Targeting Gain of Function and Resistance Mutations in Abl and KIT by Hybrid Compound Design.
J Med Chem. 2013 Jun 17;
Authors: Richters A, Ketzer J, Getlik M, Grütter C, Schneider R, Heuckmann J, Heynck S, Sos ML, Gupta A, Unger A, Schultz-Fademrecht C, Thomas R, Bauer S, Rauh D
In kinases, mutations in the catalytic domain at the gatekeeper position represent the most prominent drug resistant variants of these enzymes and significantly impair the efficacy of targeted cancer therapies. Understanding the mechanisms of drug resistance at the molecular and atomic levels will aid in the design and development of inhibitors that have the potential to overcome these resistance mutations. Herein, by introducing adaptive elements into the inhibitor core structure, we undertake the structure-based development of type II hybrid inhibitors to overcome gatekeeper drug resistant mutations in cSrc-T338M as well as clinically relevant tyrosine kinase KIT-T670I and Abl-T315I variants as essential targets in gastrointestinal stromal tumors (GISTs) and chronic myelogenous leukemia (CML). Using protein X-ray crystallography, we confirm the anticipated binding mode in cSrc, which proved to be essential for overcoming the respective resistances. More importantly, the novel compounds effectively inhibit clinically relevant gatekeeper mutants of KIT and Abl in biochemical and cellular studies.
PMID: 23773153 [PubMed - as supplied by publisher]
Synergistic effect of hydrogen peroxide on polyploidization during the megakaryocytic differentiation of K562 leukemia cells by PMA.
Exp Cell Res. 2013 Jun 12;
Authors: Ojima Y, Duncan MT, Nurhayati RW, Taya M, Miller WM
The human myelogenous cell line, K562 has been extensively used as a model for the study of megakaryocytic (MK) differentiation, which could be achieved by exposure to phorbol 12-myristate 13-acetate (PMA). In this study, real-time PCR analysis revealed that the expression of catalase (cat) was significantly repressed during MK differentiation of K562 cells induced by PMA. In addition, PMA increased the intracellular reactive oxygen species (ROS) concentration, suggesting that ROS was a key factor for PMA-induced differentiation. PMA-differentiated K562 cells were exposed to hydrogen peroxide (H2O2) to clarify the function of ROS during MK differentiation. Interestingly, the percentage of high-ploidy (DNA content >4N) cells with H2O2 was 34.8±2.3% at day 9, and was 70% larger than that without H2O2 (21.5±0.8%). Further, H2O2 addition during the first 3 days of PMA-induced MK differentiation had the greatest effect on polyploidization. In an effort to elucidate the mechanisms of enhanced polyploidization by H2O2, the BrdU assay clearly indicated that H2O2 suppressed the division of 4N cells into 2N cells, followed by the increased polyploidization of K562 cells. These findings suggest that the enhancement in polyploidization mediated by H2O2 is due to synergistic inhibition of cytokinesis with PMA. Although H2O2 did not increase ploidy during the MK differentiation of primary cells, we clearly observed that cat expression was repressed in both immature and mature primary MK cells, and that treatment with the antioxidant N-acetylcysteine effectively blocked and/or delayed the polyploidization of immature MK cells. Together, these findings suggest that MK cells are more sensitive to ROS levels during earlier stages of maturation.
PMID: 23770036 [PubMed - as supplied by publisher]
The background, discovery and clinical development of BCR-ABL inhibitors.
Drug Discov Today. 2013 Jun 13;
Authors: Lambert GK, Duhme-Klair AK, Morgan T, Ramjee MK
The story of the inhibition of BCR-ABL as a treatment for chronic myelogenous leukaemia serves to illustrate key aspects of the kinase drug discovery and development process. Firstly, elucidation of the disease mechanism enabled identification of the molecular target(s) which catalysed pharmaceutical research and resulted in Gleevec(®) (Novartis) as the first FDA approved BCR-ABL inhibitor. However, clinical success was soon tempered by the emergence of drug resistance through various mechanisms. Using rational drug design, several hypotheses were devised to overcome resistance issues leading to the development of second generation inhibitors, providing clinicians and patients with greater therapeutic choice.
PMID: 23769978 [PubMed - as supplied by publisher]
Makers of anticancer drugs are “profiteering,” say 100 specialists from around the world.
