Inactivating a protective molecule in leukemic cells to make them more vulnerable to chemotherapy might also make healthy blood-forming cells more sensitive to the toxic effects of those same drugs. These findings have been published in the Journal of Biological Chemistry by investigators at St. Jude Children's Research Hospital.
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 the "parent" cells in the 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.
The basic building block of heme is porphyrin, which is toxic to cells when it accumulates in high concentrations, according to John Schuetz, Ph.D., associate member in the department of Pharmaceutical Sciences. Schuetz is senior author of the Journal of Biological Chemistry article, which also reports on studies of a molecule called BCRP (breast cancer resistance protein), which protects HSCs from excessive levels of heme.
In conditions of low oxygen, cells tend to compensate by making more heme molecules. But the cells must also protect themselves from excess heme by making BCRP, which is capable of binding to these oxygen-carrying molecules and transporting them out through the cell membrane.
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.
In addition to heme, BCRP carries a variety of toxic and carcinogenic chemicals out of cells, including certain drugs used to treat leukemia. Researchers elsewhere are developing molecules to block BCRP in leukemic cells in order to 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. "If that happens, the patient's normal blood-forming cells could be depleted," Schuetz said. "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."
The investigators at St. Jude made their discoveries using bone marrow cells harvested from mice that either carried the gene for BCRP or lacked this gene. In conditions of low oxygen, the HSCs from mice that carried the gene for BCRP multiplied normally, apparently because they were able to rid themselves of excess heme. Similar cells from mice that lacked this gene -- and thus could not protect themselves from excess heme -- replicated only half as effectively as normal cells.
When HSCs from mice carrying the BCRP gene were kept at normal oxygen levels and given the anti-leukemic drug mitoxantrone, 40 percent survived, apparently because they used BCRP to rid themselves of that drug. However, if HSCs from mice lacking the BCRP gene were exposed to mitoxantrone under the same conditions, none of the cells survived.
Other authors of the study were Partha Krishnamurthy, Sheng Zhou, Kelly E. Mercer and Brian P. Sorrentino (St. Jude); Douglas D. Ross, Takeo Nakanishi and Kim Bailey-Dell (University of Maryland School of Medicine); and Balazs Sarkadi (National Medical Center, Budapest Hungary). This work was supported in part by NIH, a Cancer Center support grant, a VA Merit Review Grant, ALSAC and a Howard Hughes International Scholarship.
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