Synergistic Effect of SN-38 in Combination with Cetuximab on Angiogenesis and Cancer Cell Invasion.

Background: The combination of irinotecan, a topoisomerase I inhibitor with cetuximab, an antibody against epidermal growth factor receptor, produces synergistic and beneficial effects in patients with irinotecan-refractory colorectal cancer. Our hypothesis was that synergistic effects could be due to anti-angiogenesis and anti-invasion, but not to cytotoxicity.

Materials And Methods: Cytotoxicity was assessed by viability test and flow cytometry.

Synthesis, antiproliferative activity and tubulin targeting effect of acridinone and dioxophenothiazine derivatives.

The synthesis of new acridinone and dioxophenothiazine derivatives along with their tubulin polymerization inhibitory and antiproliferative activities is reported. The analysis of correlation for cytotoxic and antitubulin potential of tested compounds showed that 4-methoxyphenylethyl derivatives 18a and 19a were highly cytotoxic but were regarded to have no significant antitubulin activity. However, the introduction of a 3-hydroxy substituent leading to compounds 18e and 19e, strongly increased the antitubulin potential but was associated with a loss of the antiproliferative activity.

Mechanisms underlying resistance to cetuximab in the HNSCC cell line: role of AKT inhibition in bypassing this resistance.

EGFR is frequently overexpressed in head and neck squamous cell cancer (HNSCC). Cetuximab is a monoclonal antibody designed to interact with EGFR, block its activation, reduce the downstream signaling pathways and induce EGFR internalization. This study aims to investigate the role of the EGFR signaling pathway and EGFR internalization in a cetuximab-resistant cell line and to propose a new therapeutic strategy to optimize treatment of HNSCC.

Unusual cellular uptake of cytotoxic 4-hydroxymethyl-3-aminoacridine.

Aminoacridine derivatives display interesting chemical and biological properties in the field of antitumor agents. The synthesis of 4-hydroxymethyl-3-aminoacridine and its iodo labelled analogue allows the study of cell distribution using two innovative, complementary and powerful techniques, real time fluorescence microscopy and dynamic secondary ion mass spectrometry (SIMS). All the data point to lysosomal localization of the active molecule.

Synthesis and biological evaluation of 4-arylcoumarin analogues of combretastatins.

A series of A-ring polymethoxylated neoflavonoids was prepared by ligand coupling reactions involving either Suzuki or Stille reactions. Cytotoxicity studies indicated a potent activity against a CEM leukemia cell line for the compounds presenting a substitution pattern related to that of combretastatin A-4. The two compounds having a 3'-OH and a 4'-OCH(3) substituents on the 4-phenyl B-ring have no effect on human topoisomerases I and II but potently inhibit, in vitro, microtubule assembly.

Anti-proliferative and apoptotic effects of anandamide in human prostatic cancer cell lines: implication of epidermal growth factor receptor down-regulation and ceramide production.

Background: Anandamide (ANA) is an endogenous lipid which acts as a cannabinoid receptor ligand and with potent anticarcinogenic activity in several cancer cell types.

Methods: The inhibitory effect of ANA on the epidermal growth factor receptor (EGFR) levels expressed on the EGF-stimulated prostatic cancer cells LNCaP, DU145, and PC3 was estimated by ELISA tests. The anti-proliferative and cytotoxic effects of ANA were also evaluated on these human prostatic cancer cell lines by growth tests, flow cytometric analyses, trypan blue dye exclusion assays combined with the Papanicolaou cytological staining method.

Chromophore-modified bisnaphthalimides: DNA recognition, topoisomerase inhibition, and cytotoxic properties of two mono- and bisfuronaphthalimides.

Bisnaphthalimides represent a promising group of DNA-targeted anticancer agents. In this series, the lead compounds elinafide and bisnafide have reached clinical trials, and the search for more potent analogues remains a priority. In the course of a medicinal chemistry program aimed at discovering novel antitumor drugs based on the naphthalimide skeleton, different dimeric molecules containing two tetracyclic neutral DNA intercalating chromophores were synthesized.

Plasma stability of two glycosyl indolocarbazole antitumor agents.

In recent years, several glycosyl indolocarbazole derivatives have been developed as antitumor agents targeting the topoisomerase I-DNA complex and a few of them were evaluated in clinical trials. The lead drug in the series is compound A which bears a formylamino substituent on the N-imide F-ring. This compound has shown promising antitumor activities in vivo and was tested clinically but it has been recently replaced with a more active analogue, J-107088, bearing a (hydroxymethyl-2-hydroxy) ethylamino substituent on the N-imide F-ring.

Induction of apoptosis in HL-60 leukemia and B16 melanoma cells by the acronycine derivative S23906-1.