Authors: Laurance J
PMID: 23633224 [PubMed - indexed for MEDLINE]
Synthesis, and docking studies of some fused-quinazolines and quinazolines carrying biological active isatin moiety as cell-cycle inhibitors of breast cancer cell lines.
Drug Res (Stuttg). 2013 Mar;63(3):129-36
Authors: Radwan AA, Alanazi FK, Al-Dhfyan A
3 series of novel fused heterocyclic systems, viz. triazolo[4,3-a]quinazolin-7-ones (3), 1 2 4 5-tetrazino[4,3-a]-quinazolin-8-ones (5) and Schiff’s bases of isatin derivatives with 2-hydrazinoquinazolin-4-ones (7) have been synthesized. Several of them showed variable and promising in vitro antiproliferative activity against the MCF-7 cells. Compounds 3a-3c, 6, 7a-7 f showed promising activity (IC50=12.45-15.79 ?M). Compound 7 f possessed notable cell cycle disrupting and apoptotic activities with enhanced selectivity against cancer cells, suggesting the potential for the development of new selective cell cycle inhibitors. In silico docking study of the compound 7 f with EGFR enzyme postulated that the designed compound might act on the same enzyme target where DJK_3021_A x-ray structure acted.
PMID: 23444171 [PubMed - indexed for MEDLINE]
Delayed cytogenetic and major molecular responses associated to increased BMI at baseline in chronic myeloid leukemia patients treated with imatinib.
Cancer Lett. 2013 Jun 1;333(1):32-5
Authors: Breccia M, Loglisci G, Salaroli A, Serrao A, Mancini M, Diverio D, Latagliata R, Alimena G
Obesity, measured as body mass index (BMI), has been identified as a possible risk factor for several solid tumors as well as for chronic myeloid leukemia (CML). To date, no correlations have been reported in this latter disease between BMI at baseline and response to targeted therapies. We refer here on the impact of BMI on clinical response in 339 chronic phase (CP) CML patients treated with imatinib and 35 CP-CML patients treated frontline with nilotinib. If compared to patients with low BMI (<18.5-25), patients with increased BMI (>25-40) at diagnosis who received imatinib showed a significantly longer median time to achieve complete cytogenetic response (6.8 months vs 3.3 months, p=0.001), a reduced rate of major molecular response (77% vs 58%, p=0.01) which was also achieved in a longer median time (29 months compared to 14 months, p=0.01). Conversely, no differences were revealed with respect to BMI in patients treated frontline with nilotinib and also patients with increased BMI obtained rapidly CCyR and MMR with an incidence similar to that of underweight/normal weight patients. These results suggest that CML patients with increased weight at baseline should be followed and carefully monitored if treated with standard dose imatinib frontline for a possible early switch.
PMID: 23291359 [PubMed - indexed for MEDLINE]
Tracking molecular relapse of chronic myeloid leukemia by measuring Hedgehog signaling status.
Leuk Lymphoma. 2013 Feb;54(2):342-52
Authors: Cea M, Cagnetta A, Cirmena G, Garuti A, Rocco I, Palermo C, Pierri I, Reverberi D, Nencioni A, Ballestrero A, Gobbi M, Carella AM, Patrone F
Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder characterized by the expansion of a leukemic stem cell (LSC) clone, carrying a Philadelphia translocation, able to overcome the non-malignant hematopoietic stem cells. The tyrosine kinase inhibitors (TKIs) imatinib, nilotinib and dasatinib are gold-standard for CML treatment. Each shows an impressive rate of complete cytogenetic response in chronic phase (CP)-CML. However, relapse and treatment failure are major problems with long-term use of TKIs. A polymerase chain reaction (PCR) assay to detect the mRNA expression of BCR-ABL1 represents the main molecular approach to monitoring response to treatment. However, using this analysis it is currently not possible to prospectively identify patients whose disease will relapse due to LSC reappearance. The aim of our study was to investigate whether the mRNA expression analysis of two Hedgehog (Hh) stemness signaling molecules, Smoothened (SMO) and Patched-1 (PTCH1), could predict upcoming molecular relapse. At the time of diagnosis, patients with high Sokal risk (n = 12) showed higher and lower levels of SMO and PTCH1, respectively (p = 0.0132), compared with patients with different Sokal scores (p = 0.0316 for intermediate risk and p = 0.0340 for low risk). These data suggest that Hh signaling was functionally more active in this risk group at the time of diagnosis. Furthermore, the kinetics of Hh signaling activity during the individual medical history correlated with BCR-ABL1 mRNA level and with upcoming molecular relapse. Also, mutation analysis of BCR-ABL1 revealed that activation of Hh signaling precedes molecular relapse by several months, mostly in patients carrying the gatekeeper mutation T315I. Importantly, in vitro data showed a synergistic effect of chemical inhibitors of Hh signaling and TKIs in both wild-type and resistant (T315I) CML cell lines. Collectively our data show that monitoring Hh pathway activity contemporaneously with BCR-ABL1 mRNA level may improve the chance of early detection of patients who will experience a relapse (mainly in the high Sokal risk group), paving the way for an innovative management of this hematologic malignancy.
