7-((4-Substituted)piperazin-1-yl) derivatives of ciprofloxacin: synthesis and in vitro biological evaluation as potential antitumor agents.

Ciprofloxacin (CP), an antibiotic has been shown to have antiproliferative and apoptotic activities in several cancer cell lines. Moreover, several reports have highlighted the interest of increasing the lipophilicity to improve the antitumor efficacy. These studies have led us to synthesize new CP derivatives of various lipophilicities and to evaluate their activity in five human cancer cell lines.

Cardenolides from Pergularia tomentosa display cytotoxic activity resulting from their potent inhibition of Na+/K+-ATPase.

Two new cardenolide glycosides (1 and 2), along with six known cardenolide glycosides (3-8), have been isolated from the roots of Pergularia tomentosa. In order to investigate their potential anticancer activity, these compounds were tested in an in vitro growth inhibitory assay (a MTT colorimetric assay), including six different human cancer cell lines, and for their ability to inhibit Na(+)/K(+)-ATPase activity, in addition to the morphologic changes induced in human cancer cell lines (using computer-assisted phase-contrast microscopy). The data revealed that these cardenolides displayed marked cytotoxic activity.

IR spectroscopy as a new tool for evidencing antitumor drug signatures.

There is a growing interest for screening antitumor drugs for their mechanism of action on cancer cells. Yet, screening for "modes of action" presents a technical challenge that is beyond the capability of conventional methods used in cellular or molecular biology. Several studies have highlighted the advantages of using infrared spectroscopy for diagnostic purposes at the clinical level for identifying cell types.

Structure-activity relationship analysis of novel derivatives of narciclasine (an Amaryllidaceae isocarbostyril derivative) as potential anticancer agents.

Narciclasine (1) is a plant growth regulator that has been previously demonstrated to be proapoptotic to cancer cells at high concentrations (> or = 1 microM). Data generated in the present study show that narciclasine displays potent antitumor effects in apoptosis-resistant as well as in apoptosis-sensitive cancer cells by impairing the organization of the actin cytoskeleton in cancer cells at concentrations that are not cytotoxic (IC(50) values of 30-90 nM). The current study further revealed that any chemical modification to the narciclasine backbone generally led to compounds of variable stability, weaker activity, or even the complete loss of antiproliferative effects in vitro.

Combining bevacizumab with temozolomide increases the antitumor efficacy of temozolomide in a human glioblastoma orthotopic xenograft model.

Purpose: The aims of the present work were to investigate the in vitro and in vivo antiangiogenic effects of chronic temozolomide treatment on various glioma models and to demonstrate whether bevacizumab (Avastin) increased the therapeutic benefits contributed by temozolomide in glioma.

Experimental Design: The expression levels of various antiangiogenic factors in four glioma cell lines were evaluated after chronic in vitro treatment with temozolomide by Western blot. Proliferation and migration assays were performed on human endothelial cells incubated with supernatants of glioma cells treated with and without temozolomide.

UNBS5162, a novel naphthalimide that decreases CXCL chemokine expression in experimental prostate cancers.

Several naphthalimides have been evaluated clinically as potential anticancer agents. UNBS3157, a naphthalimide that belongs to the same class as amonafide, was designed to avoid the specific activating metabolism that induces amonafide's hematotoxicity. The current study shows that UNBS3157 rapidly and irreversibly hydrolyzes to UNBS5162 without generating amonafide.

Platinated copper(3-clip-phen) complexes as effective DNA-cleaving and cytotoxic agents.

The synthesis and biological activity of three heteronuclear platinum-copper complexes based on 3-Clip-Phen are reported. These rigid complexes have been designed to alter the intrinsic mechanism of action of both the platinum moiety and the Cu(3-Clip-Phen) unit. The platinum centers of two of these complexes are coordinated to a 3-Clip-Phen moiety, an ammine ligand and two chlorides, which are either cis or trans to each other.

