Target Mitochondrion – Exciting New Drugs on the Horizon The Light at the End of the Tunnel Is Getting Brighter
Several recent research articles have opened up exciting new opportunities in the treatment of CLL. These feature new small molecule drugs that take an entirely different approach to targeting CLL cells. These are not your father's chemotherapy drugs, most of which target the nuclear DNA of cells, with the unavoidable risk of mutagenicity. Nor are they bulky (and expensive!) monoclonal antibodies like Rituxan and Campath, which have a hard time dealing with bulky lymph nodes and bone marrow - to some degree because it is hard for these "fat ladies" to get into all the nooks and crannies of bone marrow and lymph nodes. Small molecules like the ones we discuss below are more likely to reach all these hard-to-reach parts. Here is the best part: in this new approach to treating CLL, it makes no difference if you are IgVH mutated or unmutated, CD38 positive or not, chemo-naïve or have been through the wars with every chemotherapy drug known to man. In fact, there are some indications that heavily pretreated and late Rai stage patients may respond better to this approach!
Stay with me on this story folks. These drugs have really caught the attention of some terrific researchers and they are on a fast track at a number of top notch research establishments (Dana Farber, M. D. Anderson and the Mayo Clinic, to name a few). My bet is that you will see at least a few of these in action in 2005 in several clinical trials. Some of these drugs are well known for other uses, some are quite old and even off-patent. Which brings us to the tricky question, who is going to push for their development? Money makes the world go around, we are all sufficiently grown up to know that. My worry is that without the backing of deep-pockets pharmaceutical companies with a vested interest, some of these drugs may die for lack of backing and never make it from the lab to the patient's bed side. That is where we come in, if we are smart about it and can mobilize as a group. After all we have more "skin" in this game than anyone else, right? First I have to give you a thumbnail sketch of the science. Not to worry, it is not that hard to understand and I will leave out all the details that you don't have to know, sort of give you the cartoon version. ........
A Long, Long Time Ago…
The story starts a long, long time ago, say a few billion years ago, give or take. Life consisted of very primitive single cells, barely managing to make a go of it. Then, some enterprising cell made a pact of cooperation with another tiny piece of life called a mitochondrion (plural, mitochondria). The deal was this. The mitochondria could live inside the cell. In addition to rent-free accommodations, the cell would also provide food, air, garbage removal and help when the mitochondria decides to have babies. The ultimate bed & breakfast, and lunch and dinner and ob-gyn help. In return, the mitochondrion would have to do the one thing it had figured out how to do very well, convert food to energy, make sure the cell has enough energy to do all its household chores, as well as be fed well enough to have babies itself when it wants to. Thus began the most successful partnership ever struck on this earth. And since that first cell which made this deal was a good mother, every time it had a baby it made sure the baby also had its own resident baby mitochondria. Since cells without mitochondria got only about 4 units of energy per glucose molecule while those with resident mitochondria had as much as 30-32 units of energy for the same amount of glucose. You can see why the newfangled idea caught on like wildfire, and the cells that could not adapt to the new technology died out (a simple instance of natural selection — Charles Darwin would have been proud).
To this day, all multi-cellular organisms like you and me have mitochondria in each and every cell, a pattern not much changed over the billions of years. In fact, each cell may have many mitochondria. These little "power plants" in each cell are passed on from mother to daughter, your mother gave a copy of hers to you, in each and every cell of your baby body. Fathers have little to do with it: 99.99% of the blueprints for mitochondria come from the mother. (Sorry, guys. You got sort of side-lined on that one by Mother Nature). That means most humans (and giraffes and sea snails and polar bears and petunias) have very similar mitochondria, with differences not worth discussing. That is one reason why we do not have to worry about matching mitochondrial DNA when we talk about blood transfusions or bone marrow / organ transplants, since we all have pretty near identical mitochondrial DNA. Cellular DNA (nuclear DNA) is a different matter, since we do mix it up a great deal every time a new baby is conceived. Half the DNA comes from the father and half from the mother, allowing for many variations on the theme. Isn't sex wonderful?