PMID: 22762548 [PubMed - indexed for MEDLINE]
Sequencing of NUMB transcripts in chronic myeloid leukemia detects two single nucleotide polymorphisms.
Leuk Lymphoma. 2013 Feb;54(2):421-2
Authors: Oberender C, Kaeda J, Pawlaczyk-Peter B, Daniel P, Arnold R, Dörken B, le Coutre P
PMID: 22734830 [PubMed - indexed for MEDLINE]
SPARC expression in CML is associated to imatinib treatment and to inhibition of leukemia cell proliferation.
BMC Cancer. 2013;13:60
Authors: Giallongo C, La Cava P, Tibullo D, Barbagallo I, Parrinello N, Cupri A, Stagno F, Consoli C, Chiarenza A, Palumbo GA, Di Raimondo F
BACKGROUND: SPARC is a matricellular glycoprotein with growth-inhibitory and antiangiogenic activity in some cell types. The study of this protein in hematopoietic malignancies led to conflicting reports about its role as a tumor suppressor or promoter, depending on its different functions in the tumor microenvironment. In this study we investigated the variations in SPARC production by peripheral blood cells from chronic myeloid leukemia (CML) patients at diagnosis and after treatment and we identified the subpopulation of cells that are the prevalent source of SPARC.
METHODS: We evaluated SPARC expression using real-time PCR and western blotting. SPARC serum levels were detected by ELISA assay. Finally we analyzed the interaction between exogenous SPARC and imatinib (IM), in vitro, using ATP-lite and cell cycle analysis.
RESULTS: Our study shows that the CML cells of patients at diagnosis have a low mRNA and protein expression of SPARC. Low serum levels of this protein are also recorded in CML patients at diagnosis. However, after IM treatment we observed an increase of SPARC mRNA, protein, and serum level in the peripheral blood of these patients that had already started at 3?months and was maintained for at least the 18?months of observation. This SPARC increase was predominantly due to monocyte production. In addition, exogenous SPARC protein reduced the growth of K562 cell line and synergized in vitro with IM by inhibiting cell cycle progression from G1 to S phase.
CONCLUSION: Our results suggest that low endogenous SPARC expression is a constant feature of BCR/ABL positive cells and that IM treatment induces SPARC overproduction by normal cells. This exogenous SPARC may inhibit CML cell proliferation and may synergize with IM activity against CML.
PMID: 23383963 [PubMed - indexed for MEDLINE]
Characterization of ABL exon 7 deletion by molecular genetic and bioinformatic methods reveals no association with imatinib resistance in chronic myeloid leukemia.
Med Oncol. 2012 Sep;29(3):2136-42
Authors: Meggyesi N, Kalmár L, Fekete S, Masszi T, Tordai A, Andrikovics H
In chronic myeloid leukemia (CML), the best characterized imatinib resistance mechanisms are BCR-ABL tyrosine kinase domain mutations and clonal evolution, but recently alternative splicing of BCR-ABL was also proposed as a mechanism for imatinib resistance. Among recently reported BCR-ABL splice variants, exon 7 deletion (?exon7) was characterized in this study. The frequency of ?exon7 was investigated in 30 healthy controls and in 76 CML patients at different time points of the disease course by four different molecular genetic methods (direct sequencing, fragment analysis, allele-specific and quantitative PCR). The functionality and viability of the variant protein was tested by bioinformatic prediction. The ?exon7 was abundantly detected with similar frequency in healthy controls, in imatinib naive and resistant CML patients on BCR-ABL and also on the nontranslocated ABL. The detection rate of ?exon7 (varying between 17 and 100%) was highly dependent on the expression levels of BCR-ABL or ABL and the sensitivity of detection method. According to secondary structure prediction by bioinformatic methods, the exon 7 deleted mRNA is a target for nonsense-mediated decay, and the translated protein is likely to be nonfunctional and unstable. Taken together all the above observations, we concluded that ?exon7 is a common splice variant not associating with imatinib resistance.