2,2,2-Trichloro-N-({2-[2-(dimethylamino)ethyl]-1,3-dioxo-2,3-dihydro-1H-benzo[de]isoquinolin- 5-yl}carbamoyl)acetamide (UNBS3157), a novel nonhematotoxic naphthalimide derivative with potent antitumor activity.

Amonafide (1), a naphthalimide which binds to DNA by intercalation and poisons topoisomerase IIalpha, has demonstrated activity in phase II breast cancer trials, but has failed thus far to enter clinical phase III because of dose-limiting bone marrow toxicity. Compound 17 (one of 41 new compounds synthesized) is a novel anticancer naphthalimide with a distinct mechanism of action, notably inducing autophagy and senescence in cancer cells. Compound 17 (2,2,2-trichloro-N-({2-[2-(dimethylamino)ethyl]-1,3-dioxo-2,3-dihydro-1H-benzo[de]isoquinolin-5-yl}carbamoyl)acetamide (UNBS3157)) was found to have a 3-4-fold higher maximum tolerated dose compared to amonafide and not to provoke hematotoxicity in mice at doses that display significant antitumor effects.

A lactosylated steroid contributes in vivo therapeutic benefits in experimental models of mouse lymphoma and human glioblastoma.

Various mono- and disaccharides were grafted onto a steroid backbone. Whereas in vitro these glycosylated steroids had no cytotoxic effects on six different human cancer cell lines, several of the glycosylated steroids under study did significantly modify the levels of in vitro migration of the human U373 glioblastoma, the A549 non-small-cell-lung cancer (NSCLC), and the PC-3 prostate cancer cells, with more pronounced effects in the case of a monosubstituted beta-L-fucopyranosyl-steroid (19), a monosubstituted beta-D-isomaltosyl-steroid (22), and a monosubstituted beta-D-lactosyl-steroid (24). These three compounds significantly increased the survival of conventional mice grafted subcutaneously with the P388 lymphoma, a lymphoma that metastasizes toward the liver.

The cardenolide UNBS1450 is able to deactivate nuclear factor kappaB-mediated cytoprotective effects in human non-small cell lung cancer cells.

Non-small cell lung cancers (NSCLC) are associated with very dismal prognoses, and adjuvant chemotherapy, including irinotecan, taxanes, platin, and Vinca alkaloid derivatives, offers patients only slight clinical benefits. Part of the chemoresistance of NSCLCs results from the constitutive or anticancer drug-induced activation of the nuclear factor-kappaB (NF-kappaB) signaling pathways. The present study shows that human A549 NSCLC cells display highly activated cytoprotective NF-kappaB signaling pathways.

Identification of a novel cardenolide (2''-oxovoruscharin) from Calotropis procera and the hemisynthesis of novel derivatives displaying potent in vitro antitumor activities and high in vivo tolerance: structure-activity relationship analyses.

Analysis of the methanolic extract of Calotropis procera root barks enabled the identification of a novel cardenolide (2''-oxovoruscharin) to be made. Of the 27 compounds that we hemisynthesized, one (23) exhibited a very interesting profile with respect to its hemisynthetic chemical yield, its in vitro antitumor activity, its in vitro inhibitory influence on the Na+/K+-ATPase activity, and its in vivo tolerance. Compound 23 displayed in vitro antitumor activity on a panel of 57 human cancer cell lines similar to taxol, and higher than SN-38 (the active metabolite of irinotecan), two of the most potent drugs used in hospitals to combat cancer.

Signal transduction in H2O2-induced senescence-like phenotype in human diploid fibroblasts.

A stress-induced senescence-like phenotype is induced by exposure of human diploid fibroblasts to subcytotoxic H2O2 stress. Previous studies showed that TGF-beta1 is responsible for the induction of several biomarkers of replicative senescence within 72 h after stress: senescence-like morphology, senescence-associated beta-galactosidase activity, and an increase in the mRNA steady state level of four senescence-associated genes. Other studies showed that the retinoblastoma protein is responsible for the appearance of these biomarkers in the same conditions.