Basal autophagy is pivotal for Hodgkin and Reed-Sternberg cells' survival and growth revealing a new strategy for Hodgkin lymphoma treatment.

As current classical Hodgkin lymphoma (cHL) treatment strategies have pronounced side-effects, specific inhibition of signaling pathways may offer novel strategies in cHL therapy. Basal autophagy, a regulated catabolic pathway to degrade cell's own components, is in cancer linked with both, tumor suppression or promotion. The finding that basal autophagy enhances tumor cell survival would thus lead to immediately testable strategies for novel therapies. Thus, we studied its contribution in cHL.We found constitutive activation of autophagy in cHL cell lines and primary tissue. The expression of key autophagy-relevant proteins (e.g. Beclin-1, ULK1) and LC3 processing was increased in cHL cells, even in lymphoma cases. Consistently, cHL cells exhibited elevated numbers of autophagic vacuoles and intact autophagic flux. Autophagy inhibition with chloroquine or inactivation of ATG5 induced apoptosis and reduced proliferation of cHL cells. Chloroquine-mediated inhibition of basal autophagy significantly impaired HL growth in-vivo in NOD SCID γc-/- (NSG) mice. We found that basal autophagy plays a pivotal role in sustaining mitochondrial function.We conclude that cHL cells require basal autophagy for growth, survival and sustained metabolism making them sensitive to autophagy inhibition. This suggests basal autophagy as useful target for new strategies in cHL treatment.

Hodgkin and Reed-Sternberg cells of classical Hodgkin lymphoma are highly dependent on oxidative phosphorylation.

The metabolic properties of lymphomas derived from germinal center (GC) B cells have important implications for therapeutic strategies. In this study, we have compared metabolic features of Hodgkin-Reed-Sternberg (HRS) cells, the tumor cells of classical Hodgkin's lymphoma (cHL), one of the most frequent (post-)GC-derived B-cell lymphomas, with their normal GC B cell counterparts. We found that the ratio of oxidative to nonoxidative energy conversion was clearly shifted toward oxidative phosphorylation (OXPHOS)-linked ATP synthesis in HRS cells as compared to GC B cells. Mitochondrial mass, the expression of numerous key proteins of oxidative metabolism and markers of mitochondrial biogenesis were markedly upregulated in cHL cell lines and in primary cHL cases. NFkappaB promoted this shift to OXPHOS. Functional analysis indicated that both cell growth and viability of HRS cells depended on OXPHOS. The high rates of OXPHOS correlated with an almost complete lack of lactate production in HRS cells not observed in other GC B-cell lymphoma cell lines. Overall, we conclude that OXPHOS dominates energy conversion in HRS cells, while nonoxidative ATP production plays a subordinate role. Our results suggest that OXPHOS could be a new therapeutic target and may provide an avenue toward new treatment strategies in cHL.

COX-2-dependent and potentially cardioprotective effects of negative inotropic substances released after ischemia.

During reperfusion, cardiodepressive factors are released from isolated rat hearts after ischemia. The present study analyzes the mechanisms by which these substances mediate their cardiodepressive effect. After 10 min of global stop-flow ischemia, rat hearts were reperfused and coronary effluent was collected over a period of 30 s. We tested the effect of this postischemic effluent on systolic cell shortening and Ca(2+) metabolism by application of fluorescence microscopy of field-stimulated rat cardiomyocytes stained with fura-2 AM. Cells were preincubated with various inhibitors, e.g., the cyclooxygenase (COX) inhibitor indomethacin, the COX-2 inhibitors NS-398 and lumiracoxib, the COX-1 inhibitor SC-560, and the potassium (ATP) channel blocker glibenclamide. Lysates of cardiomyocytes and extracts from whole rat hearts were tested for expression of COX-2 with Western blot analysis. As a result, in contrast to nonischemic effluent (control), postischemic effluent induced a reduction of Ca(2+) transient and systolic cell shortening in the rat cardiomyocytes (P < 0.001 vs. control). After preincubation of cells with indomethacin, NS-398, and lumiracoxib, the negative inotropic effect was attenuated. SC-560 did not influence the effect of postischemic effluent. The inducibly expressed COX-2 was detected in cardiomyocytes prepared for fluorescence microscopy. The effect of postischemic effluent was eliminated with applications of glibenclamide. Furthermore, postischemic effluent significantly reduced the intracellular diastolic and systolic Ca(2+) increase (P < 0.01 vs. control). In conclusion, the cardiodepressive effect of postischemic effluent is COX-2 dependent and protective against Ca(2+) overload in the cells.