PMID: 22038725 [PubMed - indexed for MEDLINE]
Acquisition of cytogenetic abnormalities in patients with IPSS defined lower-risk myelodysplastic syndrome is associated with poor prognosis and transformation to acute myelogenous leukemia.
Am J Hematol. 2013 Jun 13;
Authors: Jabbour E, Takahashi K, Wang X, Cornelison AM, Abruzzo L, Kadia T, Borthakur G, Estrov Z, O’Brien S, Mallo M, Wierda W, Pierce S, Wei Y, Sole F, Chen R, Kantarjian H, Garcia-Manero G
We hypothesized that the dynamic acquisition of cytogenetic abnormalities (ACA) during the follow up of myelodysplastic syndromes (MDS) could be associated with poor prognosis. We conducted a retrospective analysis of 365 patients with IPSS low or intermediate-1 risk MDS who had at least two consecutive cytogenetic analyses during the follow up. Acquisition of cytogenetic abnormalities was detected in 107 patients (29%). The most frequent alteration involved chromosome 7 in 21% of ACA cases. Median transformation-free and overall survival for patients with and without ACA were 13 vs. 52 months (P = 0.01) and 17 vs. 62 months (P = 0.01), respectively. By fitting ACA as a time-dependent covariate, multivariate Cox regression analysis showed that patients with ACA had increased risk of transformation (HR=1.40; P = 0.03) or death (HR=1.45; P = 0.02). Notably, female patients with therapy-related MDS (t-MDS) had an increased risk of developing ACA (OR= 5.26; P <0.0001), although subgroup analysis showed that prognostic impact of ACA was not evident in t-MDS. In conclusion, ACA occurs in close to one third of patients with IPSS defined lower risk MDS, more common among patients with t-MDS, but has a significant prognostic impact on de novo MDS.
PMID: 23760779 [PubMed - as supplied by publisher]
PDCD2 functions in cancer cell proliferation and predicts relapsed leukemia.
Cancer Biol Ther. 2013 Jun 1;14(6):546-55
Authors: Barboza N, Minakhina S, Medina DJ, Balsara B, Greenwood S, Huzzy L, Rabson AB, Steward R, Schaar DG
PDCD2 is an evolutionarily conserved eukaryotic protein with unknown function. The Drosophlia PDCD2 ortholog Zfrp8 has an essential function in fly hematopoiesis. Zfrp8 mutants exhibit marked lymph gland hyperplasia that results from increased proliferation of partially differentiated hemocytes, suggesting Zfrp8 may participate in cell growth. Based on the above observations we have focused on the role of PDCD2 in human cancer cell proliferation and hypothesized that aberrant PDCD2 expression may be characteristic of human malignancies. We report that PDCD2 is highly expressed in human acute leukemia cells as well as in normal hematopoietic progenitors. PDCD2 knockdown in cancer cells impairs their proliferation, but not viability relative to parental cells, supporting the notion that PDCD2 overexpression facilitates cancer cell growth. Prospective analysis of PDCD2 in acute leukemia patients indicates PDCD2 RNA expression correlates with disease status and is a significant predictor of clinical relapse. PDCD2′s role in cell proliferation and its high expression in human malignancies make it an attractive, novel potential molecular target for new anti-cancer therapies.
PMID: 23760497 [PubMed - in process]
Three-way Philadelphia translocation t(9;10;22)(q34;p11.2;q11.2) as a secondary abnormality in an imatinib mesylate-resistant chronic myeloid leukemia patient.
