Association of the common CYP1A1*2C variant [Ile462Val Polymorphism] with Chronic Myeloid Leukemia [CML] in patients undergoing Imatinib Therapy

Objective: Cytochrome P450 is one of the major drug metabolizing enzyme families and its role in metabolism of cancer drugs cannot be less emphasized. The association between single nucleotide polymorphisms [SNPs] in CYP1A1 and pathogenesis of chronic myeloid leukemia [CML] has been investigated in several studies, but the results observed vary based on varied risk factors. The objective of this study was to investigate the risk factors associated with the CYP1A1*2C [rs1048943: A>G] polymorphism in CML patients and its role in therapeutic response to imatinib mesylate [IM] affecting clinico-pathological parameters, in the Indian population

Materials and Methods: In this case-control study, CYP1A1*2C was analysed in CML patients. After obtaining approval from the Ethics Committee of oncology hospital, we collected blood samples from 132 CML patients and 140 matched controls. Genomic DNA was extracted and all the samples were analysed for the presence of the CYP1A1*2C polymorphism using allele-specific polymerase chain reaction, and we examined the relationship of genotypes with risk factors such as gender, age, phase of the disease and other clinical parameters

Results: We observed a significant difference in the frequency distribution of CYP1A1*2C genotypes AA [38 vs. 16%, P=0.0001], AG [57 vs. 78%, P=0.0002] and GG [5 vs. 6%, P=0.6635] between patients and controls. In terms of response to IM therapy, significant variation was observed in the frequencies of AA vs. AG in major [33 vs. 67%] and poor [62 vs. 31%] hematological responders, and AA vs. AG in major [34 vs. 65%] and poor [78 vs. 22%] cytogenetic responders. However, the patients with the GG homozygous genotype did not show any significant therapeutic outcome

Conclusion: The higher frequency of AG in controls indicates that AG may play a protective role against developing CML. We also found that patients with the AG genotype showed favorable treatment response towards imatinib therapy, indicating that this polymorphism could serve as a good therapeutic marker in predicting response to such therapy

Thioredoxin system: a model for determining novel lead molecules for breast Cancer chemotherapy

Thioredoxin reductase 1 [TXNRD1] and thioredoxin interacting protein [TXNIP] also known as thioredoxin binding protein 2 or vitamin D3-upregulated protein 1 are key players in oxidative stress control. Thioredoxin [TRX] is one of the major components of the thiol reducing system and plays multiple roles in cellular processes. Computational analyses of TXNRD1, TXNIP and TRX expressions have not been analyzed in relation to prognosis of breast cancer. High expression of TXNRD1 and low expression of TXNIP are associated with worst prognosis in breast cancer. Using bioinformatics applications we studied sequence analysis, molecular modeling, template and fold recognition, docking and scoring of thioredoxin as a target. The resultant model obtained was validated based on the templates from I-TASSER server and binding site residues were predicted. The predicted model was used for Threading and Fold recognition and was optimized using GROMACS. The generated model was validated using programs such as Procheck, Ramachandran plot, verify-3d and Errat value from Saves server, and the results show that the model is reliable. Next we obtained small molecules from pubchem and chembank which are databases for selecting suitable ligands for our modeled target. These molecules were screened for docking, using GOLD and scoring was obtained using Chemscore as a scoring function. This study predicted the ligand interaction of four molecules with the minimized protein modeled structure and the best ligand with top scores from about 500 molecules screened. These were 3-hydroxy-2,3-diphenylbutanoic acid, 4-amino-3-pentadecylphenol, 3-[hydroxyimino]-2,4-diphenylbutanenitrile and 2-ethyl-1,2-diphenylbutyl carbamate, which are proposed as possible hit molecules for the drug discovery and development process

Cyp1A1 polymorphisms and risk of prostate cancer a meta-analysis

Two common polymorphisms in cytrochronme P450; family 1, subfamily A, polypeptide 1 [CYP1A1]; has been implicated as a risk factor of prostate cancer, but individual studies have been inconclusive or controversial. We reviewed studies on CYP1A1 polymorphisms in patients with prostate cancer. The strategy searching in the PubMed was based on combinations of prostate cancer, CYP1A1, CYP1A1 gene polymorohism, and genetic susceptibility. The last search update was May 2008. The retrieved articles and their bibliographies of were evaluated and reviewed independently by 2 experts. We shortlisted 19 studies, of which 14 on sporadic prostate cancer were analyzed. The random effects odds ratio was 1.350 [95% confidence interval, 1.110 to 1.641; P=.003] for T/C polymorphism and 1.085 [95% confidence interval, 0.863 to 1.364; P=.49] for A/G polymorphism. The A/G polymorphism was not associated with increased risk of prostate cancer. However, the T/C polymorphism showed conflicting results in different studies, while overall, this polymorphism showed significant effects on susceptibility to prostate cancer. There was no significant between study heterogeneity for both polymorphisms with respect to distributed of alleles. This meta-analysis suggests that while the CYP1A1 T/C polymorphism is likely to considerably increase the risk of sporadic prostate cancer on a wide population basis, the A/G polymorphism may not influence this risk. However, the association of polymorphisms may be significant with respect to smoking history, diet habits, ethnicity, and race

In silico and in vitro investigations on cry4a and cry11a toxins of bacillus thuringiensis var israelensis

In the present study we attempted to correlate the structure and function of the cry11a [72 kDa] and cry4a [135 kDa] proteins of Bacillus thuringiensis var israelensis. Homology modeling and secondary structure predictions were done to locate most probable regions for finding helices or strands in these proteins. The JPRED [JPRED consensus secondary structure prediction server] secondary structure predictions were chosen for its ability to predict with high accuracies. The homology model predicted by CPH [CPH Homology Modelling server] modeler showed a distinct region of helices and sheets. The membrane spanning helices were predicted using TOPPRED [TOPPRED Topology prediction of membrane proteins server]; these helices are known to play crucial role in cell lyses. The role of one such segment corresponding to amino acids 132-150 of cry4a protein, which had a large hydrophobic moment, was elucidated. The Circular Dichroism spectra of the peptide showed helical structure in methanol and registered sheet structure in HEPES [4-[2-hydroxyethyl]-1-piperazineethanesulfonic acid]. The biological activity of this peptide was investigated. The peptide showed weak hemolytic activity in vitro. This may be due to the synthetic peptide used rather than the whole molecule in the native environment. The ability of the peptide and the alkali solubilized crystal proteins to perturb the synthetic membrane was investigated using carboxyflourescein trapped liposomes. The leakage caused by alkali solubilized extract was double than the leakage caused by synthetic peptide. In case of alkali solubilized extract, various osmoprotectants were seen to delay lytic activity. Thus it is clear that the cry proteins are highly active and lethal in their native state. Not only the membrane spanning segments but the whole molecule plays a crucial role in lysis