homoharringtonine and Lymphoma

Topics: Animals; Antineoplastic Agents; Apoptosis; bcl-2-Associated X Protein; Cadherins; Caspase 3; Caspase 9; Cell Line, Tumor; Cell Proliferation; Cephalotaxus; Curcuma; Curcumin; Drug Therapy, Combination; Homoharringtonine; Lymphoma; Mice, Inbred BALB C; Mice, Nude; Neoplasm Invasiveness; Phytotherapy; Plant Extracts; Signal Transduction; Smad3 Protein; Transforming Growth Factor beta; Xenograft Model Antitumor Assays

Harringtonine (HT) is a naturally occurring alkaloid isolated from the plant genus Cephalotaxus. It possesses antileukemic activity and has been clinically utilized for the treatment of acute leukemia and lymphoma. Sodium periodate (NaIO

Topics: Alkaloids; Antibodies, Monoclonal; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cephalotaxus; Harringtonines; HL-60 Cells; Humans; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Lymphoma; Periodic Acid

Anorexia-cachexia syndrome (ACS) is a major determinant of cancer-related death that causes progressive body weight loss due to depletion of skeletal muscle mass and body fat. Here, we report the development of a novel preclinical murine model of ACS in which lymphomas harbor elevated Myc and activated mTOR signaling. The ACS phenotype in this model correlated with deregulated expression of a number of cytokines, including elevated levels of interleukin-10 which was under the direct translational control of mTOR. Notably, pharmacologic intervention to impair protein synthesis restored cytokine production to near-normal levels, delayed ACS progression, and extended host survival. Together, our findings suggest a new paradigm to treat ACS by strategies which target protein synthesis to block the production of procachexic factors.

Topics: Animals; Anorexia; Antineoplastic Agents; Body Weight; Cachexia; Cell Line, Tumor; Colonic Neoplasms; Disease Models, Animal; Female; Harringtonines; Homoharringtonine; Humans; Interleukin-10; Kaplan-Meier Estimate; Lymphoma; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Protein Biosynthesis; Proto-Oncogene Proteins c-myc; Signal Transduction; Sirolimus; Syndrome; TOR Serine-Threonine Kinases

The process of translation occurs at a nexus point downstream of a number of signal pathways and developmental processes. Modeling activation of the PTEN/AKT/mTOR pathway in the Emu-Myc mouse is a valuable tool to study tumor genotype/chemosensitivity relationships in vivo. In this model, blocking translation initiation with silvestrol, an inhibitor of the ribosome recruitment step has been showed to modulate the sensitivity of the tumors to the effect of standard chemotherapy. However, inhibitors of translation elongation have been tested as potential anti-cancer therapeutic agents in vitro, but have not been extensively tested in genetically well-defined mouse tumor models or for potential synergy with standard of care agents.. Here, we chose four structurally different chemical inhibitors of translation elongation: homoharringtonine, bruceantin, didemnin B and cycloheximide, and tested their ability to alter the chemoresistance of Emu-myc lymphomas harbouring lesions in Pten, Tsc2, Bcl-2, or eIF4E. We show that in some genetic settings, translation elongation inhibitors are able to synergize with doxorubicin by reinstating an apoptotic program in tumor cells. We attribute this effect to a reduction in levels of pro-oncogenic or pro-survival proteins having short half-lives, like Mcl-1, cyclin D1 or c-Myc. Using lymphomas cells grown ex vivo we reproduced the synergy observed in mice between chemotherapy and elongation inhibition and show that this is reversed by blocking protein degradation with a proteasome inhibitor.. Our results indicate that depleting short-lived pro-survival factors by inhibiting their synthesis could achieve a therapeutic response in tumors harboring PTEN/AKT/mTOR pathway mutations.

Topics: Animals; Base Sequence; Cell Line, Tumor; Cyclin D1; Cycloheximide; Depsipeptides; DNA Primers; Drug Resistance, Neoplasm; Eukaryotic Initiation Factor-4E; Female; Genes, bcl-2; Genes, myc; Harringtonines; Homoharringtonine; Lymphoma; Mice; Mice, Inbred C57BL; Mutation; Myeloid Cell Leukemia Sequence 1 Protein; Peptide Chain Elongation, Translational; Proto-Oncogene Proteins c-bcl-2; Proto-Oncogene Proteins c-myc; PTEN Phosphohydrolase; Quassins; Tuberous Sclerosis Complex 2 Protein; Tumor Suppressor Proteins