Imatinib, a breakpoint cluster region (BCR)-Abelson murine leukemia(ABL) tyrosine kinase inhibitor (TKI), has revolutionized the treatment of chronic myelogenous leukemia (CML). However, development of multidrug resistance(MDR) limits the use of imatinib. In the present study, we aimed to investigate the mechanisms of cellular resistance to imatinib in CML. Therefore, we established an imatinib-resistant human CML cell line(K562-imatinib) through a stepwise selection process. While characterizing the phenotype of these cells, we found that K562-imatinib cells were 124.6-fold more resistant to imatinib than parental K562 cells. In addition, these cells were cross-resistant to second- and third-generation BCR-ABL TKIs. Western blot analysis and reverse transcription-polymerase chain reaction(RT-PCR) demonstrated that P-glycoprotein(P-gp) and MDR1 mRNA levels were increased in K562-imatinib cells. In addition, accumulation of [14C]6-mercaptopurine (6-MP) was decreased, whereas the ATP-dependent efflux of [14C]6-MP and [3H]methotrexate transport were increased in K562-imatinib cells. These data suggest that the overexpression of P-gp may play a crucial role in acquired resistance to imatinib in CML K562-imatinib cells.
ATP Binding Cassette Transporter, Sub-Family B ; genetics ; metabolism ; Antineoplastic Agents ; pharmacology ; Benzamides ; Drug Resistance, Multiple ; Drug Resistance, Neoplasm ; Fusion Proteins, bcr-abl ; antagonists & inhibitors ; Gene Expression Regulation, Neoplastic ; Humans ; Imatinib Mesylate ; K562 Cells ; Mercaptopurine ; metabolism ; Methotrexate ; metabolism ; Piperazines ; pharmacology ; Protein Kinase Inhibitors ; pharmacology ; Protein-Tyrosine Kinases ; antagonists & inhibitors ; Pyrimidines ; pharmacology ; RNA, Messenger ; metabolism

OBJECTIVETo investigate antimicrobial and bronchodialator effect of hydroalcholic extract of polyherbal drug Shirishadi containing Shirisha (Albezzia lebbeck), Nagarmotha (Cyprus rotandus) & Kantakari (Solanum xanthocarpum).

METHODSAntimicrobial activity was evaluated by disc diffusion method and MIC, MBC, MFC were calculated by micro dilution method. Hydroalcholic extract of this preparation was investigated for its phytochemical analysis, phenol and flavonoid were determined by spectrophotometric method and in vivo bronchodilator effect was analysed by convulsion time.

RESULTSThe phytochemical tests revealed presence of alkaloids, anthraquinones, carbohydrates, flavonoids, saponins and tannins. The antimicrobial result showed the MIC of 6.25 mg/mL against Staphylococcus aureus and 12.5 mg/mL for Escherichia coli and 12.5 mg/mL against remaining bacteria tested, with strong antifungal activity. The maximum inhibition zone is found against Pseudomonas aeruginosa with MIC 16 mg/mL. Drug showed significant bronchodilator effect with 27.86% & 36.13% increase in preconvulsion time of guinea pigs pretreated with 100 & 200 mg/kg body weight of extract.

CONCLUSIONSThe study reveals that the extracts possess antibacterial activity and antifungal activity in a dose dependent manner. This antimicrobial property may be due to presence of several saponins, further studies are highly needed for the drug development.

Albizzia ; chemistry ; Animals ; Anti-Bacterial Agents ; chemistry ; pharmacology ; Bacteria ; drug effects ; Bronchial Spasm ; Bronchodilator Agents ; chemistry ; pharmacology ; Guinea Pigs ; Medicine, Ayurvedic ; Microbial Sensitivity Tests ; Phytotherapy ; Plant Extracts ; chemistry ; pharmacology ; Solanum ; chemistry

In this study we examined the suitability of the-imidazo[4,5-]pyridine ring system in developing novel anticancer and anti-inflammatory agents incorporating a diaryl pharmacophore. Eight 2,3-diaryl-3-imidazo[4,5-]pyridine derivatives retrieved from our in-house database were evaluated for their cytotoxic activity against nine cancer cell lines. The results indicated that the compounds showed moderate cytotoxic activity against MCF-7, MDA-MB-468, K562 and SaOS2 cells, with K562 being the most sensitive among the four cancer cell lines. The eight 2,3-diaryl-3-imidazo[4,5-]pyridine derivatives were also evaluated for their COX-1 and COX-2 inhibitory activity. The results showed that compoundexhibited 2-fold selectivity with ICvalues of 9.2 and 21.8 µmol/L against COX-2 and COX-1, respectively. Molecular docking studies on the most active compoundrevealed a binding mode similar to that of celecoxib in the active site of the COX-2 enzyme.