6-Substituted imidazo[1,2-a]pyridines: Synthesis and biological activity against colon cancer cell lines HT-29 and Caco-2.
Eur J Med Chem. 2011 Jul 27;
Authors: Dahan-Farkas N, Langley C, Rousseau AL, Yadav DB, Davids H, de Koning CB
Abstract A range of 6-substituted imidazo[1,2-a]pyridines were synthesized using a multicomponent coupling reaction. Most of these compounds were found to exhibit excellent activity against the colon cancer cell lines HT-29 and Caco-2, whilst not showing significant toxicity against white blood cells. Our studies have shown that the proteolytic phase of apoptosis was initiated 2 h after treatment with these imidazo-[1,2-a]pyridines. The data suggests that the imidazo[1,2-a]pyridine-induced cell death in HT-29 and Caco-2 cells is mediated via pathway(s) that include the release of cytochrome c from the mitochondria to the cytosol and the activation of caspase 3 and caspase 8.
PMID: 21843907 [PubMed - as supplied by publisher]
Type III TGF-? Receptor Enhances Colon Cancer Cell Migration and Anchorage-Independent Growth.
Neoplasia. 2011 Aug;13(8):758-70
Authors: Gatza CE, Holtzhausen A, Kirkbride KC, Morton A, Gatza ML, Datto MB, Blobe GC
Abstract The type III TGF-? receptor (T?RIII or betagylcan) is a TGF-? superfamily coreceptor with emerging roles in regulating TGF-? superfamily signaling and cancer progression. Alterations in TGF-? superfamily signaling are common in colon cancer; however, the role of T?RIII has not been examined. Although T?RIII expression is frequently lost at the message and protein level in human cancers and suppresses cancer progression in these contexts, here we demonstrate that, in colon cancer, T?RIII messenger RNA expression is not significantly altered and T?RIII expression is more frequently increased at the protein level, suggesting a distinct role for T?RIII in colon cancer. Increasing T?RIII expression in colon cancer model systems enhanced ligand-mediated phosphorylation of p38 and the Smad proteins, while switching TGF-? and BMP-2 from inhibitors to stimulators of colon cancer cell proliferation, inhibiting ligand-induced p21 and p27 expression. In addition, increasing T?RIII expression increased ligand-stimulated anchorage-independent growth, a resistance to ligand- and chemotherapy-induced apoptosis, cell migration and modestly increased tumorigenicity in vivo. In a reciprocal manner, silencing endogenous T?RIII expression decreased colon cancer cell migration. These data support a model whereby T?RIII mediates TGF-? superfamily ligand-induced colon cancer progression and support a context-dependent role for T?RIII in regulating cancer progression.
Cancer selective metallocenedicarboxylates of the fungal cytotoxin illudin M.
J Med Chem. 2011 Aug 18;
Authors: Schobert R, Seibt S, Mahal K, Ahmad A, Biersack B, Effenberger-Neidnicht K, Padhye S, Sarkar FH, Mueller T
Abstract The diester 2a obtained from 1,1'-ferrocenedicarboxylic acid and the highly and indiscriminately cytotoxic fungal metabolite illudin M (1) displayed antiproliferative activity at submicromolar IC50(72 h) values against a panel of eight cancer cell lines. Compound 2a was about forty times less toxic than 1 to non-malignant human foreskin fibroblasts (HF). The analogous bis(illudinyl M) 1,1'-ruthenocenedicarboxylate (2b) exhibited submicromolar IC50(72 h) values only against MDA-MB-231 and MCF-7/Topo breast carcinoma and HL-60 leukemia cells. Cytotoxicity studies in the presence of inhibitors of c-Jun N-terminal kinase (JNK) or extracellular signal-regulated kinase (ERK) revealed that the high efficacy of 2a, but not that of 2b, against HCT-116 colon cancer cells depends on active JNK/ERK signaling. A new illudin M lactone 5 was of low anticancer activity, but its ruthenocene diester 6b also reached single-digit micromolar IC50(72 h) values in HCT-116, MCF-7, and HL-60 leukemia cells while not affecting HF. Compounds 2a and 6b were tolerated by mice symptom-free at single doses as high as 25 mg/kg body weight which is evidence for them being chemically stable under physiological conditions. Compound 2a displayed a manageable in vivo toxicity profile when given repeatedly in high doses.
PMID: 21848340 [PubMed - as supplied by publisher]
Abstract ABSTRACT: BACKGROUND: We and others have previously reported that resveratrol (RSV) suppresses colon cancer cell proliferation and elevates apoptosis in vitro and/or in vivo, however molecular mechanisms are not fully elucidated. Particularly, little information is available on RSV's effects on metabolic pathways and the cell-extra cellular matrix (ECM) communication that are critical for cancer cell growth. To identify important targets of RSV, we analyzed whole protein fractions from HT-29 advanced human colon cancer cell line treated with solvent control, IGF-1 (10 nM) and RSV (150 uM) using LC/MS/MS-Mud PIT (Multidimensional Protein Identification Technology). RESULTS: Pentose phosphate pathway (PPP), a vital metabolic pathway for cell cycle progression, was elevated and suppressed by IGF-1 and RSV, respectively in the HT-29 cell line. Enzymatic assays confirmed RSV suppression of glucose-6 phosphate dehydrogenase (rate limiting) and transketolase, key enzymes of the PPP. RSV (150 uM) suppressed, whereas IGF-1 (10 nM) elevated focal adhesion complex (FAC) proteins, talin and pFAK, critical for the cell-ECM communication. Western blotting analyses confirmed the suppression or elevation of these proteins in HT-29 cancer cells treated with RSV or IGF-1, respectively. CONCLUSIONS: Proteomic analysis enabled us to establish PPP and the talin-pFAK as targets of RSV which suppress cancer cell proliferation and induce apoptosis in the colon cancer cell line HT-29. RSV (150 uM) suppressed these pathways in the presence and absence of IGF-1, suggesting its role as a chemo-preventive agent even in obese condition.
PMID: 21849056 [PubMed - as supplied by publisher]
Vectorized ferrocenes with estrogens and vitamin D(2): synthesis, cytotoxic activity and docking studies.
Dalton Trans. 2011 Aug 18;
Authors: Vera J, Gao LM, Santana A, Matta J, Meléndez E
Abstract Three ferrocene complexes vectorized with estrogens and vitamin D(2) were synthesized and fully characterized by spectroscopic, electrochemical and computational methods. The synthesis of these esters was accomplished by reacting ferrocenoyl chloride with the corresponding ROH groups (R = ergocalciferol, estradiol, estrone). The cytotoxicity of these complexes in HT-29 colon cancer and MCF-7 breast cancer cell lines was investigated in vitro. Only ferrocenoyl 17?-hydroxy-estra-1,3,5(10)-trien-3-olate showed good cytotoxic activity in both cell lines, exceeding those of ferrocenium and ferrocene. In MCF-7, ferrocenoyl 17?-hydroxy-estra-1,3,5(10)-trien-3-olate exhibited remarkable IC(50), in the low micromolar range. This may be attributed to the presence of the estradiol vector. Docking studies between alpha-estrogen receptor ligand binding site and ferrocenoyl 17?-hydroxy-estra-1,3,5(10)-trien-3-olate revealed some key hydrophobic interactions that might explain the cytotoxic activity of this ester.
PMID: 21850331 [PubMed - as supplied by publisher]
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