increase storage levels. Coke prevents reuptake of dopamine, so active concentrations are up but the releasing cell doesn't see a change in its internal dopamine storage levels. Alcohol, on the other hand, is a glutamate blocker, which increases sensitivity to glutamate signals.
5. Opioids have been shown to be directly neurotoxic. It's unclear on whether this is a significant contributor above and beyond the respiratory depression in real life settings. In the lab, though, heroin, heroin metabolites (6-mono-acetyl morphine and morphine), fentanyl, have all been shown to be directly neurotoxic, though not all equivalently so.
6. MDMA is also shown to be directly neurotoxic, and (at least in a rat model) MDMA metabolites are more neurotoxic than MDMA itself.
7. Adulterants, through their toxic effects, also directly fuck up tissues. We see increased activation of cell-suicide pathways when heroin is induced, but we also see that the degree of activation is inversely proportional to the purity of the heroin.
I can probably go on for a while. I'm sorry if the above is a bit rambly, I didn't really stop and outline it as an essay. I hope that sheds some light, though.
I took a Biopsychology of Drugs class in college and found it fascinating. Do you know of any good (text)books on the subject?
edit: actually only sections of it are available online. The book isn't hard to find, though.
First, what's your opinion on alpha lipolic acid and MDMA neurotoxicity? Given its popularity and its rising use it'd be great to have a simple way to prevent MDMA-induced neurotoxicity, and ALA is pretty widely available and relatively cheap, but there doesn't seem to have been much research on its use in humans.
And second, how bad are the neurotoxic effects of these drugs? The internet has anecdotes in all directions, from people claiming serious issues from only a few low doses of (cocaine/opiates/MDMA/etc) to people claiming no issues whatsoever from significantly more extensive use at higher doses. I realize that every person is very different, and this is a sort of "how long is a piece of string" question, but what is your personal feeling? More and more college students are experimenting with MDMA and cocaine especially - do you think a few low doses cause serious permanent damage, or do you think the neurotoxicity wouldn't be serious enough for concern, or somewhere in the middle?
1. We have a shitty understanding of chronic MDMA toxicity in human beings. Rat and primate models of MDMA differ in the primarily damaged pathways (non-human primates it has a pronounced effect on serotonergic cells; in rats it has a pronounced effect on dopaminergic cells). It's also a "dirty" drug, in that it hits a number of different receptor types - which means its downstream effects are going to be in a bunch of different pathways. And even those receptors are dirty - the serotonin 2A receptor that MDMA hits is involved in a wide variety of cellular functions.
Beyond that, we do know that a number of MDMA metabolites are directly capable of forming free radicals (such as quinone and thioester compounds), and oxidative damage is a serious problem in any cell tissue, but especially in brain, where cell replacement is generally too slow to matter. In rats, we've directly observed the production of compounds due to free radical exposure after MDMA injection, strongly suggesting that that is a mechanism of damage in the brain. (We also find that in rats that over-express copper superoxide dismutase, an antioxidant mechanism, there's resistance to MDMA toxicity.)
MDMA has also been shown to induce neuronal apoptosis that is inhibited by serotonin2A blockage, but... serotonin2A has such a wide variety of effects, I won't even guess as to what the direct pathway of that interaction is, much less how to block it.
ALA is a fine anti-oxidant. However, I wouldn't put my eggs in that basket, for the following reasons:
1. Anti-oxidants mitigate the damage of oxidizers, the way that cops on the street mitigate street crime. Some of the cops are gonna do stuff you don't like (we also depend on free radical mechanisms for destroying nascent cancer cells and bacteria - ALA doesn't discriminate); some of the criminals are going to slip by anyway (oxidizing damage will continue to accrue, if slower).
2. ALA to my knowledge has been studied to the extent of "we gave rats ALA and MDMA for two weeks, and the ALA group seemed to have less grossly visible brain damage." I expect diminished brain function long before we have significantly detectable anatomic changes. (There's also a tiny crap study or two showing it didn't have any protective benefit at all, but I tend not to lean on 'tiny crap studies'.)
