silvestrol and Lymphoma

Hematologic malignancies account for a substantial percentage of cancers worldwide, and the heterogeneity and biological characteristics of leukemias and lymphomas present unique therapeutic challenges. Although treatment options exist for most of these diseases, many types remain incurable and the emergence of drug resistance is pervasive. Thus, novel treatment approaches are essential to improve outcome. Nearly half of the agents used in cancer therapy today are either natural products or derivatives of natural products. The enormous chemical diversity in nature, coupled with millennia of biological selection, has generated a vast and underexplored reservoir of unique chemical structures with biologic activity. This review will describe the investigation and application of natural products derived from higher plants in the treatment of leukemia and lymphoma and the rationale behind these efforts. In addition to the approved vinca alkaloids and the epipodophyllotoxin derivatives, a number of other plant compounds have shown promise in clinical trials and in preclinical investigations. In particular, we will focus on the discovery and biological evaluation of the plant-derived agent silvestrol, which shows potential for additional development as a new therapeutic agent for B-cell malignancies including chronic lymphocytic leukemia.

Topics: Antineoplastic Agents, Phytogenic; Biological Products; Drug Screening Assays, Antitumor; Humans; Leukemia; Lymphoma; Models, Biological; Molecular Structure; Triterpenes

The rocaglates/rocaglamides are a class of natural products known to display potent anticancer activity. One such derivative, silvestrol, has shown activity comparable to taxol in certain settings. Here, we report the synthesis of various rocaglamide analogues and identification of a hydroxamate derivative (-)-9 having activity similar to silvestrol in vitro and ex vivo for inhibition of protein synthesis. We also show that (-)-9 synergizes with doxorubicin in vivo to reduce Eμ-Myc driven lymphomas.

Topics: Animals; Antineoplastic Agents; Benzofurans; Cell Line, Tumor; Cell Survival; Doxorubicin; Drug Screening Assays, Antitumor; Drug Synergism; Eukaryotic Initiation Factor-4F; Humans; Hydroxamic Acids; Lymphoma; Mice; Mice, Inbred C57BL; Microsomes, Liver; Protein Subunits; Protein Synthesis Inhibitors; Stereoisomerism; Structure-Activity Relationship; Triterpenes

Disablement of cell death programs in cancer cells contributes to drug resistance and in some cases has been associated with altered translational control. As eukaryotic translation initiation factor 4E (eIF4E) cooperates with c-Myc during lymphomagenesis, induces drug resistance, and is a genetic modifier of the rapamycin response, we have investigated the effect of dysregulation of the ribosome recruitment phase of translation initiation on tumor progression and chemosensitivity. eIF4E is a subunit of eIF4F, a complex that stimulates ribosome recruitment during translation initiation by delivering the DEAD-box RNA helicase eIF4A to the 5' end of mRNAs. eIF4A is thought to prepare a ribosome landing pad on mRNA templates for incoming 40S ribosomes (and associated factors). Using small molecule screening, we found that cyclopenta[b]benzofuran flavaglines, a class of natural products, modulate eIF4A activity and inhibit translation initiation. One member of this class of compounds, silvestrol, was able to enhance chemosensitivity in a mouse lymphoma model in which carcinogenesis is driven by phosphatase and tensin homolog (PTEN) inactivation or elevated eIF4E levels. These results establish that targeting translation initiation can restore drug sensitivity in vivo and provide an approach to modulating chemosensitivity.

Topics: Animals; Apoptosis; Benzofurans; Cell Line; Cell Line, Tumor; Disease Models, Animal; Doxorubicin; Drug Resistance, Neoplasm; Drug Synergism; Eukaryotic Initiation Factor-4A; Eukaryotic Initiation Factor-4E; Female; HeLa Cells; Humans; Lymphoma; Mice; Mice, Inbred C57BL; Peptide Chain Initiation, Translational; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerases; Polyribosomes; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; Sirolimus; Thapsigargin; Triterpenes