benzyloxycarbonylvalyl-alanyl-aspartyl-fluoromethyl-ketone and Leukemia--Monocytic--Acute

Apoptosis is an essential form of cell death, the failure of which can lead to cancer development. Cancer including leukemia is usually treated with chemotherapeutic drugs that can be effective, but frequently problems are encountered that impair the success of the treatment. Butyrate is a short-chain fatty acid that can have many effects on different cells, including apoptosis.. The effect of a combination treatment with butyrate and antineoplastic agents Ara-C, etoposide and vincristine is evaluate on the leukemic cell line THP-1.. We show that butyrate increased apoptosis induced by the three agents as seen by measurement of DNA content, annexin exposure and morphological characteristics. We also demonstrate that the process of apoptosis induced by butyrate and chemotherapeutic drugs involves the participation of caspases and induced activation of caspase-3, -8 and -9.. We believe that butyrate could be a promising therapeutic agent for the treatment of leukemia in combination with other antineoplastic drugs.

Topics: Amino Acid Chloromethyl Ketones; Antineoplastic Agents; Apoptosis; Blotting, Western; Butyrates; Caspase Inhibitors; Caspases; Cell Line, Tumor; Cytarabine; DNA Replication; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Drug Synergism; Drug Therapy, Combination; Etoposide; Humans; Leukemia, Monocytic, Acute; Vincristine

We found that evodiamine, a major alkaloidal component of Evodiae Fructus (Goshuyu in Japan), inhibited proliferation of several tumor cell lines, but had less effect on human peripheral blood mononuclear cells (PBMC). We used human cervical cancer cells, HeLa, as a model to elucidate the molecular mechanisms of evodiamine-induced tumor cell death. The results showed that evodiamine induced oligonucleosomal fragmentation of DNA in HeLa cells and increased the activity of caspase-3, but not that of caspase-1, in vitro. Both evodiamine-induced DNA fragmentation and caspase-3 activity were effectively inhibited by a caspase-3 inhibitor, z-DEVD-fmk (z-Asp-Glu-Val-Asp-fmk). In addition, evodiamine increased the expression of the apoptosis inducer Bax, but decreased the expression of the apoptosis suppressor Bcl-2 in mitochondria. Taken together, our data indicated that evodiamine alters the balance of Bcl-2 and Bax gene expression and induces apoptosis through the caspase pathway in HeLa cells.

Topics: Alkaloids; Amino Acid Chloromethyl Ketones; Animals; Antineoplastic Agents, Phytogenic; Apoptosis; bcl-2-Associated X Protein; Caspase 3; Caspases; Cell Division; Cysteine Proteinase Inhibitors; Dactinomycin; DNA Fragmentation; Drug Screening Assays, Antitumor; Enzyme Activation; Evodia; Fibrosarcoma; Fluorouracil; Furans; Gene Expression Regulation, Neoplastic; Genes, bcl-2; HeLa Cells; Hepatocytes; Heterocyclic Compounds, 4 or More Rings; Humans; Indole Alkaloids; Leukemia, Monocytic, Acute; Leukocytes, Mononuclear; Melanoma; Mice; Mitochondria; Molecular Structure; Neoplasm Proteins; Oligopeptides; Plant Extracts; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Quinazolines; Rats; Rats, Inbred BUF; Sarcoma 180; Tumor Cells, Cultured

Interleukin-1 beta converting enzyme (ICE)-like proteases, which are synthesized as inactive precursors, play a key role in the induction of apoptosis. We now demonstrate that benzyloxycarbonyl-Val-Ala-Asp (OMe) fluoromethylketone (Z-VAD.FMK), an ICE-like protease inhibitor, inhibits apoptosis by preventing the processing of CPP32 to its active form. These results suggest that novel inhibitors of apoptosis can be developed which prevent processing of proforms of ICE-like proteases.

Topics: Amino Acid Chloromethyl Ketones; Amino Acid Sequence; Apoptosis; Caspase 3; Caspases; Cysteine Endopeptidases; Cysteine Proteinase Inhibitors; Enzyme Activation; Humans; Leukemia, Monocytic, Acute; Leukemia, T-Cell; Molecular Sequence Data; Oligopeptides; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Protease Inhibitors; Tumor Cells, Cultured