No abstract

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.Classical Hodgkin lymphoma (cHL) accounts for approximately 30% of all lymphomas. 1-3 The origin of Hodgkin and Reed-Sternberg (HRS) cells, the tumor cells of cHL, was uncertain for many years. However, several studies demonstrated their derivation from (post-)germinal center (GC) B cells and showed crippling mutations in their B cell receptor genes. [1][2][3] This was a surprising finding since survival of B cells usually depends on the integrity of the B cell receptor (BCR) signaling pathway.The metabolic differences between GC B-cell-derived lymphomas and their precursor cells have not been investigated thoroughly; however, metabolic properties of tumor cells usually diverge significantly from their nonmalignant precursor cells. Generally, energy production in cancer cells is strongly dependent on glycolysis. Furthermore, increased fatty acid synthesis and high rates of glutaminolysis play a pivotal role in the metabolism of cancer cells. [4][5][6][7][8] Warburg and coworkers showed that cancer cells convert approximately tenfold more glucose to lactate than normal tissues under aerobic conditions. 9 Under these conditions, the amount of reducing equivalents available for biosynthesis is limited. 4,10 These observations led to the hypothesis that tumor cells acquire a significant growth advantage by favoring glucose conversion to lactate even under high oxygen supply (aerobic glycolysis). This switch to aerobic glycolysis, often referred to as the Warburg effect, may occur because of mutations in genes involved in oxidative phosphorylation (OXPHOS) as demonstrated for a subset of cancers. 4,[11][12][13][14] Other cancer types carry out enhanced glycolysis and mitochondrial respiration

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.

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.

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 Ca2+ 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 Ca2+ 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 Ca2+ increase ( P < 0.01 vs. control). In conclusion, the cardiodepressive effect of postischemic effluent is COX-2 dependent and protective against Ca2+ overload in the cells.