14 research outputs found
Down-regulation of Survivin enhances sensitivity to BPR0L075 in human cancer cells via caspase-independent mechanisms
Background: BPR0L075 [6-methoxy-3-(3',4',5'-trimethoxy-benzoyl)-1H-indole] is a novel anti-cancer compound. It inhibits tubulin polymerization and induces mitochondrial-dependent apoptosis in various human cancer cells with different multi-drug resistance (MDR) status. Over-expression of an anti-apoptotic molecule, survivin, causes drug-resistance in various cancers. Survivin inhibits apoptosis by interfering caspase-3 and promotes cell growth by stabilizing microtubule networks. Here, we determined the effects of down-regulation of survivin in BPR0L075 (L075) treatment. Methods: Western blot analysis was used to determine the expression level of survivin in L075-untreated/-treated human oral carcinoma KB and nasopharyngeal carcinoma HONE-1 cancer cells. siRNA was used to down-regulate endogenous survivin. MTT cell viability assay, real-time caspase-3 activity assay and immuno-fluorescence microscopy were used to analyze downstream effects. Results: Survivin expression was up-regulated in both KB and HONE-1 cells in response to L075 treatment. Down-regulation of survivin induced hyper-sensitivity to L075 in KB and re-stored sensitivity to L075 in KB-derived L075-resistant KB-L30 cancer cells. At the molecular level, down-regulation of survivin induced changes in microtubule dynamics in both KB and KB-L30 cells. Surprisingly, down-regulation of survivin did not enhance the activity of caspase-3 in L075 therapy. Instead, down-regulation of survivin induced translocation of the apoptosis-inducing factor (AIF) from cytoplasm to nucleus. Conclusion: Down-regulation of survivin improved drug sensitivity to L075 in both KB and L075-resistant KB-L30 cancer cells, possibly through a tubulin-dependent and caspase-independent mechanism. We suggest that combining BPR0L075 and survivin inhibitor may give better clinical outcome than the use of BPR0L075 monotherapy in future clinical trials
BPR1K653, a Novel Aurora Kinase Inhibitor, Exhibits Potent Anti-Proliferative Activity in MDR1 (P-gp170)-Mediated Multidrug-Resistant Cancer Cells
Over-expression of Aurora kinases promotes the tumorigenesis of cells. The aim of this study was to determine the preclinical profile of a novel pan-Aurora kinase inhibitor, BPR1K653, as a candidate for anti-cancer therapy. Since expression of the drug efflux pump, MDR1, reduces the effectiveness of various chemotherapeutic compounds in human cancers, this study also aimed to determine whether the potency of BPR1K653 could be affected by the expression of MDR1 in cancer cells.BPR1K653 specifically inhibited the activity of Aurora-A and Aurora-B kinase at low nano-molar concentrations in vitro. Anti-proliferative activity of BPR1K653 was evaluated in various human cancer cell lines. Results of the clonogenic assay showed that BPR1K653 was potent in targeting a variety of cancer cell lines regardless of the tissue origin, p53 status, or expression of MDR1. At the cellular level, BPR1K653 induced endo-replication and subsequent apoptosis in both MDR1-negative and MDR1-positive cancer cells. Importantly, it showed potent activity against the growth of xenograft tumors of the human cervical carcinoma KB and KB-derived MDR1-positive KB-VIN10 cells in nude mice. Finally, BPR1K653 also exhibited favorable pharmacokinetic properties in rats.BPR1K653 is a novel potent anti-cancer compound, and its potency is not affected by the expression of the multiple drug resistant protein, MDR1, in cancer cells. Therefore, BPR1K653 is a promising anti-cancer compound that has potential for the management of various malignancies, particularly for patients with MDR1-related drug resistance after prolonged chemotherapeutic treatments
Synthesis of 4-(benzamide)-and 4- (phthalimide)-substituted phenoxypropanolamines and their <img src='/image/spc_char/beta.gif' border=0><sub>1</sub>-, <img src='/image/spc_char/beta.gif' border=0><sub>2</sub>-adrenergic receptor binding studies
1441-1445N-[4-(2-Hydroxy-3-isopropylaminopropoxy)phenyl]-1-oxo-isoindoline 3 possess a cardioselective -adrenergic receptor binding affinity. Herein we attempted to
synthesize the unreduced compound N-[4-(2-hydroxy-3-isopropylaminopropoxy)phenyl]phthalimide
4. But, reaction of N-[4-(2,3-epoxypropoxy)phenyl]phthalimide
