rocaglamide and Leukemia-Lymphoma--Adult-T-Cell

Multiple myeloma (MM) is an incurable malignancy by the presently known therapies. TRAIL is a promising anticancer agent that virtually not shows any toxicity to normal cells. We have recently carried out clinical trials with a human circularly permuted TRAIL, CPT, against MM saw a partial response in approximate 20-30% of patients. In the current study, we investigated the cause of CPT resistance and revealed that the majority of the MM patients express elevated levels of c-FLIP. Knockdown of c-FLIP expression by siRNA alone was sufficient to increase CPT-mediated apoptosis in a CPT-resistant human MM cell line U266. To overcome CPT resistance, we investigated the combination of CPT with Rocaglamides(s) in MM which has been shown to inhibit c-FLIP expression in vitro. We show that Rocaglamide(s) overcomes CPT resistance in U266 in vitro and significant increases in anti-tumor efficacies of CPT in mice xenografted with U266. Similar results were also obtained in mice xenografted with the CPT-resistant human acute T-cell leukemia cell line Molt-4. Our study suggests that the combination of Rocaglamide(s) with CPT may provide a more efficient treatment against myeloma and leukemia.

Topics: Animals; Benzofurans; CASP8 and FADD-Like Apoptosis Regulating Protein; Cell Line, Tumor; Drug Resistance, Neoplasm; Humans; Leukemia-Lymphoma, Adult T-Cell; Mice; Multiple Myeloma; Recombinant Proteins; TNF-Related Apoptosis-Inducing Ligand; Xenograft Model Antitumor Assays

The human T-cell leukemia virus type-1 (HTLV-1)-associated adult T-cell leukemia/lymphoma (ATL) is incurable by currently known therapies. ATL samples and cell lines derived from ATL patients show restricted sensitivity to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and CD95 ligand (CD95L). We have recently shown that HTLV-1-infected cells express elevated levels of cellular caspase-8 FLICE-inhibitory protein (c-FLIP) conferring resistance to receptor-mediated apoptosis. This finding underscores the demand to develop new strategies for treatment of ATL. In this study, we show that the naturally occurring herbal compound Rocaglamide (Roc) sensitizes CD95L- and TRAIL-induced apoptosis in HTLV-1-infected cells by downregulation of c-FLIP expression. Investigation of the molecular mechanism of Roc-mediated downregulation of c-FLIP revealed that it inhibits phosphorylation of the translation initiation factor 4E (eIF4E), a key factor that controls the rate-limiting step of translation, through inhibition of the MEK-ERK-MNK1 signaling pathway. This event prevents de novo synthesis of short-lived proteins such as c-FLIP in HTLV-1-infected cells. Our data suggest that Roc may serve as an adjuvant for TRAIL-based anticancer therapy.

Topics: Antineoplastic Agents; Apoptosis; Benzofurans; Carrier Proteins; CASP8 and FADD-Like Apoptosis Regulating Protein; Cell Line, Tumor; Down-Regulation; Eukaryotic Initiation Factor-4E; Extracellular Signal-Regulated MAP Kinases; Fas Ligand Protein; Human T-lymphotropic virus 1; Humans; Intracellular Signaling Peptides and Proteins; Leukemia-Lymphoma, Adult T-Cell; MAP Kinase Kinase Kinases; Phosphorylation; Protein Biosynthesis; Protein Serine-Threonine Kinases; Signal Transduction; TNF-Related Apoptosis-Inducing Ligand