Immunoadsorption in dilated cardiomyopathy: 6-month results from a randomized study.

BACKGROUND: Various randomized studies evidenced that immunoadsorption (IA) repeated at monthly intervals induced acute and prolonged hemodynamic benefit in patients with severe heart failure due to dilated cardiomyopathy. Some findings indicate that the use of only one course of IA therapy may also induce prolonged beneficial effects. METHODS: This randomized study included 22 patients suffering from severe heart failure (left ventricular ejection fraction [LVEF] <35%) due to dilated cardiomyopathy. The first group (11 patients) was treated with four IA courses at monthly intervals. The second group (11 patients) received one IA course only without repetition. In all patients of the 2 groups, each course was performed in one IA session on 5 consecutive days. At 3 and 6 months after the beginning of this study, left ventricular function and hemodynamics were reevaluated in both groups. RESULTS: Immunoadsorption treatment repeated at monthly intervals induced improvement in LVEF after 6 months, that is, from 28.1% +/- 1.5% to 37.0% +/- 1.6% (+/-SEM; P < .01 vs baseline). Patients treated in only one IA course experienced comparable improvement of LVEF after 6 months, that is, from 26.5% +/- 2.2% to 34.8% +/- 2.9% (P < .01 vs baseline). In the group with repeated IA courses, cardiac index increased from baseline 2.2 +/- 0.1 to 2.8 +/- 0.2 L min(-1) m(-2) after 6 months (P < .01 vs baseline). In comparison, during the 6 months of this study in the group with one IA course, cardiac index increased from 2.1 +/- 0.1 to 2.7 +/- 0.2 L min(-1) m(-2). After 3 and 6 months, there were no significant differences between the 2 groups with respect to LVEF and all measured hemodynamic parameters. CONCLUSIONS: One course of IA treatment may induce improvement of left ventricular function over a period of 6 months, with results comparable to those received by IA treatment repeated at monthly intervals.

Effects of immunoadsorption on the nt-BNP and nt-ANP plasma levels of patients suffering from dilated cardiomyopathy.

Immunoadsorption (IA) represents an additional therapeutic approach in patients with severe heart failure due to dilated cardiomyopathy (DCM). nt-BNP and nt-ANP plasma levels are prognostic markers in patients with heart failure. The effect of IA on nt-BNP and nt-ANP plasma levels is unknown. In this case control study, 30 patients suffering from severe heart failure (LVEF < 35%) due to DCM were included. In 15 patients, IA was carried out in four courses of monthly intervals until month 3. For analysis of the acute and prolonged effects, the plasma levels of nt-BNP and nt-ANP were determined before and after each IA course. In 15 comparable DCM patients (controls), plasma levels of nt-BNP and nt-ANP were determined at baseline and after 3 months. LVEF remained stable during this study in the control group. In contrast, in the IA group after 3 months, LVEF increased from 29.7 +/- 1 to 38.6 +/- 2%, P < 0.001. In the control group, the nt-BNP and nt-ANP plasma levels remained stable during the 3 months of the study. In the IA group after the first IA course, the level of nt-BNP was acutely reduced from 1501 +/- 328 to 925 +/- 151 fmol/mL, P < 0.01. In addition, the nt-ANP level was reduced from 4439 +/- 1271 to 2897 +/- 825 fmol/mL, P < 0.01. In the IA group, the reduction of these two parameters remained detectable after 3 months before the last course: nt-BNP: 714 +/- 119 fmol/mL, nt-ANP: 2227 +/- 427 fmol/mL, P < 0.05. The improvement of left ventricular function during IA is accompanied by a reduction of nt-BNP and nt-ANP plasma levels in patients with DCM.