naphthoquinones and Lymphoma--Large-B-Cell--Diffuse

Few effective therapeutic options exist for patients with refractory diffuse large B-cell lymphoma (DLBCL). YM155 is a survivin suppressant with activity against DLBCL in a phase I trial. This phase II study was conducted to better characterize the toxicity and efficacy of this small molecule in patients with refractory DLBCL.. Forty-one patients with a median age of 66 years and 3 prior regimens were enrolled and treated with a YM155 dose of 5 mg/m(2)/d by continuous infusion for 168 hours every 21 days for up to 15 cycles of treatment. The median number of completed cycles was 3.. One patient had a complete remission (CR) (2.4%) with an additional 2 patients (5.9%) responding, with a median progression-free survival of 58 days.. YM155 was well tolerated with major toxicities including anemia and fatigue. Whereas YM155 had limited single-agent activity, preclinical data suggest its role in combination with other agents, including rituximab, and a study of that combination in ongoing.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Disease-Free Survival; Drug Administration Schedule; Early Termination of Clinical Trials; Female; Humans; Imidazoles; Inhibitor of Apoptosis Proteins; Lymphoma, Large B-Cell, Diffuse; Male; Middle Aged; Naphthoquinones; Survivin; Young Adult

Diffuse large B-cell lymphoma (DLBCL), the most common type of aggressive non-Hodgkin lymphoma (NHL), has highly heterogeneous molecular characteristics. Although some patients initially respond to standard R-CHOP therapy, 30-40% develop refractory disease or suffer relapse. Signal transducer and activator of transcription 3 (STAT3), which regulates multiple oncogenic processes, has been found to be constitutively activated in various cancers, including DLBCL, suggesting its potential as a therapeutic target. In this study, we determined that 34% (23/69) of DLBCL patients expressed pSTAT3 (Y705) in tumour tissues. Napabucasin, a novel STAT3 inhibitor, exhibited potent cytotoxicity against NHL cell lines in a dose-dependent manner. Mechanistic studies demonstrated that napabucasin induced intrinsic and extrinsic cell apoptosis, downregulated the expression of STAT3 target genes, including the antiapoptotic protein Mcl-1, and regulated the ROS-mediated mitogen-activated protein kinase (MAPK) pathway. Most importantly, in vivo studies revealed the suppressive efficacy of napabucasin as a monotherapy without obvious toxicity. Furthermore, preliminary combination studies of napabucasin with doxorubicin showed significant synergism both in vitro and in vivo. Thus, our studies provide evidence that napabucasin alone or in combination is a promising therapeutic candidate for DLBCL patients.

Topics: Benzofurans; Caspases; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Doxorubicin; Drug Synergism; Female; Humans; Lymphoma, Large B-Cell, Diffuse; MAP Kinase Signaling System; Naphthoquinones; STAT3 Transcription Factor; Xenograft Model Antitumor Assays

The treatment of activated B cell-like DLBCL (ABC-DLBCL) is one of the urgent unmet medical needs because it is the most resistant DLBCL subtype to current therapies eagerly awaiting effective therapeutic strategies. Recently, the paracaspase MALT1 has emerged as a promising therapeutic target for the treatment of ABC-DLBCL. Herein, we report a new class of MALT1 inhibitors developed by high-throughput screening and structure-based drug design. The original hit, 4-amino-1,2-naphthoquinone series inhibited MALT1 activity but suffered from poor cellular activity. The extensive pharmacophore search led to the discovery of structurally similar β-lapachone that is a direct inhibitor of MALT1 and possesses favorable physicochemical properties. Molecular simulation studies suggested the possibility of the formation of a covalent bond between MALT1 and β-lapachone, which was corroborated by experimental wash-out studies. Inspired by this, we explored the structure-activity relationships by incorporating electron-withdrawing substituents at C8 position of β-lapachone. These MALT1 inhibitors exhibited potent antiproliferative activity to OCI-LY3 cell line and inhibited the cleavage of CYLD mediated MALT1.

Topics: Antineoplastic Agents; Caspases; Cell Line, Tumor; Cell Proliferation; Humans; Lymphoma, Large B-Cell, Diffuse; Models, Molecular; Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; Naphthoquinones; Neoplasm Proteins; Structure-Activity Relationship

