Showing papers by "Kalpana Joshi published in 2011"

Traditional Medicine to Modern Pharmacogenomics: Ayurveda Prakriti Type and CYP2C19 Gene Polymorphism Associated with the Metabolic Variability

Abstract: Traditional Indian medicine—Ayurveda—classifies the human population into three major constituents or Prakriti known as Vata, Pitta and Kapha types. Earlier, we have demonstrated a proof of concept to support genetic basis for Prakriti. The descriptions in Ayurveda indicate that individuals with Pitta Prakriti are fast metabolizers while those of Kapha Prakriti are slow metabolizers. We hypothesized that different Prakriti may have different drug metabolism rates associated with drug metabolizing enzyme (DME) polymorphism. We did CYP2C19 (Phase I DME) genotyping in 132 unrelated healthy subjects of either sex by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. We observed significant association between CYP2C19 genotype and major classes of Prakriti types. The extensive metabolizer (EM) genotype (*1/*1, *1/*2, *1/*3) was found to be predominant in Pitta Prakriti (91%). Genotype (*1/*3) specific for EM group was present only in Pitta Prakriti. Poor metabolizer (PM) genotype (*2/*2, *2/*3, *3/*3) was highest (31%) in Kapha Prakriti when compared with Vata (12%) and Pitta Prakriti (9%). Genotype (*2/*3) which is typical for PM group was significant in Kapha Prakriti (odds ratio = 3.5, P = .008). We observed interesting correlations between CYP2C19 genotypes and Prakriti with fast and slow metabolism being one of the major distinguishing and differentiating characteristics. These observations are likely to have significant impact on phenotype-genotype correlation, drug discovery, pharmacogenomics and personalized medicine.

Profiling single nucleotide polymorphisms (SNPs) across intracellular folate metabolic pathway in healthy Indians

Abstract: Background & objectives: Many pharmacologically-relevant polymorphisms show variability among different populations. Though limited, data from Caucasian subjects have reported several single nucleotide polymorphism (SNPs) in folate biosynthetic pathway. These SNPs may be subjected to racial and ethnic differences. We carried out a study to determine the allelic frequencies of these SNPs in an Indian ethnic population. Methods: Whole blood samples were withdrawn from 144 unrelated healthy subjects from west India. DNA was extracted and genotyping was performed using PCR-RFLP and Real-time Taqman allelic discrimination for 12 polymorphisms in 9 genes of folate-methotrexate (MTX) metabolism. Results: Allele frequencies were obtained for MTHFR 677T (10%) and 1298 C (30%), TS 3UTR 0bp (46%), MDR1 3435T and 1236T (62%), RFC1 80A (57%), GGH 401T (61%), MS 2756G (34%), ATIC 347G (52%) and SHMT1 1420T (80%) in healthy subjects (frequency of underlined SNPs were different from published study data of European and African populations). Interpretation & conclusions: The current study describes the distribution of folate biosynthetic pathway SNPs in healthy Indians and validates the previous finding of differences due to race and ethnicity. Our results pave way to study the pharmacogenomics of MTX in the Indian population.

A novel inhibitor of hypoxia-inducible factor-1α P3155 also modulates PI3K pathway and inhibits growth of prostate cancer cells

Abstract: Hypoxia-inducible factor-1 (HIF-1) is a master regulator of the transcriptional response to hypoxia. It is essential for angiogenesis and is associated with tumor progression and overexpression of HIF-1α has been demonstrated in many common human cancers. Therefore, HIF-1α is one of the most compelling anticancer targets. To identify HIF-1α inhibitors, luciferase reporter gene assay under hypoxia and normoxia was used. Detailed studies such as western blotting, RT-PCR, immunofluorescence were carried out to elucidate its mechanism of action. Antiangiogenic activity of P3155 was demonstrated by migration assay and tube formation assay. Efficacy study of P3155 was performed on PC-3 xenograft model. P3155 showed specific HIF-1α inhibition with IC50 of 1.4 μM under hypoxia. It suppressed HIF-1α expression as well as PI3K/Akt pathway and abrogated expression of HIF-1-inducible gene viz. vascular endothelial growth factor (VEGF). P3155 in combination with HIF-1α siRNA showed significant synergistic effect. In addition, it demonstrated significant in vivo efficacy and antiangiogenic potential in prostate cancer cell lines. We have identified a novel HIF-1α inhibitor P3155 that also modulates PI3K/Akt pathway, which may contribute to its significant in vitro and in vivo antitumor activity.

Development of Novel Inhibitors Targeting HIF‐1α Towards Anticancer Drug Discovery.

Abstract: Pyridylpyrimidine based potent and selective inhibitors of HIF-1α are designed and synthesized.