3. ALA as a protective mechanism relies on oxidation being the main mechanism of damage. It might be; we don't know. If the main mechanism of damage is serotonin-pathway-driven apoptosis, or serotonin-pathway-driven neuronal structural change, or dopaminergic-pathway-etc. then ALA will not play a meaningful role in preventing long-term damage. It would just be hitting entirely the wrong mechanism.
Bottom-lining it: if a patient said "I'm definitely going to do MDMA and you can't talk me out of it, should I take ALA to try and mitigate the harm?" I'd say yes, sure, it's not likely to do meaningful harm if you're not on it for years (or don't have a disease that causes you to have an impaired oxidative immune function.) If a patient said, "I'm curious about MDMA but only if I can do it safely, can I do it if I take it with ALA?" my answer would have to be, "There's no good evidence that ALA is protective, and several mechanisms of damage besides the one that ALA acts on. If you're not comfortable doing MDMA without ALA, I wouldn't do it with ALA."
As to how bad the effects are:
No one really knows. My professional opinion is that most of the low-grade effects are likely to be behavioral/psychiatric, and due to our generally poor ability to quantify and track psychiatric symptoms, and the social confounders that accompany drug use, we're unlikely to have any good idea about what their adverse effects are. My most honest answer is a profession of ignorance.
My personal opinion is that, assuming someone is healthy and doesn't have any particular underlying risk factor, almost none of these drugs are going to do meaningful neurological harm if done a couple of times. My bigger concern lies in (a) people with underlying psychiatric risk factors, (b) in combinations (alcohol + coke + etc.), and (c) non-neurological effects.
Opioids can absolutely kill you stone dead the first time you take them - but not from its neurotoxic effect. Given the spate of fentanyl being cut into the street drugs these days, and unregulated dosing, it's the one drug I'd tell people to stay away from like their life depends on it. Though obviously if you're taking a prescription pill one time at low dose, it's a different story.
Is there more information or sources you can share on that? I'm interested because 1) I'm close to someone who suffers from both alcoholism and an eating disorder, and 2) I worry about excess amounts of glutamate on the brain.
There's a lot to go through.
The idea that there is or ever will be a "cancer cure" is a popular misconception. There are hundreds--if not thousands--of cancer variants. The more targeted the treatments are, the fewer patients any one treatment can help. It takes a decade or more and hundreds of millions of dollars for each targeted treatment. There's still an enormous need for broad-spectrum treatments in addition to targeted ones.
It's conceptually similar to the mRNA covid vaccine. The framework has been figured out and tested, then it's only a matter of days to create the vaccine once you have the target genetic signature.
[1] https://www.sciencedirect.com/science/article/abs/pii/S07356...
"Morphine is protective against doxorubicin-induced cardiotoxicity in rat" https://pubmed.ncbi.nlm.nih.gov/17988779/
"Morphine enhances doxorubicin-induced cardiotoxicity in the rat" https://pubmed.ncbi.nlm.nih.gov/24531975/
Probably because it's what they were studying which led to the analysis? A drug doesn't have to be unique to be important in understanding side effects...or off-label use if that's how you want to think of it.
Getting funding to study all of them at once is more challenging, so it shouldn't be a surprise that it's constrained to one.
It's like a study finding that "opioid X" gets you high via mu-opioid receptors. It's not really a finding; it's the null hypothesis.
More likely it's a liability check. The null hypothesis characterization is incidental.
The grand (and still largely unsolved) challenge is not killing them, it‘s sparing the rest of the body while doing so.
https://www.youtube.com/channel/UCBbnbBWJtwsf0jLGUwX5Q3g
It's a wild and highly resistant world we don't know nearly enough about.
I think this paper's intentions was merely to understand it all better (which is a great thing0, while most people are taking issue, or at least providing much needed context, with an article suggesting some utility in fighting cancer.
I think that it's possible but unlikely that loperamide is having a unique effect, because (a) they've shown that it's operating via the ATF4 mechanism, which is the same mechanism we see in other opioids (and multiple other drugs), and (b) loperamide's activity has generally been pretty well characterized and it doesn't really stand out (it's by no means a new drug - I remember taking it as a generic twenty years ago.)
