Imatinib is clinically effective in treating chronic myelocytic leukemia (CML) patients, but the imatinib resistant cells often caused the relapses and resulted in the failure of treatment. Agents against these imatinib resistant cells are of great importance for CML therapy. As the drug resistance and relapses of tumor were thought to be closely associated with cancer stem cells, we thus try to investigate if the effects of imatinib on the resistant or stem cell population in CML could be enhanced by arsenic trioxide, an effective remedy for acute myelocytic leukemia. It is reported that the Philadelphia chromosome-positive (Ph+), CD34+ cells from chronic phase CML patients were found to be resistant to imatinib, and the primitive Ph+ stem cells that have been described in the chronic phase of CML are CD34+/CD38-. Remarkably, a recent report showed that Ph+, CD34+/CD38+ progenitor cells from chronic phase CML patients are capable of self-renewal and engraftment into NOD-SCID mice. We thus identified and sorted these two populations (CD34+/CD38- and CD34+/CD38+) of cells from human Ph+ K562 CML cells and study the effects of imatinib and arsenic trioxide on their cell survival and expression of c-Kit, the receptor for stem cells factor, which is required for CML hematopoiesis. The results from flow cytometric detection showed that the proportion of CD34+CD38- and CD34+CD38+ cells within K562 cells were 0.87 and 4.74 %, respectively. The c-Kit was highly expressed in CD34+/CD38- cells but almost not detected in CD34+/CD38+ cells. Both arsenic trioxide and imatinib could effectively reduced the highly expressed c-Kit in CD34+/CD38- cells accompanied with significant decrease in cell viability, and appeared to have additive effects when combined imatinib with arsenic trioxide. Intriguingly, the CD34+/CD38+ cells were more resistant to both imatinib and Arsenic trioxide than CD34+/CD38- cells, and the enhancement effect of Arsenic trioxide on imatinib-exerted inhibition was more significant in this population of cells. Our results indicated that the CD34+/CD38+ cells should be regarded as more life-threatened population to CML patients subjected to imatinib treatment and combining imatinib in conjunction with arsenic trioxide may provide beneficial effects on elimination of these two populations of cells in CML patients.
Date:
2009-05
Relation:
Cancer Research. 2009 May;69:Abstract number 1078.
