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We evaluated the potential role of photoradiation therapy with a benzoporphyrin derivative, monoacid ring A (BPD-MA), and dihematoporphyrin ether (DHE), for the ex vivo purging of residual tumor cells from autologous bone marrow (BM) grafts. BPD-MA and DHE photosensitizing activity was tested against two human large-cell lymphoma cell lines and colony-forming unit-leukemia (CFU-L) derived from patients with acute myelogenous leukemia (AML). In mixing experiments, 4-log elimination of tumor cell lines was observed after 1 hour of incubation with 75 ng/mL of BPD-MA or 30 minutes of treatment with 12.5 µg/mL of DHE followed by white light exposure. By comparison, using the same concentration of BPD-M A, the mean recovery of normal BM progenitors was 4% ± 0.8% (mean ± SD) for granulocyte-macrophage colony-forming unit (CFU-GM) and 5% ± 0.8% for burst-forming unit-erythroid (BFU-E). Similarly, DHE treatment resulted in the recovery of 5.2% ± 2% and 9.8% ± 3% of CFU-GM and BFU-E, respectively. Furthermore, equivalently cytotoxic concentrations of both DHE and BPD-MA and light were found not to kill normal pluripotent stem cells in BM, as demonstrated by their survival in two-step long-term marrow culture at levels equal to untreated controls. The T-lymphoblastic leukemia cell line CEM and its vinblastine (VBL)-resistant subline CEM/VBL, along with the acute promyelocyte leukemia cell line HL-60 and its vincristine (VCR)-resistant subline HL-60/VCR, were also tested. BPD-MA at 75 ng/mL was able to provide a greater than 4-log elimination of the drug-sensitive cell lines, but only a 34% and 55% decrease of the drug-resistant HL-60/VCR and CEM/VBL cell lines, respectively. On the contrary, 12.5 µg/mL of DHE reduced the clonogenic growth of all the cell lines by more than 4 logs. Further experiments demonstrated decreased uptake of both BPD-MA and DHE by the resistant cell lines. However, all the cell lines took up more DHE than BPD-MA under similar experimental conditions. Our results demonstrate the preferential cytotoxicity of BPD-MA and DHE toward neoplastic cell lines and CFU-L from AML patients. In addition, DHE was slightly more effective in purging tumor cells expressing the p-170 glycoprotein. These results suggest that photoradiation with DHE would be useful for in vitro purging of residual drug-resistant leukemia and lymphoma cells.

Introduction:Aberrant PI3K/AKT signaling is frequently observed in B cell precursor acute lymphoblastic leukemia (B-ALL) resulting in increased cell proliferation and survival. Casein kinase II (CK2) is a regulator of both, PI3K signaling and epigenetic mechanisms in hematological neoplasms. CK2 induces downregulation of de novomethylation and DNA damage response control. However, it is unclear if maintenance methylation is also influenced by CK2. We performed extended in vitroand in vivoanalyses with CK2 inhibitor CX-4945 (CX) alone and in combination with hypomethylating agent Decitabine (DEC) or PI3K pathway inhibitors to enhance anti-leukemic efficiency. We hypothesized that demethylation and CK2 blockade act synergistically and have anti-leukemic activity.