Oncol Lett. 2013 May;5(5):1656-1658
Authors: Al-Achkar W, Wafa A, Ikhtiar A, Liehr T
Chronic myelogenous leukemia (CML) is characterized by the Philadelphia (Ph) chromosome created by the reciprocal translocation t(9:22)(q34;q11), resulting in the chimeric gene breakpoint cluster region (BCR)-Abelson (ABL). Variant Ph chromosome translocations involving chromosomes other than 9 and 22 occur in 5-10% of CML cases. In the present study, a novel case of a Ph chromosome-positive CML in the chronic phase (CP) is reported, with a three-way Ph translocation involving three chromosomal regions, 9q34, 10p11.2 and 22q11.2, in addition to the loss of the Y chromosome, where the latter was a secondary abnormality. Since the majority of CML cases are currently treated with imatinib, variant rearrangements generally have no specific prognostic significance, although the mechanisms involved in resistance to therapy have yet to be investigated. The underlying mechanisms and prognostic implications of these cytogenetic abnormalities are discussed in the present study.
PMID: 23759955 [PubMed - as supplied by publisher]
Targeting phosphatidylinositol 3-kinase signaling in acute myelogenous leukemia.
Expert Opin Ther Targets. 2013 Jun 11;
Authors: Evangelisti C, Evangelisti C, Bressanin D, Buontempo F, Chiarini F, Lonetti A, Soncin M, Spartà A, McCubrey JA, Martelli AM
Introduction: Despite continuous advances in our knowledge of the biology of acute myelogenous leukemia (AML), the prognosis of AML patients treated with standard chemotherapy is still poor, especially in the elderly. Therefore, there is a need for novel targeted and less toxic therapies, particularly for patients who develop resistance to traditional chemotherapeutic drugs. Constitutively active phosphatidylinositol 3-kinase (PI3K) signaling characterizes many types of tumors, including AML, where it negatively influences response to therapeutic treatments. Areas covered: The literature data showed that small inhibitor molecules targeting PI3K signaling induced cell cycle arrest, apoptosis and decreased drug-resistance in AML cells. PI3K inhibitors were also capable of targeting leukemic initiating cells (LICs), the most relevant target for leukemia eradication, whereas they tended to spare healthy hematopoietic stem cells. Expert opinion: Data emerging from pre-clinical settings suggest that the PI3K pathway is critically involved in regulating proliferation, survival and drug-resistance of AML cells. Therefore, we propose that novel drugs targeting this signaling pathway may offer a novel and less toxic treatment option for AML patients, most likely in combination with a lower dosage of traditional chemotherapeutic agents or other innovative therapeutic agents.
PMID: 23755894 [PubMed - as supplied by publisher]
Autologous peripheral blood stem cell transplantation with granulocyte colony-stimulating factor combined conditioning regimen as a postremission therapy for acute myelogenous leukemia in first complete remission.
Int J Hematol. 2013 Jun 11;
Authors: Eto T, Takase K, Miyamoto T, Ohno Y, Kamimura T, Nagafuji K, Takamatsu Y, Teshima T, Gondo H, Taniguchi S, Akashi K, Harada M
We retrospectively analyzed the outcomes of 81 patients with non-M3 acute myelogenous leukemia (AML) in first complete remission (CR1) who were treated with high-dose chemotherapy (HDCT) and autologous peripheral blood stem cell transplantation (Auto-PBSCT) by the Fukuoka Blood and Marrow Transplantation Group between 1989 and 2005. Cytogenetically, 16 patients were defined as good risk, 56 as intermediate risk, and nine as poor risk, following the Southwest Oncology Group criteria. The pre-transplant conditioning regimen consisted of high-dose busulfan, etoposide, and cytarabine (BEA regimen), combined with priming by granulocyte colony-stimulating factor (G-CSF). Disease-free survival (DFS) and overall survival at 5 years were 64.0 % (95 % CI 52.5-73.4) and 66.4 % (95 % CI 54.9-75.6) after Auto-PBSCT at a median follow-up time of 103 months (range 3-240 months), respectively. Two patients died of transplant-related pulmonary complications 6 months after Auto-PBSCT without relapse. The 5-year DFS rates of patients in the genetically good-, intermediate-, and poor-risk groups were 80.8, 64.3, and 33.3 %, respectively, but there was no significant difference statistically among the risk groups (log-rank p = 0.0579). These observations suggest that HDCT supported by Auto-PBSCT with the BEA regimen combined with G-CSF priming is a therapeutic option for postremission therapy of AML in CR1.