Think of a cartoon picture of a B-cell. Inside the cell is a nucleus, which is where the all important cellular DNA resides, the mastermind that controls everything. This cellular DNA is a hugely complex affair, it has to take care of all the functions of the cell. Since it is so complex and damage to it is so catastrophic, we have developed very powerful and complex mechanisms for protecting it from all sorts of damage, radiation, chemotherapy and so on (see Cytogenetics of ATM and P53). Obviously, cancer cells also become very good at using these defense mechanisms to their own advantage, which is why they are so hard to kill. No question about it, the nucleus of the B-cell is like a strong and well-guarded fortress, and the strands of cellular DNA are the crown jewels in the citadel, hard to take down.
Mitochondria, on the other hand, have lived a sheltered life these many billions of years. Nicely cocooned inside the cell, they have their own "digs" defined by a couple of sturdy membranes. Never having to lift a finger to make a living or find their own food, and not having to do much except the one major task of providing power for their host cell, they have had little reason to build any defenses. The cell provides glucose and oxygen, the mitochondria put out energy and water. That's the deal. Mitochondrial DNA is therefore a simple affair, short and sweet, with none of the complex safety features and defenses that you are likely to find in the cellular DNA. This is only a cartoon version of how mitochondria and cells cooperate. If you wish to learn more, here is good link with nice pictures and stuff: Cytochemistry .
How Does This Help Define a Cancer Therapy Strategy?
By now you must have guessed where I am going with this. Taking down the cellular DNA tucked away in the fortress (nucleus) is a tough thing to do. But what about the poorly guarded power plants that are within the cell? What if we can sabotage the mitochondria and blow up the power plants? For starters, the cell will die for the simple reason it has no more power, it will starve to death. Another reason is that power plants are notorious for producing and storing all sorts of toxic waste. Dump all that toxic garbage into the cell and the cell is quickly poisoned beyond redemption. It does not matter what the mastermind cellular DNA has to say about it, mitochondrial death is hard to reverse. When its mitochondria die, the cell dies with them. That, in a nutshell, is the new (actually not so new – the concept has been around for a while) approach to treating CLL and presumably other cancers. Think like a terrorist – don't go after the hard-to-get cellular DNA living in the nucleus, go after the 'softer' target of mitochondria. Here are some approaches that are showing promise, all of them deal with the common theme of mitochondrial damage.
1. Increase the Garbage Production
Mitochondria are normally very efficient at converting glucose and oxygen into power the cell can use, the major by-product being water; this is very efficient usage of oxygen, but not quite perfect. One of the waste products they produce is extremely reactive oxygen species such as peroxides. ROS ("Reactive Oxygen Species") are toxic because they can attack just about any thing. As the mitochondria get old and worn out, their efficiency decreases, possibly because of damage by their own ROS, and they get into a vicious cycle of making more and more of ROS.
Cancer cells are inherently wasteful and spendthrift with energy, they are selfish and not good team players looking out for everyone's welfare. Their energy requirements go up tremendously especially when they are proliferating. Mitochondria in cancer cells are therefore often driven to ever-increasing loads, which means ever-increasing amounts of ROS, with ever-increasing damage to the mitochondrial DNA. Chemotherapy drugs also do a number on the mitochondria. Remember, we said cellular DNA is well protected, but not so mitochondrial DNA. So it is possible for some cancer cell to survive chemotherapy, but at the expense of damage to their mitochondrial DNA. In an elegant piece of research, researchers at M. D. Anderson have connected the dots and shown that CLL patients who have undergone chemotherapy are almost sure to have damaged mitochondria, and therefore their mitochondria are producing more of the toxic ROS.
Abstract:
See the original posters and other review review athttp://www.startaid.com/comment/1412310/Cucumis---Бесплатная-служба-online-перевода.html