betadex and Leukemia

Medicine/nanotechnology as a new and applicable technique according to drug delivery systems has gained great consideration for cancer treatment. Polysaccharides including, cellulose, β-cyclodextrin and sodium carboxymethyl cellulose and chitosan as natural bio-materials, are appropriate candidates for designing and formulations of these nanosystems because of the exceptional advantages such as bio-compatibility, bio-degradability, non-toxicity, and gelling characteristics. An intelligent drug delivery platform based on these hybrids nowadays is developed, which can be used for dual-responsive dual-drug delivery. Nanotechnology accompany with biological molecules has been carefully considered to decrease the drawbacks of conventional cancer treatments. Consequently, this review is intended to state and investigate on the latest development on the combination treatment of platforms based on the hybrids of anticancer drugs/nanoparticles/Polysaccharides in the fields of biomedical therapeutics and cancer therapy owing to the bio-compatibility, great surface area, good chemical and mechanical features, the challenges and future perspectives are reported as well.

Topics: beta-Cyclodextrins; Carboxymethylcellulose Sodium; Chitosan; Drug Carriers; Drug Delivery Systems; Humans; Leukemia; Nanoparticles; Sodium

We evaluated the usefulness of PGE2 on chemotherapy-associated oral mucosal lesions of the patients with hematological malignancies and compared the efficacy of the troche with that of the tablet. One hundred and fifty three patients were given 0.5 mg of these PGE2 topically three times daily. One hundred and fourty five cases were evaluable (Tablet; 85, Troche; 60). 1) Symptoms and signs were improved in 102/144 (70.8%) and 102/145 (70.3%), respectively. The overall response rate was 70.3%. 2) The improvement rates were 77.5% (55/71), 85.7% (6/7) and 62.7% (32/51) in leukocyte count-increased, -unchanged and -decreased patients, respectively. 3) No background factor of the patients except performance status affected the improvement rate. 4) Higher improvement rate was noted in the PGE2 early starting group (within 5 days after the appearance of oral lesions) than the late group (6 days and thereafter) (76.5% v.s. 55.8%: U-test p less than 0.1, chi2-test p less than 0.05). 5) There was no difference in the efficacy rate between the tablet and the troche. 6) Mild side effects were seen in 10 cases. These results suggest that topical administration of PGE2 is safe and useful for improving chemotherapy-associated oral mucosal lesions of patients with hematological malignancies.

Topics: Administration, Oral; Adult; Aged; beta-Cyclodextrins; Cyclodextrins; Dinoprostone; Drug Evaluation; Female; Humans; Leukemia; Male; Middle Aged; Mouth Mucosa; Myelodysplastic Syndromes; Stomatitis, Aphthous; Tablets

tRNase ZL-utilizing efficacious gene silencing (TRUE gene silencing) is an RNA-mediated gene expression control technology with therapeutic potential. Recently, our group demonstrated that a heptamer, mh1 (Bcl‑2), targeting human Bcl-2 mRNA, can be taken up by cells without the use of any transfection reagents and can induce the apoptosis of leukemia cells. However, little is known regarding the mechanism of naked small guide (sg)RNA uptake by cultured cells. Therefore, in the present study the effects of various inhibitors on the induction of apoptosis by naked sgRNA treatment were investigated in order to identify the uptake pathway required for sgRNA function in cultured cells. Addition of the endocytosis inhibitors chlorpromazine, nystatin or methyl‑β‑cyclodextrin together with naked effective sgRNA was unable to diminish the apoptosis‑inducing effects of naked sgRNA or the reduction in target mRNA, suggesting that functional uptake of sgRNA by cells is clathrin‑, caveolae‑ and raft‑independent. Next, chloroquine, an inhibitor of lysosome acidification, and brefeldin A, an inhibitor that blocks protein transport from the Golgi apparatus to the endoplasmic reticulum were administered. In the presence of these compounds, the apoptosis‑inducing effects of naked sgRNA were reduced. These results suggest that a vesicular transport process is involved in sgRNA‑mediated TRUE gene silencing. A greater understanding of how naked sgRNAs enter cells and how they reach their target RNAs may aid in the design of more specifically‑targeted and potent sgRNA drugs.