PMID: 23754766 [PubMed - as supplied by publisher]
Synthesis, characterization and biological evaluation of some novel P-heterocyclic androst-4-ene derivatives.
Mol Divers. 2013 Jun 9;
Authors: Krsti? NM, Pavlovi? VD, Novakovi? IT, Mati? IZ, Sladi? DM
The reactions of 21-hydroxyprogesterone with Lawesson’s reagent in toluene or [Formula: see text] gave four P-heterocyclic androst-4-ene derivatives (two tautomeric pairs): 4-(3-thioxoandrost-4-en-17[Formula: see text]-yl)-1,3,2-oxathiaphosphole-2- sulfide (2), 4-(3-thioxoandrost-4-en-17[Formula: see text]-ylidene)-1,3,2-oxathiaphospholane-2-sulfide (3), 4-(3-oxoandrost-4-en-17[Formula: see text]-yl)-1,3,2-oxathiaphosphole-2-sulfide (4), and 4-(3-oxoandrost-4-en-17[Formula: see text]-ylidene)-1,3,2- oxathiaphospholane-2-sulfide (5). The structures of all novel 17-substituted steroids were elucidated from their analytic and spectral data (HRMS, IR, 1D NMR and 2D NMR-HSQC, HMBC, NOESY, COSY). The detailed NMR analysis for all compounds revealed the presence of two pairs of signals in approx. 8:2 ratio indicating the existence of two diastereoisomers (a and b) with different configurations at the phosphorus atom. A parallel analysis of heteronuclear 2D [Formula: see text]-[Formula: see text] spectra (HSQC and HMBC) and homonuclear 2D spectra (NOESY and COSY) enabled complete [Formula: see text] and [Formula: see text] assignments of each isomer and provided evidence for the preferred configuration on phosphorus atom. Cytotoxic activity in vitro was tested against four tumor cell lines (human cervix carcinoma HeLa cells, chronic myelogenous leukemia K-562 and two human breast carcinoma MDA-MB-361 and MDA-MB-453 cells). Compounds 3a,b and 4a,b showed a poor activity against HeLa and MDA-MB-453 cell lines, while against MDA-MB-361 cell line, all tested compounds exerted very weak cytotoxic effect. All compounds exerted moderate activity against K562 cells. Antimicrobial activity against Gram-positive, Gram-negative bacteria and fungal cells, and toxicity to brine shrimp Artemia salina were evaluated. All tested compounds showed strong antifungal activity.
PMID: 23748368 [PubMed - as supplied by publisher]
2-Cinnamamido, 2-(3-phenylpropiolamido), and 2-(3-phenylpropanamido)benzamides: Synthesis, antiproliferative activity, and mechanism of action.
Eur J Med Chem. 2013 May 14;65C:427-435
Authors: Raffa D, Maggio B, Raimondi MV, Cusimano MG, Giandomenico A, Carollo A, Conaldi PG, Bai R, Hamel E, Daidone G
Several new benzamides 4a-q were synthesized by stirring in pyridine the acid chlorides 3a-q with the appropriate anthranilamide derivatives 2a-g. Some of the synthesized compounds were evaluated for their in vitro antiproliferative activity against a panel of 5 human cell lines (K562 human chronic myelogenous leukemia cells, MCF-7 breast cancer cells, HTC-116 and HT26 colon cancer cells and NCI H460 non-small cell lung cancer cells).
PMID: 23747810 [PubMed - as supplied by publisher]
Photo-bio-synthesis of irregular shaped functionalized gold nanoparticles using edible mushroom Pleurotus florida and its anticancer evaluation.
J Photochem Photobiol B. 2013 May 20;125C:63-69
Authors: Bhat R, Sharanabasava VG, Deshpande R, Shetti U, Sanjeev G, Venkataraman A
A green chemistry approach to the synthesis of gold nanoparticles using edible mushroom Pleurotus florida (Oyster mushroom) by photo-irradiation method has been attempted. The mixture containing the aqueous gold ions and the mushroom extract was exposed to sunlight; this resulted in the formation of biofunctionalized gold nanoparticles. These nanoparticles were characterized using various techniques like UV-visible spectroscopy; X-ray diffraction studies, Energy dispersive X-ray analysis, Field emission scanning electron microscopy, Atomic force microscopy, Transmission electron microscopy and Fourier transform infrared spectrometry. The obtained biofunctionalized gold nanoparticles showed effective anti-cancer property against four different cancer cell lines A-549 (Human lung carcinoma), K-562 (Human chronic myelogenous leukemia bone marrow), HeLa (Human cervix) and MDA-MB (Human adenocarcinoma mammary gland) and no lethal effect is observed in Vero (African green monkey kidney normal cell) cell lines.