I'll admit it's possible in the broad sense because ATF4 isn't some super-specific pathway. It's a stress response signal. So while I think (b) above makes a unique mechanism unlikely, (a) by itself isn't a slam-dunk - there are a lot of stress signals that induce cell death when they get amped up enough, and can inhibit cell death if blocked off.
just playing devil's advocate for the paper -- I happen to agree with witty's original comment thesis (except for the argument based on the authority of the journal it was published in)
Where he reviews a paper that shows in 2 males, loperamide lead to cardiac arrhythmia and death. The doses they took arent clear but it's in the heroic range. (50x-100x 'normal')
If you're desperate to get off opiates and unwilling to do suboxone or methadone, I'm not sure a doctor, if you can afford one, would even mention loperamide.
From the paper:
> We previously screened a library containing autophagy-inducing compounds and identified the Food and Drug Administration-approved drug loperamide (LOP) as potent inducer of ACD in the glioblastoma multiforme (GBM) cell line MZ-54 [7]
7: Zielke S, Meyer N, Mari M, et al. Loperamide, pimozide, and STF-62247 trigger autophagy-dependent cell death in glioblastoma cells. Cell Death Dis. 2018;9:994
I feel that there should be a special name for this kind of publications they are so common: https://www.ncbi.nlm.nih.gov/pmc/?term=cancer+cells+in+vitro
Loperamide is an opiate that acts locally (and probably via the bloodstream too) on the intestines, but doesn’t get into the brain, so you get the anti-diarrhea effects without pain relief/getting high/slow breathing of opiates.
Some randos on the internet believe that you could consume a bottle of loperamide and overcome that inability to get into the brain. In theory that’s true (since the brain barrier is actively pumping it back out and there’s gotta be a limit to that rejection), but I don’t think it’s worked out in practice other than causing massive constipation.
The article touches on this:
> In future studies it has to be explored, for example, how loperamide can be transported into the brain and cross the blood-brain barrier. > Nanoparticles might be a feasible option.
But it remains to be seen what opiate-like effects it would have on the brain if it got through.
For a short-term treatment, this could be managed/mitigated. Mechanically (this machine will breathe for you while we knock out your drive to breathe) or chemically: an opiate-antagonist (naloxone infusion or naltrexone tablets). Whether this would counteract the effect of loperamide remains to be seen.
I also wonder what made loperamide special or if opiates in general would have the same effect. It would be interesting to see if long-term opiate users get this particular tumour less.
It's a medication that gets stolen by drug users which is a bit frustrating if it's not working for them.
BNF and Department of Health (England) don't describe addiction to loperamide, but do describe its use as an adjunctive treatment for people trying to come off opioids, which suggests it's not that problematic: https://bnf.nice.org.uk/treatment-summary/substance-dependen...
https://assets.publishing.service.gov.uk/government/uploads/...
> Prescribing symptomatically can reduce some of the physical effects of withdrawal. There is no systematic evidence that any of these medicines work to improve outcome but they may be useful for the clinician in situations where it is not possible to prescribe effective opioid substitution. Particular care is needed concerning the risks of polypharmacy and ensuring appropriate supervision and support in such cases.
> •Diarrhoea – loperamide 4mg immediately followed by 2mg after each loose stool for up to five days; usual dose 6-8mg daily, maximum 16mg daily.
As someone who suffers from IBS and takes loperamide regularly, while its not necessarily an addiction, I see forums of people (especially on /r/ibs) saying that it causes a dependency. I saw posts where people kept upping the dose until it got to a point where it doesnt work anymore and you would have to increasingly take larger amounts to have the same effect. Heck some take as many as 3 after every meal. I cant imagine doing that.
I try to avoid doing this and luckily I can get away with one every few days but I dread the day I have to be in that situation.
One thing I noticed is that - it gives me incredible mental boost a day after taking it. It just makes me feel normal and that to me is a 'boost'.
I've read that loperamide doesn't just quell bowel problems with opioid withdrawal, but that it lessens cognitive symptoms, as well.
Sounds like there might be some active metabolites, or that peripheral opioid receptor activation can affect cognition.
I'm not sure why this happened, but my suspicion is that while hospitalized I was infected by MRSA, and to try to get rid of it they were dumping some of the more toxic anti-bacterials into me to get rid of the MRSA (which took a year and a half to get rid of.)
Honestly the whole thing about people abusing it and FDA clamping down works against normal people who are genuinely using it.
