ABSTRACT
BACKGROUND: Pharmacogenomics (PGx) examines the influence of genetic variation on drug responses. With more and more Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines published, PGx is gradually shifting from the reactive testing of single gene toward the preemptive testing of multiple genes. But the profile of PGx genes, especially for the intra-country diversity, is not well understood in China. METHODS: We retrospectively collected preemptive PGx testing data of 22,918 participants from 20 provinces of China, analyzed frequencies of alleles, genotypes and phenotypes of pharmacogenes, predicted drug responses for each participant, and performed comparisons between different provinces. RESULTS AND CONCLUSION: After analyzing 15 pharmacogenes from CPIC guidelines of 31 drugs, we found that 99.97% of individuals may have an atypical response to at least one drug; the participants carry actionable genotypes leading to atypical dosage recommendation for a median of eight drugs. Over 99% of the participants were recommended a decreased warfarin dose based on genetic factors. There were 20 drugs with high-risk ratios from 0.18% to 58.25%, in which clopidogrel showed the highest high-risk ratio. In addition, the high-risk ratio of rasburicase in GUANGDONG (risk ratio (RR) = 13.17, 95%CI:4.06-33.22, p < 0.001) and GUANGXI (RR = 23.44, 95%CI:8.83-52.85, p < 0.001) were significantly higher than that in all provinces. Furthermore, the diversity we observed among 20 provinces suggests that preemptive PGx testing in different geographical regions in China may need to pay more attention to specific genes. These results emphasize the importance of preemptive PGx testing and provide essential evidence for promoting clinical implementation in China.
Subject(s)
Pharmacogenetics , Pharmacogenomic Testing , Humans , Retrospective Studies , China , Pharmacogenetics/methods , GenotypeABSTRACT
The lysosome inhibitors bafilomycin A1 and chloroquine have both lysosomotropic properties and autophagy inhibition ability, and are promising clinical agents to be used in combination with anticancer drugs. In order to investigate this combination effect, HepG2 cells were treated with bafilomycin A1, chloroquine, or/and doxorubicin, and their proliferative ability, induction of apoptosis, and the changes of lysosomal membrane permeabilization and mitochondrial membrane potential were studied. The results demonstrate that treatment with bafilomycin A1 or chloroquine alone at a relatively low concentration promotes the inhibitory effect of doxorubicin on cell growth and apoptosis. Further studies reveal that bafilomycin A1 and chloroquine promote lysosomal membrane permeabilization and the reduction of mitochondrial membrane potential induced by doxorubicin. Our findings suggest that bafilomycin A1 and chloroquine potentiate the anticancer effect of doxorubicin in hepatic cancer cells and that supplementation of conventional chemotherapy with lysosome inhibitors may provide a more efficient anticancer therapy.
Subject(s)
Antineoplastic Agents/pharmacology , Chloroquine/pharmacology , Doxorubicin/pharmacology , Lysosomes/drug effects , Macrolides/pharmacology , Cell Proliferation/drug effects , Cell Proliferation/physiology , Cell Survival/drug effects , Cell Survival/physiology , Dose-Response Relationship, Drug , Drug Synergism , Hep G2 Cells , Humans , Lysosomes/physiology , Membrane Potential, Mitochondrial/drug effects , Membrane Potential, Mitochondrial/physiologyABSTRACT
OBJECTIVES: TMEPAI (transmembrane prostate androgen-induced protein) has been reported to be overexpressed during tumour progression; however, little is known concerning transcriptional mechanisms regulating TMEPAI gene expression. MATERIALS AND METHODS: In this study, the TMEPAI gene promoter has been identified and characterized, and the effects of Sp1 on TMEPAI-induced viability of A549 cells were evaluated, using MTT and colony formation assays. RESULTS: We found that the sequence between -298 and +24 consists of basal promoter activity for TMEPAI. Further analysis indicated that two Sp1-binding sites are crucial for maintaining basal transcriptional activity of the TMEPAI promoter, and chromatin immunoprecipitation assays confirmed direct binding of Sp1 to the TMEPAI promoter. In addition, Sp1 up-regulated TMEPAI protein expression, as well as Sp1 promoting TMEPAI-induced cell proliferation. CONCLUSIONS: These results indicate that the sequence between -298 and +24 consists of the basal promoter activity for TMEPAI. Sp1 promotes TMEPAI expression and contributes to cell proliferation.