The benzoacronycine derivative S23906-1 is a highly potent antitumor agent with a broad spectrum of activity against different human solid tumor xenografts. The marked cytotoxic potential of this drug may be the result of its interaction with DNA but the precise mechanism of action remains unclear at present. We have investigated the induction of apoptosis in human promyelocytic leukemia HL-60 and murine melanoma B16 cells treated with S23906-1.

Apoptosis induced by the homocamptothecin anticancer drug BN80915 in HL-60 cells.

The homocamptothecin (hCPT) derivative BN80915 containing a seven-membered lactone ring represents one of the most potent topoisomerase I inhibitors described. This anticancer agent, currently undergoing phase I clinical trials, has been shown to produce a greater number of DNA strand breaks than conventional camptothecins with a six-membered lactone ring. To shed light on the mechanism of action of hCPT at the cellular level, we compared the effects of BN80915 and the classic camptothecin SN-38, the active metabolite of irinotecan, on HL-60 human promyelocytic cancer cells.

DNA topoisomerase II inhibition by peroxisomicine A(1) and its radical metabolite induces apoptotic cell death of HL-60 and HL-60/MX2 human leukemia cells.

Peroxisomicine A(1) (T-514) is a dimeric anthracenone first isolated from the plant Karwinskia humboldtiana. The compound presents a high and selective toxicity toward liver and skin cell cultures and is currently the subject of preclinical studies as an antitumor drug. To date, the molecular basis for its diverse biological effects remains poorly understood.

Relationship between cell cycle changes and variations of the mitochondrial membrane potential induced by etoposide.

Etoposide, a clinically useful anticancer drug, is a potent inhibitor of topoisomerase II. The DNA strand breaks caused by this epipodophyllotoxin lead to apoptotic death of tumor cells. Flow cytometry was used to investigate the relationship between the effects of the drug on the cell cycle of human leukemia HL-60 cells and the variations of the mitochondrial transmembrane potential (DeltaPsi(mt)).

Cytotoxicity and cell cycle effects of the plant alkaloids cryptolepine and neocryptolepine: relation to drug-induced apoptosis.

Cryptolepine and neocryptolepine are two indoloquinoline derivatives isolated from the roots of the african plant Cryptolepis sanguinolenta. These two alkaloids, which only differ by the respective orientation of their indole and quinoline rings, display potent cytotoxic activities against tumour cells and present antibacterial and antiparasitic properties. Our previous molecular studies indicated that these two natural products intercalate into DNA and interfere with the catalytic activity of human topoisomerase II.

Apoptotic response of HL-60 human leukemia cells to the antitumor drug TAS-103.

TAS-103 is a DNA intercalating indeno-quinoline derivative that stimulates DNA cleavage by topoisomerases. This synthetic drug has a broad spectrum of antitumor activity against many human solid tumor xenografts and is currently undergoing clinical trials. We investigated the induction of apoptosis in human promyelocytic leukemia cells treated with TAS-103.

Inhibition of topoisomerase II by the marine alkaloid ascididemin and induction of apoptosis in leukemia cells.

Ascididemin (ASC) is a pentacyclic DNA-intercalating agent isolated from the Mediterranean ascidian Cystodytes dellechiajei. This marine alkaloid exhibits marked cytotoxic activities against a range of tumor cells, but its mechanism of action remains poorly understood. We investigated the effects of ASC on DNA cleavage by human topoisomerases I and II.

The plant alkaloid usambarensine intercalates into DNA and induces apoptosis in human HL60 leukemia cells.

Usambarensine is a plant alkaloid isolated from the roots of Strychnos usambarensis collected in Central Africa. This bis-indole compound displays potent antiamoebic activities and shows antigardial, antimalarial and cytotoxic effects. Usambarensine is highly toxic to B16 melanoma cells and inhibits the growth of leukemia and carcinoma cells.

Effects of vitamin D3 derivatives on growth, differentiation and apoptosis in tumoral colonic HT 29 cells: possible implication of intracellular calcium.

In addition to the effects on tumor cell differentiation and growth inhibition, vitamin D3 derivatives may exert other cellular actions such as the inhibition of angiogenesis or the induction of apoptosis. In this study, we demonstrated that vitamin D3 derivatives, 1,25-dihydroxyvitamin D3, the natural derivative and Ro 23-7553, a synthetic derivative, displayed complex effects in tumoral colonic HT 29 cells. Indeed, as a function of the stage of culture, they induced either apoptosis or differentiation along with a constant cell cycle blockade in G1.

Vitamin-D3 derivatives and breast-tumor cell growth: effect on intracellular calcium and apoptosis.

Vitamin-D3 derivatives are now well-recognized growth inhibitors of numerous tumoral cells and in particular breast-cancer cells. However, the mechanisms by which they operate are not well established. Among the wide range of physiological and biological functions of vitamin-D3 derivatives, the best described include their action on calcium homeostasis.