**5. Cholesterol metabolism disorder**

It is known that cell membranes contain lipid rafts, belonging to CH-rich microdomains. These components of the cell membrane are involved in intracellular signal transduction processes mediated by the receptor and in the self-renewal of ES cells. (Lee et al., 2010) The administration of methyl-beta-cyclodextrin, that is a CH-sequestering agent useful for the lipid raft destruction, is able to restore the activity of large conductance background K(+) channels. This favors the activation by stretch. (Nam et al., 2007) The depletion of CH from the cell membranes leads to lipid rafts destruction, that are responsible for bloking the translocation of leukemia inhibitory factor receptor and gp 130 (Port et al., 2007).

A group of Russian researchers studied the role of membrane CH in a line of human leukaemia K562 cells regarding the regulation of mechanosensitive cation channels activated by stretch. They consider that the above-mentioned suppression of this channel activation in leukemia cell line by methyl-beta-cyclodextrin is produced by F-actin rearrangement due to lipid raft destruction. (Morachevskaya et al., 2007)

In a study conducted on a group of 184 adults who had ALL in their childhood, the overall prevalence of MS has been even higher - 9.2%. Peripheral stem cell allografts after total body irradiation favored the occurrence of hypertriglyceridemia, low HDL-cholesterol and

In Sweden a group of adults was analysed; they survived after ALL during childhood and were submitted to radio-and chemotherapy. Those who received treatment for 5 years with GH compared with those not treated so for 8 years, showed significant changes in HDLcholesterol, glucose and apolipoprotein B / apolipoprotein A1 ratio, and MS was

Another study conducted in Sweden on adults who had childhood leukemia, found an augmentation of total body fat, especially of trunk adiposity and an evolution towards an unfavorable lipid spectrum. These observations were correlated with low levels of endocrine secretion of GH, a consequence of previous cranial irradiation. (Jarfelt et al., 2005) An interesting combination of diseases was described in a 54 years old woman: after being diagnosed with chronic neutrophilic leukemia a liver biopsy was made. The histopathological diagnosis was of nonalcoholic steatohepatitis (NASH) with neutrophilic infiltrate. The authors consider that the leukemia cells that infiltrated the liver contributed to the emergence of NASH. The administration of cytosine arabinoside contributed to a

There are few studies on the metabolism of chylomicrons in patients with cancer. The study of a group of patients with Hodgkin and nonHodgkin lymphoma, as compared to a healthy control group, led to the observation that after an intravenous administration of a chylomicron-like emulsion, the levels of CH, TG and VLDL were significantly higher in patients with lymphoma because of the profound disturbance of the chylomicrons lipolysis

A very interesting observation was achieved in a line of promyelocytic leukemia NB4 cells: the administration of peroxisome proliferator-activated receptor gamma ligands was able not only to induce differentiation but also to favor lipogenesis in NB4 cells. This fact suggests a close link between differentiation and lipogenesis process in human myeloid cells

It is known that cell membranes contain lipid rafts, belonging to CH-rich microdomains. These components of the cell membrane are involved in intracellular signal transduction processes mediated by the receptor and in the self-renewal of ES cells. (Lee et al., 2010) The administration of methyl-beta-cyclodextrin, that is a CH-sequestering agent useful for the lipid raft destruction, is able to restore the activity of large conductance background K(+) channels. This favors the activation by stretch. (Nam et al., 2007) The depletion of CH from the cell membranes leads to lipid rafts destruction, that are responsible for bloking the

A group of Russian researchers studied the role of membrane CH in a line of human leukaemia K562 cells regarding the regulation of mechanosensitive cation channels activated by stretch. They consider that the above-mentioned suppression of this channel activation in leukemia cell line by methyl-beta-cyclodextrin is produced by F-actin rearrangement due to

translocation of leukemia inhibitory factor receptor and gp 130 (Port et al., 2007).

increased fasting glucose level (Oudin et al., 2011).

significantly less frequent. (Follin et al., 2010)

significant decrease in fat degeneration. (Yoshida et al., 2004)

and their removal deficit. (Gonçalves et al., 2003)

thus stimulated. (Yasugi et al., 2006).

**5. Cholesterol metabolism disorder** 

lipid raft destruction. (Morachevskaya et al., 2007)

In the regulation of lipid and CH metabolism liver X receptors are also involved, they are nuclear receptors. They can modulate the proliferation and survival of both normal and malignant B and T lymphocytes. (Geyeregger et al., 2009)

The correlation between increasing CH in lipid domains and the possible cancerosus cell transformation is very interesting (Ajith et al., 2008). It is believed that CH is important for cell proliferation, because low serum CH values may be the result of high cellular CH need of cancerous cells. Low serum CH values correlate with elevated levels of CH in lymphocytes. Evidence of low levels of CH in the culture medium is due to the development of lymphoma cells, which would consume more CH for their own proliferation. The experimental administration of mevastatin in vitro, which inhibits CH synthesis, did not determine a significant variation of the concentration of CH in the culture medium, while cell growth diminished. (Pugliese et al., 2010)

Low serum CH levels are also frequently found in acute leukemia patients. These patients have significantly lower serum values of CH, HDL-cholesterol, and LDL-cholesterol. A possible explanation for the low levels of HDL-cholesterol in the patients with acute leukemia could be an increased expression of a possible selective site for HDL-cholesteryl ester. (Gonçalves et al., 2005)

