Club Cell

    Club Cell is the new hang-out spot. It has a large staff of burly bouncers who can escort certain guests out of the club. Each bouncer has a unique job to escort some guests out of certain exits he guards. But in spite of this security system, not everything inside the club runs smoothly.

    It’s time to call in researchers at St. Jude Children’s Research Hospital. Both normal and tumor cells have proteins in their membranes that act like bouncers to escort some guests out of the cells. When these protective proteins are functioning, chemotherapy drugs cannot accumulate and kill the offending cells. Top-notch investigators at St. Jude are seeking ways to block the function of certain bouncers so they can send in chemotherapy drugs and save the day. But if the bouncers in normal cells are blocked and chemotherapy drugs accumulate in those cells, the results can be catastrophic.

    John Schuetz, PhD, of St. Jude Pharmaceutical Sciences heads a team charged with investigating the function of the protective proteins that guard each exit. Schuetz says that sometimes chemotherapy does not work because cancer cells have many bouncers who escort chemotherapy drugs out of the club. He and his team are still trying to find out more about these proteins. “In the lab, we are trying to understand the function of each protein,” Schuetz says. “We know what about one-quarter of them do, and we are working on researching more.”

    About a decade ago, researchers thought there was only one of these proteins, which transported molecules out of the cell. “Now we know there are many,” Schuetz says. “There are about 50 of these proteins. Our lab is intensively studying a couple of those. What we’ve done with the two recent ones is to identify their unique biological roles.”

    By identifying more protective proteins, researchers can ultimately combine chemotherapy drugs with inhibitors that block certain protein functions. “We envision co-administering the chemotherapy drugs to patients with an inhibitor to block the protein at the time when the drug peaks at high levels. The drug can then more effectively kill the tumor cells,” Schuetz says.

    Blocked exit doors

    Drugs do not enter the club through specific doors; they can just move in through the cell membrane. But they can only exit the cell with the help of a protective protein. Schuetz and his colleagues have learned to take exquisite care when blocking the exits from Club Cell. For instance, the researchers recently discovered that inactivating a protective protein in leukemia cells to make the cells more vulnerable to chemotherapy might also make healthy, blood-forming cells more sensitive to the toxic effects of those same drugs.

    The St. Jude researchers based their conclusion on results of a study of a molecule whose normal function is to rid hematopoietic stem cells (HSCs) of a potentially toxic molecule called heme. HSCs are parent cells in bone marrow that give rise to red and white blood cells. Heme is an oxygen-carrying molecule that is a key part of enzymes used by cells to extract energy from food and by red blood cells to carry oxygen to tissues.

    When oxygen levels are low—a situation known as hypoxia—the cell wants to make as much heme as possible to trap as much oxygen as it can. But the cells must also protect themselves from excess heme, which can poison the cell. The cell makes what is known as the breast cancer resistance protein (BCRP), which is capable of binding to heme molecules and transporting them out of the cell.

    According to Schuetz, the ability of cells to rid themselves of excess heme is especially important in the bone marrow, where HSCs are normally exposed to a low-oxygen environment that stimulates the cells to produce more of this molecule.

    Kicking toxins out of the club

    Brian Sorrentino, MD, St. Jude Experimental Hematology director, has expertise in blood and bone marrow cells and developed a laboratory model that lacked the protective protein BCRP. Researchers in the Schuetz lab then used this model to test the role of BCRP in cell survival under low oxygen conditions. In addition to heme, BCRP carries a variety of toxic chemicals out of cells, including certain drugs used to treat leukemia. Researchers outside of St. Jude are developing molecules that block BCRP in leukemic cells and make them more vulnerable to chemotherapy. However, drugs that block BCRP in leukemic cells would also block this molecule in healthy HSCs, leaving them vulnerable to toxic chemotherapy drugs and less able to survive in low oxygen conditions.

    “If BCRP function is blocked for a long time, the patient’s normal blood-forming cells could be depleted,” Schuetz says. “And that would reduce the body’s ability to produce healthy red and white blood cells, which would certainly complicate the patient’s medical condition.”

    According to Sorrentino, the main message this research sends to investigators is that the blocked protein may protect stem cells from oxygen starvation. “We don’t think that blocking the protein is a good idea, since it could render stem cells vulnerable to other harmful elements,” Sorrentino says. “Our work has significance for those who are attempting to block the protein in order to enhance chemotherapy. These strategies could be harmful to stem cells not only as they relate to hypoxia injury, but also by increasing the sensitivity of normal bone marrow stem cells to chemotherapy drugs.”

    The double whammy

    Schuetz and his team developed a laboratory model that lacked a transporter found in the brain’s protective barrier. Researchers in his lab then collaborated with Clinton Stewart, PharmD, also of Pharmaceutical Sciences, who has been studying drug delivery to the brain. The collaborators discovered that a protective protein called Mrp4 prevented some chemotherapeutic drugs from entering the brain. This protein was also known to protect tumor cells from chemotherapy drugs.

    “The benefit of this research is a double whammy for brain tumors,” Schuetz says. “If you can block this protective transporter you can get more drug into the brain and also more drug into the tumor so you stand a better chance of killing the tumor.”

    Schuetz is also collaborating with St. Jude colleagues such as Erin Schuetz, PhD (Pharmaceutical Sciences), on genetic variations in the transporters.

    “Someone may have a particular protective protein that does not work as well as that same protein would in another person,” he says. “Knowing this, we might be able to explain why a drug works in one person and not in another. Within five years, I hope to see pre-clinical models for all of the protective transport proteins. This will help us really predict what a transporter will do and more accurately adjust treatment to fit a patient’s needs. That will have tremendous effect on our patients at St. Jude.”

    Reprinted from autumn 2004 Promise magazine

     

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