Topics: Apoptosis; bcl-2-Associated X Protein; beta-Cyclodextrins; Cell Line, Tumor; Chlorpromazine; Endocytosis; Endoplasmic Reticulum; Gene Silencing; Golgi Apparatus; HEK293 Cells; HL-60 Cells; Humans; Leukemia; Nystatin; RNA, Guide, Kinetoplastida; RNA, Messenger; Transfection

GLUT1 is the predominant glucose transporter in leukemia cells, and the modulation of glucose transport activity by cytokines, oncogenes or metabolic stresses is essential for their survival and proliferation. However, the molecular mechanisms allowing to control GLUT1 trafficking and degradation are still under debate. In this study we investigated whether plasma membrane cholesterol depletion plays a role in glucose transport activity in M07e cells, a human megakaryocytic leukemia line. To this purpose, the effect of cholesterol depletion by methyl-β-cyclodextrin (MBCD) on both GLUT1 activity and trafficking was compared to that of the cytokine Stem Cell Factor (SCF). Results show that, like SCF, MBCD led to an increased glucose transport rate and caused a subcellular redistribution of GLUT1, recruiting intracellular transporter molecules to the plasma membrane. Due to the role of caveolae/lipid rafts in GLUT1 stimulation in response to many stimuli, we have also investigated the GLUT1 distribution along the fractions obtained after non ionic detergent treatment and density gradient centrifugation, which was only slightly changed upon MBCD treatment. The data suggest that MBCD exerts its action via a cholesterol-dependent mechanism that ultimately results in augmented GLUT1 translocation. Moreover, cholesterol depletion triggers GLUT1 translocation without the involvement of c-kit signalling pathway, in fact MBCD effect does not involve Akt and PLCγ phosphorylation. These data, together with the observation that the combined MBCD/SCF cell treatment caused an additive effect on glucose uptake, suggest that the action of SCF and MBCD may proceed through two distinct mechanisms, the former following a signalling pathway, and the latter possibly involving a novel cholesterol dependent mechanism.

Topics: Benzamides; beta-Cyclodextrins; Cell Line, Tumor; Cell Membrane; Cell Proliferation; Cell Survival; Cholesterol; Cytoplasmic Vesicles; Endocytosis; Extracellular Signal-Regulated MAP Kinases; Glucose; Glucose Transporter Type 1; Humans; Imatinib Mesylate; Leukemia; Nystatin; Phloretin; Phospholipase C gamma; Phosphorylation; Piperazines; Protein Kinase Inhibitors; Protein Processing, Post-Translational; Protein Transport; Protein-Tyrosine Kinases; Proto-Oncogene Proteins c-akt; Pyrimidines; Stem Cell Factor

This study focuses on the functional role of cellular cholesterol in the regulation of mechanosensitive cation channels activated by stretch in human leukaemia K562 cells. The patch-clamp method was employed to examine the effect of methyl-beta-cyclodextrin (MbetaCD), a synthetic cholesterol-sequestering agent, on stretch-activated single currents. We found that cholesterol-depleting treatment with MbetaCD resulted in a suppression of the activity of mechanosensitive channels without a change in the unitary conductance. The probability that the channel was open significantly decreased after treatment with MbetaCD. Fluorescent microscopy revealed F-actin reorganization, possibly involving actin assembly, after incubation of the cells with MbetaCD. We suggest that suppression of mechanosensitive channel activation in cholesterol-depleted leukaemia cells is due to F-actin rearrangement, presumably induced by lipid raft destruction. Our observations are consistent with the notion that stretch-activated cation channels in eukaryotic cells are regulated by the membrane-cytoskeleton complex rather than by tension developed purely in the lipid bilayer.

Topics: Actins; beta-Cyclodextrins; Cholesterol; Cytoskeleton; Humans; Ion Channels; K562 Cells; Leukemia; Patch-Clamp Techniques

The antitumor ether lipid ET-18-OCH(3) promotes apoptosis in tumor cells through intracellular activation of Fas/CD95. Results of this study showed that ET-18-OCH(3) induces cocapping of Fas and membrane rafts, specialized plasma membrane regions involved in signaling, before the onset of apoptosis in human leukemic cells. Patches of membrane rafts accumulated Fas clusters in leukemic cells treated with ET-18-OCH(3). Sucrose gradient centrifugation of Triton X-100 cell lysates showed that Fas translocated into membrane rafts following ET-18-OCH(3) treatment of T-leukemic Jurkat cells. Disruption of membrane raft integrity by methyl-beta-cyclodextrin or filipin inhibited ET-18-OCH(3)-induced apoptosis in leukemic primary cells and cell lines. Fas clustering was also inhibited by methyl-beta-cyclodextrin. These data indicate that ET-18-OCH(3) reorganizes membrane rafts to trigger apoptosis in human leukemic cells, and that Fas coaggregation with membrane rafts is required for ET-18-OCH(3)-induced apoptosis. This translocation of Fas into membrane rafts may provide a mechanism for amplifying Fas signaling by reorganization of membrane microdomains.

Topics: Apoptosis; beta-Cyclodextrins; Cell Membrane; Centrifugation, Density Gradient; Cholesterol; Cyclodextrins; fas Receptor; Filipin; HL-60 Cells; Humans; Jurkat Cells; Leukemia; Membrane Lipids; Microscopy, Confocal; Phospholipid Ethers; Signal Transduction