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The Chloroquine Story in Cancer Continues

Almost immediately after Pfizer and Novartis provided evidence that chloroquine (used in several chemotherapy regimes) doesn’t do what people thought, another drug company (AstraZeneca, along with coworkers at Dundee) is out with a paper suggesting what it might be doing instead. The answer, if it’s the answer, is not an obvious one: it seems to be interfering with cholesterol biosynthesis. Chloroquine’s effects on bladder cancer cell lines, it turns out, can be shut down by providing the cells with extra cholesterol, and those effects can be recapitulated by giving them statin drugs or disrupting their cholesterol synthesis pathways by RNA interference.

The mechanism seems to involve lysosomal cell death, which until recently has been a little-appreciated process. (That link takes you to a full-text review which will get you up to speed, should you desire). It’s been tricky to study, because most cell death processes eventually involve the lysosomes (and their membranes), so the fact that they have a pathway all to themselves has not always been obvious. And even with the renewed attention, the exact mechanisms are not well worked out. This latest paper might provide some clues, as well as pointing out some ways to take advantage of this process in cancer therapy. The mechanism here would seem to be the cholesterol needed in lysosomal membranes to keep them from becoming too permeable.

One specific finding of this paper is that tumors with FGFR3 mutations look as if they would respond well to cholesterol pathway disruption (via chloroquine or what have you) and mTOR inhibitors. A broader implication is that cholesterol biosynthesis itself may prove to be important in a whole range of chemotherapy regimes – and this should not be a particularly difficult idea to check in the clinic. This work should give both cell biologists and clinicians some interesting experiments to set up, with results that I look forward to. And I’ll be very happy to add this one to the list of examples the next time someone tells me about how pharma does no research of its own, etc. and very much etc.

19 comments on “The Chloroquine Story in Cancer Continues”

  1. Todd

    Knowing this, I’m curious what cholesterol levels look in patients before and during treatment. It shouldn’t be an incredibly difficult study to do, but it definitely is striking. It also suggests cholesterol’s value as a biomarker outside of heart disease.

  2. anoano

    Nice of Dundee and AZ to wait for people to publish results about Chloroquine to then put what they have in the open (I doubt they did all the experiments just now after Pfizer and Novartis released the information).

    1. Matt King in reply to anoano

      We actually submitted our paper in July, it just takes this long to come through peer review…

    2. Norbert Schtumpf in reply to anoano

      Also, the findings in the recent Pfizer-Novartis publication weren’t exactly news to people following the field closely. Anticancer effects of chloroquine that are not mediated via inhibition of autophagy are not hard to find in the literature. Likewise, the protective effect of cholesterol on lysosomal cell death has been around for a while.

      Autophagy. 2012 Feb 1;8(2):200-12. doi: 10.4161/auto.8.2.18554. Epub 2012 Feb 1.

      Chloroquine sensitizes breast cancer cells to chemotherapy independent of autophagy.

      Maycotte P1, Aryal S, Cummings CT, Thorburn J, Morgan MJ, Thorburn A.

      Chloroquine (CQ) is a 4-aminoquinoline drug used for the treatment of diverse diseases. It inhibits lysosomal acidification and therefore prevents autophagy by blocking autophagosome fusion and degradation. In cancer treatment, CQ is often used in combination with chemotherapeutic drugs and radiation because it has been shown to enhance the efficacy of tumor cell killing. Since CQ and its derivatives are the only inhibitors of autophagy that are available for use in the clinic, multiple ongoing clinical trials are currently using CQ or hydroxychloroquine (HCQ) for this purpose, either alone, or in combination with other anticancer drugs. Here we show that in the mouse breast cancer cell lines, 67NR and 4T1, autophagy is induced by the DNA damaging agent cisplatin or by drugs that selectively target autophagy regulation, the PtdIns3K inhibitor LY294002, and the mTOR inhibitor rapamycin. In combination with these drugs, CQ sensitized to these treatments, though this effect was more evident with LY294002 and rapamycin treatment. Surprisingly, however, in these experiments CQ sensitization occurred independent of autophagy inhibition, since sensitization was not mimicked by Atg12, Beclin 1 knockdown or bafilomycin treatment, and occurred even in the absence of Atg12. We therefore propose that although CQ might be helpful in combination with cancer therapeutic drugs, its sensitizing effects can occur independently of autophagy inhibition. Consequently, this possibility should be considered in the ongoing clinical trials where CQ or HCQ are used in the treatment of cancer, and caution is warranted when CQ treatment is used in cytotoxic assays in autophagy research.


      Am J Pathol. 2011 Feb;178(2):629-39. doi: 10.1016/j.ajpath.2010.10.030.

      Attenuation of the lysosomal death pathway by lysosomal cholesterol accumulation.

      Appelqvist H1, Nilsson C, Garner B, Brown AJ, Kågedal K, Ollinger K.

      In the past decade, lysosomal membrane permeabilization (LMP) has emerged as a significant component of cell death signaling. The mechanisms by which lysosomal stability is regulated are not yet fully understood, but changes in the lysosomal membrane lipid composition have been suggested to be involved. Our aim was to investigate the importance of cholesterol in the regulation of lysosomal membrane permeability and its potential impact on apoptosis. Treatment of normal human fibroblasts with U18666A, an amphiphilic drug that inhibits cholesterol transport and causes accumulation of cholesterol in lysosomes, rescued cells from lysosome-dependent cell death induced by the lysosomotropic detergent O-methyl-serine dodecylamide hydrochloride (MSDH), staurosporine (STS), or cisplatin. LMP was decreased by pretreating cells with U18666A, and there was a linear relationship between the cholesterol content of lysosomes and their resistance to permeabilization induced by MSDH. U18666A did not induce changes in expression or localization of 70-kDa heat shock proteins (Hsp70) or antiapoptotic Bcl-2 proteins known to protect the lysosomal membrane. Induction of autophagy also was excluded as a contributor to the protective mechanism. By using Chinese hamster ovary (CHO) cells with lysosomal cholesterol overload due to a mutation in the cholesterol transporting protein Niemann-Pick type C1 (NPC1), the relationship between lysosomal cholesterol accumulation and protection from lysosome-dependent cell death was confirmed. Cholesterol accumulation in lysosomes attenuates apoptosis by increasing lysosomal membrane stability.