10 with isopropylamine opened the
phthalimide ring to give N-[4-(2-hydroxy-3-isopropylaminopropoxy)phenyl]-2-isopropylcarbamoylbenzamide
12 instead of 4 as expected. While treatment of 10 with tert-butylamine
gives N-[4-(3-tert-butylamino-2-hydroxypropoxy)phenyl]phthalimide 15. Further, reaction of 15 with isopropylamine opened the
phthalimide ring to yield N-[4-(3-tert-butylamino-2-hydroxypropoxy)phenyl]-2-isopropylcarbamoylbenzamide
16. Also, reaction of N-[4-(2,3-epoxypropoxy)phenyl]-5,6-dimethoxyphthalimide
11 with isopropylamine affords the
phthalimide ring opened analogue N-[4-(2-hydroxy-3-isopropylaminopropoxy)phenyl]-2-isopropylcarbamoyl-5,6-dimethoxybenzamide 13. Compounds 12, 13, 15 and 16 have been tested for their in
vitro 1-
and 2-adrenergic
receptor binding affinity using turkey erythrocyte membrane (1) and lung homogenate of rats (2). The percentage inhibition of [3H]DHA
binding to both 1-
and 2-adrenergic
receptors are compared with that of the standard non-selective -adrenergic blocking agent propranolol 1 and selective agent atenolol. All the tested compounds exhibit
binding affinity to 1-adrenergic receptors at the tested concentration [10-5
M] and most of them (12, 15, 16) exhibit cardioselectivity (selectivity ratio > 1). The dimethoxy analogue 13
shows selectivity towards 2-adrenergic receptor (selectivity ratio < 1)
Targeting autophagy with small molecules for cancer therapy
Autophagy is a conserved lysosomal-dependent catabolic process that maintains the cellular homeostasis by recycling misfolded proteins and damaged organelles. It involves a series of ordered events (initiation, nucleation, elongation, lysosomal fusion and degradation) that are tightly regulated/controlled by diverse cell signals and stress. It is like a double-edged sword that can play either a protective or destructive role in cancer, by pro-survival or apoptotic cues. Recently, modulating autophagy by pharmacological agents has become an attractive strategy to treat cancer. Currently, a number of small molecules that inhibit autophagy initiation (e.g., ULK kinase inhibitors), nucleation (e.g., Vps34 inhibitors), elongation (e.g., ATG4 inhibitors) and lysosome fusion (e.g., chloroquine, hydroxyl chloroquine, etc.) are reported in pre-clinical and clinical study. Also a number of small molecules reported to induce autophagy by targeting mammalian target of rapamycin (e.g., rapamycin analogs) or adenosine 5’-monophosphate-activated protein kinase (e.g., sulforaphane). The study results suggest that many potential “druggable” targets exist in the autophagy pathway that could be harnessed for developing new cancer therapeutics. In this review, we discuss the reported autophagy modulators (inhibitors and inducers), their molecular mode of action and their applications in cancer therapy
Delineating the active site architecture of G9a lysine methyltransferase through substrate and inhibitor binding mode analysis: a molecular dynamics study
<p>Mono- and di-methylation of the H3K9 residue in the histone tail by G9a lysine methyltransferase is associated with transcriptional suppression of genes. Here, we use molecular dynamics simulation and free energy calculations of five different modified/mutated G9a substrate peptides to elucidate the rationale behind the substrate binding to G9a. We also investigated the binding energy contribution based architecture of the active site of G9a to understand substrate and inhibitor binding. Wild-type peptide (H3K9) shows better binding affinity than mono- and di-methylated lysine (K9) and other modified peptides (K9A and R8A). Arg8 of the substrate peptide is crucial for determining the degree of conformational freedom/stability of the wild-type substrate peptide, as well as binding to G9a. Our results also suggest that the G9a active site is segregated into energy rich and low regions, and the energy rich region alone is used by the inhibitors for binding. These insights into the active site architecture should be taken into consideration in virtual screening experiments designed to discover novel inhibitors for G9a. In particular, compounds that could interact with the six residues of G9a – Asp1074, Asp1083, Leu1086, Asp1088, Tyr1154 and Phe1158 – should be preferentially tested in G9a inhibition biological assays.</p> <p>Communicated by Ramaswamy H. Sarma</p