40, 38, 36, ... -> freedom
If a drug is metabolized in the liver then instead of ingesting a bottle of pills (most likely not safe, certainly not recommended), the way to bypass the liver is to use suppositories. Again, safety-wise it is not a sensible thing to do.
Or transdermal or intranasal or sublingual or through the lungs or ...
But I think the issue here is that the blood-brain barrier is actively pumping it back out, not immediate liver metabolism.
I’ve updated my post a bit. I probably shouldn’t have said “locally” since it gets into the bloodstream and should have an effect from the other side too.
Blood-brain barrier is another obstacle to cross. Quinidine taken with loperamide blocks transport protein P-glycoprotein and causing loperamide to have opioid like effects in the brain.
Edit: I know the article is more than that, but I hope that this research can get more attention and they can publish a paper with more results.
It costs > 1 billion dollars to bring a drug to market and put it through clinical trials. This means most off-label drug uses like this will never reach cancer patients because the drug patent will expire leaving no backer that can make back the cost (even if the cost is less than a billion for off-label drug use). This situation is similar for most complementary and alternative medicine: there are many compounds shown to be anti-cancerous even beyond test tubes in mouse models and initial studies in humans. But there is nobody able to take them through clinical trials.
> ...several studies have shown the induction of autophagic cell death (ACD) by natural compounds or Food and Drug Administration-approved drugs in multiple cancer cell lines. Among these, glioblastomas seem to be particularly vulnerable to the induction of ACD, thus highlighting ACD induction in the context of glioblastoma as an attractive therapeutic strategy to selectively trigger cancer cell death.
Glioblastoma [2], "also known as glioblastoma multiforme (GBM), is the most aggressive type of cancer that begins within the brain." Autophagy [3] "is the natural, regulated mechanism of the cell that removes unnecessary or dysfunctional components."
[1] https://www.tandfonline.com/doi/full/10.1080/15548627.2020.1...
Consider that new drugs cost 1 to 2 billion to come to market, needing extensive tests in petri dishes, cells, animals, young male human volunteers, and then mass drug trials. It is very slow and challenging work to find new drug molecules that are both safe and effective.
But, there are hundreds of disorders, we can't test all safe drugs for effective actions against all disorders. If we have great repurposing, probably through mass automation of tests and computer modeling, then we can make a gold mine of already existing gold nuggets.
This was true of dexamethasone for covid, seems true of loperamide, and could be true for dozens of other compounds already in our pharmacy and medicine cabinet. This is the biggest opportunity in drug development, and HN has technical, computational talent, so consider this area!!!
If Loperamide alone (as opposed to other opiods) ends up being useful for this treatment in humans, I wonder what the impact will be on the price or OTC availability, if any - possibly nil because a special method of application might be required (nanoparticles)? Has something similar to this happened previously with another OTC drug and actually made it to market?
The research group led by Dr Sjoerd van Wijk from the Institute of Experimental Cancer Research in Paediatrics at Goethe University already two years ago found evidence indicating that the anti-diarrhoea drug loperamide could be used to induce cell death in glioblastoma cell lines. They have now deciphered its mechanism of action and, in doing so, are opening new avenues for the development of novel treatment strategies.
AKA, drug belonging to [drug class] that kills [neuronal tissue] will also kill [bad neuronal tissue] through same mechanism as [general drug class].
The key question is "if putting a shit-ton of opioids (which already cross into the brain) in cancer patients doesn't already meaningfully treat this condition, why do we imagine that delivering the same class of drug past the blood-brain barrier suddenly will?"
Having worked in a breast cancer lab once upon a time, I can tell you: because run-of-the-mill cell biology doesn't get grant funding if you don't attach "early cancer diagnostics" or "potential cancer treatment" to the grant application.
It appears that as they say now that they have identified the specific mechanism of cell death that can start looking at ways to target the tumor cells without flooding the rest of the brain with loperamide or other opiates. It will be a good trick but better than the other (non) options for glioblastoma.
Isn't the low-tech option simply to substitute loperamide for heroin, an opiate that's extremely effective at crossing the blood-brain barrier?
How significant is this? I'm sure there are a lot of things that will kill a cancer cell in a petri dish.