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new med series

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For awhile now I have been meaning to write something a little more relevant than dishing out details of my crzy energiser bunny life that I lead in the suburbs. Of course that would mean ‘work’. As in prep on my part. I mean, I can write that I saw a wolf in the woods from my backyard and you’d accept it, but can’t say the same for stuff that is a litle more scientific or exact now can I? Heh, you’d probably laugh, but you’d also call me a quack and what not. In any case, as I was scrambling occasionally last month to get some posts going everyday, I reached out to dear friends in the blogworld to help me out. Schmetterling, is a self-proclaimed nerd geek. Apart from that binding factor, there’s Madras and I am told even Goodshe (yay) links. Then again, both of us are fun girls (yes, am calling myself a girl and we are all going to stick to that!), and since she’s in the research field in medicine, I just love her even more. 

I’d asked her if she’d do a writeup for me on what she was currently working on, and she chose the subject and broke it down for us who don’t ahve anything to do with research or medicine. Apart from researching if tylenol or advil works better I mean. She wrote one within 24 hours. It was so good that I didn’t want to just let it flow into this assembly line I was churning out every day in October. Then I was celebrating my successful run so much that it slipped my mind completely till last week. 
Now that she and I are in love with what we’ve conjured up, we plan to make this a feature. Every 1st and 3rd Wednesday of the month, I will post in this series. It will be medico related, no techy stuff for me, and I along with whoever else is authoring will hope to make some of the mysteries seem less daunting and approachable to the rest of us. Researchers and what they do surely needs to reach a wider audience than just journals. 
If anyone wants to contribute or have suggestions, please email me at kowthas02 AT gmail.com or leave a comment and we’ll be on our way. 
Here we go: 
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When Rads asked me to write a guest post, in response to a comment on her XDRTB post, of course I jumped up and down with enthusiasm. In honor of October being Breast Cancer Awareness Month, the nerds in us sighed contentedly at our choice of topic:    

The Multiple Faces of Multi-Drug Resistant(MDR) Pumps

MDR Pumps are a cellular mechanism that exist to kick toxins out. These pumps were first discovered in cancer cell membranes, where they were found in abundance and were later attributed to be the major reason for failure or resistance to chemotherapy. Much probing into life in general led scientists to discover MDR pumps in organisms as little as marine worms. So what are these mysterious MDR pumps?

 Figure from Figarello et al. (2003) –     

Molecular Pharmacology of Chemo-Resistant Leishmania,
AVFT v.22 n.1 Caracas ene. 2003                
If you’re from Madras(or pretty much any other place!), you know all about those water pumps that carry ground water all the way up to a tank in your house, and it was perhaps your responsibility (or the watchman in your flat’s responsibility) to switch the ‘motor’ on every morning to fill the water tank. MDR pumps, like any other pump, use cellular energy pockets (stored as Adenosine Tri Phosphate or ATP) to carry certain substances across the membrane, effectively “jettisoning” them back into the blood stream(or the extra-cellular space) from the cell. These cellular energy pockets are made from various processes involving oxygen, and the break down of the food you ingest. These MDR pumps are made from certain specific proteins and tend to line the cell membranes. The cell membrane has very high integrity with respect to substances it allows to pass through it – and it has specific “influx” transporter pumps for glucose, sodium and all other essentials of life. If a substance then “tricks” the membrane into allowing it inside the cell, MDR pumps recognize the breach, bind this substance and kick it right back out where it belongs(or not!). These pumps line all the major organs of the body, where the organ would potentially come into contact with a world outside it’s own micro-homeostatic environment – like the liver, the brain, the breast, etc. However, the MDR pumps don’t always work towards the well-being of the organism. They just do their jobs and seldom differentiate between a normal cell and a cancerous cell.                                                                                                                                               
Chemotherapy, the treatment of cancer with chemical drugs, has been one of the major forms of cancer therapy. Chemotherapy drugs are usually cell-death inducers that try and trick the cell membrane into believing that they are “protein-like substances”. The MDR-pumps however, are just doing their jobs, by recognizing these cell-killing molecules and effluxing them out. This may seem to be a victory for the cell, but for the patient afflicted by cancer – not so much. To add salt to the wound, cancer cells seem to over-express MDR pumps arbitrarily, making patients and doctors helplessly look for other treatment options.
                                            
Bacteria are known to be notorious for their multi-drug resistance pumps. So much so, that there was a debate on how dilute hospital sanitizers(biocides) should be, to ideally kill bacteria and not cause them to become resistant. Evolution and Darwin’s adaptation can be quite the pain in all the wrong places, because the wrong side of dilution in hospital biocides could cause the bacteria to develop strains that express more MDR pumps, effectively making them biocide-resistant – and then going on to climb into the throat and tonsils of patients, rendering them resistant to medication.    