  3. Matt King

    Hi Derek. More accurately, the mechanism is that anti-cancer therapeutics which suppress cholesterol metabolism (e.g. mTOR inhibitors in FGFR3-mutant bladder cancers) render cells more sensitive to chloroquine-induced lysosomal cell death. Chloroquine further supports this mechanism by blocking utilisation of extracellular cholesterol (by neutralising the lysosome), thereby rendering cancer cells dependent on the biosynthesis pathway to maintain cellular (and lysosomal) membrane cholesterol homeostasis (and lysosomal membrane integrity).

  4. Vader

    And now I’m wondering about the implications for statin as a prophylactic for cardiovascular disease. I think it’s fairly widely believed now that the lowering of cholesterol, per se, is probably not the mechanism, but could lysosomal cell death in plaque somehow be implicated?

    I apologize if I have just displayed stunning ignorance. I’m a physicist, not a doctor.

    1. Brian in reply to Vader

      Is it possible or sensible to look through medical records to find out if patients on chemo who are taking statins do better or worse than patients on similar chemo schedules who are not on statins? If so, has this kind of analysis ever been done?

    2. Mark Thorson in reply to Vader

      I’m pretty wary about prophylactic use of statins. There seems to be a rather strong connection to risk of developing dementia, especially with regard to the lipophilic statins. Bear in mind that the brain is a fatty organ, full of cholesterol. The source of cholesterol used for industrial purposes (cosmetics, vitamin D manufacture, etc.) is the brains and spinal cords of cattle.

      1. Derek Lowe the pitcher in reply to Mark Thorson

        That factoid about cattle reminds me of v-CJD,

  5. Robert

    Interesting article. Brings back memories of when I worked in the area of HMG-CoA reductase inhibition (earliest days of my career as a medicinal chemist — now retired). We had a consultant at the time (Marvin D. Siperstein) who postulated that cholesterol synthesis inhibition might be useful as part of an anticancer approach. His work dates back to the early 1960s (google “cholesterol cancer siperstein”). Since then, there have been periodic articles and studies looking at the issue, with some showing a favorable effect. Others have claimed either no effect or negative effects. Having been out of the game for a number of years now, I don’t know what the current thoughts are in this area.

  6. partial agonist

    All sorts of essential nutrients need to be hogged by the malignant cells, via up-regulated active transport mechanisms or by hyped-up production, so this makes sense on first principles.

    Do tumor cells use cholesterol transporters that are rarely used by non-cancer cells? If so, maybe there is a transport part of the equation as well as a biosynthesis component.

    We never can have too many useful intervention mechanisms, to avoid the drug resistance end-around,

    1. Derek Lowe the pitcher in reply to partial agonist

      I thought there is no such thing as cholesterol transporters since cholesterol is permeable to cell membranes. It is similar to less appreciated fact that there are no membrane receptors to steroid hormones, but those receptors are nuclear receptors.

      1. Ty in reply to Derek Lowe the pitcher

        I don’t know if cholesterol molecules are floating around in the blood by themselves, but they do get transported in packets called LDL, etc. Also, once in the lysosome, NPC1 is a cholesterol transporter into the cytosol. Maybe cells need faster and more controlled flux for cholesterol?

  7. HTSguy

    @…the pitcher: if that is so, what is GPR30?

    1. Derek Lowe the pitcher in reply to HTSguy

      I guess I was wrong (or more precisely how I phrased it by using the word “no”). My writing was motivated the misconception held by most people think that receptors are primarily located in the membrane, and are unable to appreciate that for most steroid hormone receptors are nuclear receptors. I remember there was a question on a practice MCAT (it was on MCAT Question of the Day, but I am too lazy to find the precise question) that most people got wrong because they thought some steroid hormone receptor was a surface receptor.

      Well, the existence of a GPCR isn’t really surprising, since it is not impossible that having a GPCR for a steroid hormone would confer some selective advantage (as GCPR signalling is faster than nuclear receptors to exert its effects).

      GPCR… I initially said “GCPR”, but the Maoist in me noticed the mistake; it is the Great Proletarian Cultural Revolution.

  8. gippgig

    Anyone test combining chloroquine with amphotericin (which acts by pulling ergosterol and to a lesser extent cholesterol out of membranes).

  9. DV Henkel-Wallace

    gippgig, I believe ergosterol is only an issue when treating diseases of fungi 🙂 (and well, if using allylamines, diseases _due to_ fungi).

    I was initially interested in the discussion of use of Chloraquine for serum cholesterol reduction, but a quick glance at the lit seemed to say that the effect does not seem to be that significant. However I’m not sure how dangerous it really is as I spent years on chloroquine prophylaxis while living in malarial regions of the globe, but perhaps Mark Thorson is right that I shall develop dementia. Like him I am somewhat concerned about the long term effects of statin prophylaxis. Seemingly harmless, but these longitudinal / geriatric studies are tricky!

  10. jonathan

    Apologies for not yet having read the details in the primary research article, but I do know that any phenotypic screen can turn up amphiphiles at typical screening concentrations, whether they are drugs or “synthetics”. Association with modulation of cholesterol mobility is common. It doesn’t mean those compounds are useful.

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