PMID: 23747539 [PubMed - as supplied by publisher]
miR-29b suppresses CML cell proliferation and induces apoptosis via regulation of BCR/ABL1 protein.
Exp Cell Res. 2013 May 1;319(8):1094-101
Authors: Li Y, Wang H, Tao K, Xiao Q, Huang Z, Zhong L, Cao W, Wen J, Feng W
MicroRNAs (miRNAs) are small RNAs that regulate gene expression posttranscriptionally and are critical for many cellular pathways. Recent evidence has shown that aberrant miRNA expression profiles and unique miRNA signaling pathways are present in many cancers. Here, we demonstrate that miR-29b is markedly lower expressed in CML patient samples. Bioinformatics analysis reveals a conserved target site for miR-29b in the 3′-untranslated region (UTR) of ABL1. miR-29b significantly suppresses the activity of a luciferase reporter containing ABL1-3′UTR and this activity is not observed in cells transfected with mutated ABL1-3′UTR. Enforced expression of miR-29b in K562 cells inhibits cell growth and colony formation ability thereby inducing apoptosis through cleavage of procaspase 3 and PARP. Furthermore, K562 cells transfected with a siRNA targeting ABL1 show similar growth and apoptosis phenotypes as cells overexpression of miR-29b. Collectively, our results suggest that miR-29b may function as a tumor suppressor by targeting ABL1 and BCR/ABL1.
PMID: 23428668 [PubMed - indexed for MEDLINE]
SLC22A1-ABCB1 haplotype profiles predict imatinib pharmacokinetics in Asian patients with chronic myeloid leukemia.
PLoS One. 2012;7(12):e51771
Authors: Singh O, Chan JY, Lin K, Heng CC, Chowbay B
OBJECTIVE: This study aimed to explore the influence of SLC22A1, PXR, ABCG2, ABCB1 and CYP3A5 3 genetic polymorphisms on imatinib mesylate (IM) pharmacokinetics in Asian patients with chronic myeloid leukemia (CML).
PATIENTS AND METHODS: Healthy subjects belonging to three Asian populations (Chinese, Malay, Indian; n?=?70 each) and CML patients (n?=?38) were enrolled in a prospective pharmacogenetics study. Imatinib trough (C(0h)) and clearance (CL) were determined in the patients at steady state. Haplowalk method was applied to infer the haplotypes and generalized linear model (GLM) to estimate haplotypic effects on IM pharmacokinetics. Association of haplotype copy numbers with IM pharmacokinetics was defined by Mann-Whitney U test.
RESULTS: Global haplotype score statistics revealed a SLC22A1 sub-haplotypic region encompassing three polymorphisms (rs3798168, rs628031 and IVS7+850C>T), to be significantly associated with IM clearance (p?=?0.013). Haplotype-specific GLM estimated that the haplotypes AGT and CGC were both associated with 22% decrease in clearance compared to CAC [CL (10(-2) L/hr/mg): CAC vs AGT: 4.03 vs 3.16, p?=?0.017; CAC vs CGC: 4.03 vs 3.15, p?=?0.017]. Patients harboring 2 copies of AGT or CGC haplotypes had 33.4% lower clearance and 50% higher C(0h) than patients carrying 0 or 1 copy [CL (10(-2) L/hr/mg): 2.19 vs 3.29, p?=?0.026; C(0h) (10(-6) 1/ml): 4.76 vs 3.17, p?=?0.013, respectively]. Further subgroup analysis revealed SLC22A1 and ABCB1 haplotypic combinations to be significantly associated with clearance and C(0h) (p?=?0.002 and 0.009, respectively).
CONCLUSION: This exploratory study suggests that SLC22A1-ABCB1 haplotypes may influence IM pharmacokinetics in Asian CML patients.
PMID: 23272163 [PubMed - indexed for MEDLINE]