Ever had a common cold once too often, and your doctor switched antibiotics the second time around you went back to see him? MDR efflux pumps in the bacteria take it upon themselves to find all these antibiotics the body forces inside them and throw them back into your body, effectively conferring you with more phlegm as they wallow arround in your bronchi and tonsils.

All this talk? Researchers are trying to develop more and more drugs for chemotherapy, that are more hydrophobic(water-hating), that penetrate in to the cell through different uptake mechanisms, instead of just tricking the cell membrane. A promising approach has been by modulating the transit times of these drugs at the membrane entry point. By lowering the layover, and carrying out transport faster through the membrane – the transport process itself seems to pass the notice of the MDR pump, thereby showing positive results.
With protein structures being discovered and crystallized, more and more parts of the MDR pump (which is made up of many many proteins) are being characterized- scientists are coming up with more ideas to deter the function of component proteins, thereby rendering the pump itself quite useless. Another approach has been to pick out the mother gene of the MDR pump, and silence its expression, thereby fighting the pump at the genetic level. Blocking of the MDR pump by providing it with “pseudo” substrates is another approach in clinical trials as I write.

The dirt on why cancer is a deadlier diesease (than I thought it was before) is becoming clearer as I write this – it uses the body’s own cellular mechanisms to grow, spread and flourish. The impairment of these very fundamental cellular mechanisms come at the cost of impeding the body’s normal function, as is evident by the ugly side-effects of any form of chemotherapy. Cancer therapy has proven to be a wide spectrum of possibilities with multivarious targets, ifs and buts included – and even as scientists continue to scour the bottom of the ocean for slugs and sea organisms to study how nature effectively uses MDR protein pumps, who will win this battle of Nature Vs. Nature?

***
Interesting? 
Rads
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9 replies on “new med series”
  1. says: Priya

    Yes! Very interesting and informative. Good job you guys.
    Schmetterling, your write up was great, you managed to break it down to a level that was understandable to everyone. Here’s a video I saw a while back, giving another perspective on how cancer works. Nature vs Nature it is, sadly!

  3. says: rads

    hehe, thanks both of you 🙂

    Priya, interesting video, and what a fine speaker and prodigy?! TED’s an amazing place, it hosts a great collection of fine speakers in such diverse fields. It’s like brainy non-arty youtube 😀

    max: I love video games too, but I didn’t do comp sci 😛

  5. says: some body

    nice post, though in the beginning i went ‘what the …!’

    “Bacteria are known to be notorious for their multi-drug resistance pumps. So much so, that there was a debate on how dilute hospital sanitizers(biocides) should be, to ideally kill bacteria and not cause them to become resistant. Evolution and Darwin’s adaptation can be quite the pain in all the wrong places, because the wrong side of dilution in hospital biocides could cause the bacteria to develop strains that express more MDR pumps, effectively making them biocide-resistant – and then going on to climb into the throat and tonsils of patients, rendering them resistant to medication. ”

    this would be similar to how the human body reacts to a low dose or alternative strain of the virus in vaccinations – for example, the polio vaccine (low grade virus) or the small pox vaccine (cow-pox virus). right?

    “To add salt to the wound, cancer cells seem to over-express MDR pumps arbitrarily, making patients and doctors helplessly look for other treatment options.”

    is it very difficult to mask the cancer drugs very much like a trojan horse so the mdrs fail to recognize the threat (to the cancerous cells)? maybe we could literally encapsulate the drug (i.e., make a micro-capsule) which then slips past the defenses … on the other hand, how do you ensure that this does not kill the good cells?

    – s.b.

  7. says: Schmetterling

    @somebody: all good questions 😛 in any case, the vaccines do indeed work that way – including the ubiquitous flu vaccines, wherein they give you a low dose of the flu strain going around this season, hoping you’ll pick up resistance.
    masking cancer drugs is basically what a lot of research focuses on, but there are only certain ways to mask them so they’ll get through a membrane and into the cell. the finite options available to encapsulate the drug led to trying to speed up the entry process; a reason why chemotherapy has the kind of horrible side effects i would assume is because it’s not extremely specific – it kills a good many good cells along with the bad cells, owing to insufficient targeting mechanisms.

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