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A letter to the editor is presented on Lambert-Eaton syndrome associated with interferon alfa treatment for chronic myeloid leukemia.

Objective: An aberrant production of inflammatory cytokines, with resultant febrile response, is a cardinal finding of hemophagocytic syndrome. A role of inflammatory cytokines on phagocytosis and clearance of apoptotic cells or particles has been shown, but effects of cytokines or hyperthermia on phagocytosis of viable blood cells were not fully understood. We examined effects of cytokines and hyperthermia on phagocytosis, and externalization of phosphatidylserine on the surface of phagocytosed blood cells, to clarify the pathophysiology of hemophagocytic syndrome., Methods: THP-1 macrophage cells were incubated with non-opsonized and opsonized sheep erythrocytes (SE) in the presence of tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), macrophage-colony stimulating factor (M-CSF), interleukin (IL)-6, IL-10 or IL-18, and phagocytic activity was analyzed. Co-operative effect between cytokines was also examined. In addition, SE were incubated at 37 or 39°C, and phagocytic activity was analyzed. After treatment of SE with cytokine or hyperthermia, phosphatidylserine expression of the cell surface was analyzed by detecting Annexin V-positive cells., Results: IL-6, IL-10 and IL-18 significantly increased phagocytosis of non-opsonized SE, but IFN-γ suppressed it. Phagocytosis of opsonized SE was significantly increased by any of the cytokines. IFN-γ suppressed and IL-10 enhanced phagocytic activity induced by other cytokines in non-opsonized SE, while in opsonized SE, both cytokines co-operated with other cytokines to enhance phagocytosis. Incubation of SE at a high temperature (39°C) resulted in increased phagocytic activity, as compared to SE incubated at 37°C. Cytokines and a high temperature did not increase the number of Annexin V-positive SE., Conclusions: IL-6, IL-10 and IL-18 can augment phagocytosis of viable blood cells, whether cells are opsonized or not. Hyperthermia also enhances phagocytosis. These in vitro data suggest that therapy for targeting cytokine (IL-6, IL-10 or IL-18) by using biologics or small molecule drugs may be beneficial for the treatment of hemophagocytic syndrome. Unlike the case of apoptotic cells, phagocytosis of viable blood cells seems to be mediated via phosphatidylserine-independent manner., (© 2018 by the Association of Clinical Scientists, Inc.)

Arsenic trioxide (ATO) is an approved treatment for acute promyelocytic leukemia (APL). It has also shown potential for treatment of multiple myeloma and various solid tumors including breast cancer. The requirement of high, toxic concentrations for the induction of apoptosis in non-APL and solid tumor cells is a major limitation for its use in other hematological malignancies and solid tumors. We have examined whether inducers of differentiation of leukemia cells can control the growth of solid tumor cells. In the present study, we found that cotylenin A, a plant growth regulator and a potent inducer of differentiation in myeloid leukemia cells, significantly potentiated both ATO-induced inhibition of cell growth in a liquid culture, and ATO-induced inhibition of anchorage-independent growth in a semi-solid culture in human breast cancer MCF-7 and MDA-MB-231 cells. ISIR-005 (a synthetic cotylenin A-derivative) was also able to enhance ATO-induced growth inhibition. The combined treatment with cotylenin A and ATO induced cleaved caspase-7 in MCF-7 cells at the concentrations which ATO alone scarcely induced and cotylenin A alone only weakly induced. Expression of survivin in MCF-7 cells was markedly decreased with the presence of both cotylenin A and ATO, although the expression of survivin was only slightly decreased by cotylenin A or ATO alone. The pretreatment with N-acetylcysteine significantly reduced the combination treatment-induced cell growth inhibition. These data suggest that induction of cleaved caspase-7, inhibition of survivin and oxidative responses are important events in the corporative inhibition in the growth of MCF-7 cells induced by both cotylenin A and ATO. Furthermore, we found that the combined treatment with cotylenin A and ATO also could be effective in suppressing the invasive capacity of MDA-MB-231 cells determined with the impedance-based xCELLigence Real-Time Cell Analysis technology. These results suggest that cotylenin A is an attractive enhancer for the ATO-induced anticancer activities in human breast cancer.

It has been established that acute promyelocytic leukemia (APL) cells are induced to terminally differentiate by all-trans retinoic acid (ATRA), however, the clearance of differentiated APL cells in vivo has not been well understood. Here, we documented the elimination of terminally differentiated APL cells by histiocytes in bone marrow during differentiation induction therapy. In two ATRA-treated APL patients, bone marrow showed the striking phagocytosis of differentiated APL cells by histiocytes just before the achievement of complete remission. Histiocytes phagocytosed APL cells at the terminal stage of differentiation prior to the late apoptotic event of cell lysis. Engulfed APL cells then undergo morphological features of late apoptosis and finally fragmentation in the cytoplasm of histiocytes. This swift and efficient elimination of APL cells undergoing apoptosis by the histiocytes in bone marrow may be possible pathway, at least partially, for the clearance of differentiated APL cells.

Tumor necrosis factor-alpha (TNF-alpha) induces both rapid onset of apoptosis and monocytic differentiation in HL-60 human myeloid leukemia cells. In this study, we examined the effect of activation of protein kinase C (PKC) in c-Myc protein expression in association with the induction of apoptosis and differentiation in TNF-alpha-treated HL-60 cells. Pretreatment with phorbol 12-myristate 13-acetate (PMA), an activator of PKC, prevented TNF-alpha-induced rapid onset of apoptosis, which occurs at 3 h culture with TNF-alpha, concomitantly with the up-regulation of c-Myc protein expression. In addition, PMA enhanced TNF-a-induced differentiation at 24h treatment. This was documented by the expression of integrin Mac-1 molecule (CD11b) on the cell surface and the cellular adhesion to the plastic bottom of the flask, indicating the differentiation along with the monocyte/macrophage lineage. These results indicate that activation of PKC not only counteracts apoptosis but also enhances differentiation in TNF-alpha-treated HL-60 cells. Up-regulation of c-Myc protein evoked by pretreatment with PMA for a short time could disturb the signaling pathway of the ceramide and sphingosine, which are known to function as the endogenous modulators mediating the apoptotic signal of TNF-alpha. Our results strongly suggest the role of c-Myc protein as a mediator of cytoprotective effect of PKC pathway, and PKC pathway opposes apoptosis and consequently undergo differentiation via rapid up-regulated c-Myc protein expression during TNF-alpha signaling of HL-60 cells. Our findings provide a new insight for a role of PKC and c-Myc protein with special reference to the regulatory mechanisms in the decision of cellular fate, differentiation or apoptosis.