Malignant, proliferative cells have an intense metabolism of CH, while decreased intake of CH is responsible for decreasing cell proliferation. In a human line of promyelocytic HL-60 cells, an inhibition of cell cycle progression from G2 phase can be obtained by an enzymatic inhibition of CH synthesis at a stage before 7-dehydrocholesterol production. Drugs such as zaragozic acid or SKF 104976 can induce the expression of antigen 11c, a cluster of differentiation. These products have a comparable action to all-trans retinoic acid, which induces monocyte differentiation. (Sánchez-Martín et al., 2007)

Chronic lymphocytic leukemia (CLL) is a heterogenous malignant hemopathy. In these patients, in the presence of UM-IGHV, which is a negative prognostic factor, there are increased levels of CH and lactate and low levels of glycerol and 3-hydroxybutyrate. (MacIntyre et al., 2010)

CD5 antigen is responsible for CH synthesis and even for adipogenesis. It is known that malignant cells from CLL are undergoing a process of continuous stimulation due to CD5 activation and cell survival. (Gary-Gouy et al., 2007) A continuous activation of an antiapoptotic pathway explains the CLL cells survival. Apolipoprotein E4-very low density lipoproteins is responsible for the high level of apoptosis in CLL cells. Lipoprotein lipase is the enzyme that metabolizes very low density lipoproteins to low-density lipoprotein. It was observed that an increase of lipoprotein lipase mRNA levels is present in CLL patients with shorter survival. (Weinberg et al., 2008)

CH synthesis is also increased in patients with T-ALL who are glucocorticoid resistant (Beesley et al., 2009).

The growth of a promyelocytic leukemia cell line – HL-60 can be experimentally supressed by sodium cholesteryl sulfate, cholesteryl bromide, and cholesteryl-5alpha. The first two are responsible for the cell arrest in S and G2/M phases, and the last product – in the G2/M phase. (Ishimaru et al., 2008)

It was found that in xenotransplanted severely combined immunodeficient mice the most abundant bone marrow CH amounts are located in leukemia-rich sites. In vitro, in leukemic cells CH is able to stimulate FLT-1 expression and VEGF production. Human leukemic cells from patients with AML are significantly richer in CH than normal cells and this CH augmentation represents a marker of aggressive evolution. (Casalou et al., 2011)

Cholesterol and Triglycerides Metabolism Disorder in Malignant Hemopathies 397

The first monoclonal antibody that was approved for the treatment of B-cell lymphoproliferative malignancies was rituxan, a chimeric monoclonal anti-CD20 antibody. It has been observed that the monoclonal antibody attachment to CD20 produces a redistribution of these antigens to lipid rafts, which are specialized membrane microdomains. If rituxan is not used, the CD20 antigen affinity to lipid rafts is small. Intracellular calcium entry and apoptosis have been completely eliminated experimentally by extracting CH, which has led to the destruction of the integrity of lipid raft structures and to the dissociation of CD20 antigen from a fraction that is resistant to Triton X-100. From this it results that for the activation of caspase induced by CD20- lipid rafts appear to have an

In multidrug resistance two populations of P-glycoprotein (P-gp) are involved. One is located in the membrane regions that are resistant to detergent; it has optimal P-gp ATPase activity; the verapamil can activate it and the orthovanadate can inhibit it almost entirely. The other population is located in another part of the membrane; it has less activity than Pgp ATPase of the first population; the verapamil can inhibit it, and its sensitivity to the orthovanadate is less. The first population of Pgp is surrounded by deposits of CH that may have the role to stimulate the P-gp ATPase activity, but the CH near the second population

Rituximab induced apoptosis may be diminished by depletion of membrane deposits of CH, which does not allow the association to the detergent-insoluble lipid rafts of the antigen hypercrosslinked CD20. Under the action of rituximab, the antibody-bound CD20, found in lipid rafts in a high-affinity structure, activates src family kinases, interfering with the

Besides their CH-lowering effects, statins have pleiotropic effects, including the antileukemic ones observed in vitro and in vivo (Sassano et al., 2009), but they disrupt the binding (Winiarska et al., 2008) and the antitumour activity of rituximab (Ennishi et al., 2010), as a consequence of the changing of the antigen CD20 conformation (Ennishi et al., 2010; Winiarska et al., 2008). Statins interfere with the detection of CD20 as well as the antilymphomatous function of the rituximab (Winiarska et al., 2008). But in a study that analyzed the progression-free survival in 3 years and overall survival in a group of patients with diffuse large B-cell lymphoma, including some patients who were taking statins, it was found that there were no statistically significant differences, fact that advocates the idea that statins used in clinical treatment do not alter the prognosis of patients with diffuse large B-

After chemotherapy, the blasts of acute myeloid leukemia (AML) respond by increasing cellular content of CH, which increases resistance to treatment. (Kornblau et al., 2007) Statins are pharmacologic inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoA reductase) - the regulatory enzyme of CH synthesis (Nonaka et al., 2009; Sassano et al., 2007). In vitro, they block HMG-CoA reductase and by this they contribute to restore sensitivity to chemotherapy. (Kornblau et al., 2007) HMG-CoA regulates not only the synthesis of CH but also that of the higher isoprenoids, as geranylgeranyl pyrophosphate (Fuchs et al., 2008). By the inhibition of the prenylation processes, in vitro, statins reduce cellular proliferation and stimulate apoptosis of cancerous cells (Nonaka et al., 2009; Sassano et al., 2007). It was found that simvastatin inhibits geranylgeranylation processes of small

of Pgp does not seem to have such a role. (Barakat et al., 2005)

cell lymphoma under R-CHOP treatment. (Ennishi et al., 2010)

**8. Statins as adjuvant treatment in malignant hemopathies** 

signal-transmission mechanism, which it inhibits. (Unruh et al., 2005)

essential role. (Janas et al., 2005)