There remains an unmet therapeutic need for patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). The purpose of this study was to evaluate the therapeutic potential of sepantronium bromide (YM155), a survivin suppressant, in combination with either bendamustine or both bendamustine and rituximab using DLBCL models.. Human DLBCL cell lines, DB, SU-DHL-8, and WSU-DLCL2, were treated with YM155 in combination with bendamustine. Cell viability, apoptosis induction, protein expression, and cell-cycle distribution were evaluated. Furthermore, antitumor activities of YM155, in combination with bendamustine or both bendamustine and rituximab, were evaluated in mice bearing human DLBCL xenografts.. The combination of YM155 with bendamustine showed greater cell growth inhibition and sub-G1 population than either agent alone. YM155 inhibited bendamustine-induced activation of the ATM pathway and accumulation of survivin at G2-M phase, with greater DNA damage and apoptosis than either single agent alone. In a DLBCL DB murine xenograft model, YM155 enhanced the antitumor activity of bendamustine, resulting in complete tumor regression without affecting body weight. Furthermore, YM155 combined with bendamustine and rituximab, decreased FLT-PET signals in lymph nodes and prolonged overall survival of mice bearing disseminated SU-DHL-8, an activated B-cell-like (ABC)-DLBCL xenografts when compared with the combination of either rituximab and bendamustine or YM155 with rituximab.. These results support a clinical trial of the combination of YM155 with bendamustine and rituximab in relapsed/refractory DLBCL.

Topics: Animals; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Bendamustine Hydrochloride; Cell Line, Tumor; Cell Proliferation; Cell Survival; Humans; Imidazoles; Inhibitor of Apoptosis Proteins; Lymphoma, Large B-Cell, Diffuse; Mice; Naphthoquinones; Neoplasm Recurrence, Local; Nitrogen Mustard Compounds; Rituximab; Survivin; Xenograft Model Antitumor Assays

Survivin and STAT3 pathway have been reported to be important for the growth of diffuse large B-cell lymphoma (DLBCL) cells. Here we investigated the antitumor activity of sepantronium bromide (YM155), a survivin suppressant, in combination with STAT3 inhibitors in DLBCL cell lines in vitro. YM155 synergistically enhanced STAT3 inhibitors (AG490 and STA-21)-induced apoptosis in DLBCL cell lines. Moreover, rituximab, which shows inhibitory activity against STAT3, also sensitized DLBCL cell lines to YM155 regardless of sensitivity to rituximab. These results suggest that combining the inhibition of survivin with STAT3 pathway is an attractive and potentially effective way for the treatment of DLBCL.

Topics: Antineoplastic Agents; Apoptosis; Blotting, Western; Cell Cycle; Cell Proliferation; Drug Synergism; Drug Therapy, Combination; Flow Cytometry; Humans; Imidazoles; Inhibitor of Apoptosis Proteins; Lymphoma, Large B-Cell, Diffuse; Naphthoquinones; Polycyclic Compounds; STAT3 Transcription Factor; Survivin; Tumor Cells, Cultured; Tyrphostins

Through cytotoxicity screening with naphthoquinone derivatives, a novel compound 6-(1-oxoallkyl)-5,8-dimethoxy-1,4-naphthoquinone-S17 (DMNQ-S17) showed its potency against human myeloid leukemia U937 cells. Thus, to elucidate the apoptotic mechanism of DMNQ-S17, this study was performed in myeloid leukemia U937 cells by 2,3-bis [2-methoxy-4-nitro-5-sulfophenyl]-2H-tetrazolium-5-carboxanilide (XTT) assay, eletrophoretic mobility shift assay (EMSA), terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) assay, 4',6-diamidino-2-phenylindole (DAPI) staining, and Western blotting. In the present study, DMNQ-S17 inhibited constitutive NF kappaB activation and its transcriptional activity in U937 cells. In addition, DMNQ-S17 induced apoptotic features such as apoptotic bodies, cell shrinkage and chromatin condensation in U937 cells. Consistently, flow cytometric analysis showed that DMNQ-S17 increased sub-G1 portion and TUNEL positive cells in a concentration-dependent manner. Furthermore, DMNQ-S17 effectively attenuated mitochondrial membrane potential, released cytochrome C, activated caspase-3 expression, and cleaved poly (ADP-ribose) polymerase (PARP). Reversely, caspase-3 and -9 inhibitors also blocked the DMNQ-S17 induced caspase-3 activation and PARP cleavage in U937 cells. Taken together, these findings suggest that DMNQ-S17 can be a potent anticancer candidate for myeloid leukemias by the suppression of NF-kappaB activation leading to the activation of caspase-3 in human myeloid leukemia U937 cells.

Topics: Antineoplastic Agents; Apoptosis; Caspase 3; Caspase Inhibitors; Cytochromes c; Drug Screening Assays, Antitumor; Enzyme Inhibitors; Fluorescent Dyes; Humans; In Situ Nick-End Labeling; Indoles; Leukemia, Myeloid; Lymphoma, Large B-Cell, Diffuse; Male; Membrane Potential, Mitochondrial; Naphthoquinones; NF-kappa B; Poly(ADP-ribose) Polymerases; Prostatic Neoplasms; U937 Cells