pg-545 and Lymphoma

pg-545 has been researched along with Lymphoma* in 3 studies

Other Studies

3 other study(ies) available for pg-545 and Lymphoma

ArticleYear
The heparanase inhibitor PG545 is a potent anti-lymphoma drug: Mode of action.
    Matrix biology : journal of the International Society for Matrix Biology, 2019, Volume: 77

    It is now well recognized that heparanase, an endo-β-D-glucuronidase capable of cleaving heparan sulfate (HS) side chains at a limited number of sites, promotes tumorigenesis by diverse mechanisms. Compelling evidence strongly implies that heparanase is a viable target for cancer therapy, thus encouraging the development of heparanase inhibitors as anti-cancer therapeutics. Here, we examined the efficacy and mode of action of PG545, an HS-mimetic heparanase inhibitor, in human lymphoma. We found that PG545 exhibits a strong anti-lymphoma effect, eliciting lymphoma cell apoptosis. Notably, this anti-lymphoma effect involves ER stress response that was accompanied by increased autophagy. The persistent ER stress evoked by PG545 is held responsible for cell apoptosis because apoptotic cell death was attenuated by an inhibitor of PERK, a molecular effector of ER stress. Importantly, PG545 had no such apoptotic effect on naïve splenocytes, further encouraging the development of this compound as anti-lymphoma drug. Surprisingly, we found that PG545 also elicits apoptosis in lymphoma cells that are devoid of heparanase activity (i.e., Raji), indicating that the drug also exerts heparanase-independent function(s) that together underlie the high potency of PG545 in preclinical cancer models.

    Topics: Animals; Antibodies, Monoclonal; Antineoplastic Agents; Apoptosis; Autophagy; Carcinogenesis; Cell Cycle Checkpoints; Cell Line, Tumor; Endoplasmic Reticulum Stress; Enzyme Inhibitors; Gene Expression Regulation; Glucuronidase; Heparin; Heparitin Sulfate; Humans; Lymphocytes; Lymphoma; Mice; Mice, Inbred NOD; Mice, SCID; Primary Cell Culture; Saponins; Spleen; Xenograft Model Antitumor Assays

2019
Heparan sulfate mimetic PG545-mediated antilymphoma effects require TLR9-dependent NK cell activation.
    The Journal of clinical investigation, 2016, Volume: 126, Issue:1

    Heparan sulfate (HS) is an essential component of the extracellular matrix (ECM), which serves as a barrier to tumor invasion and metastasis. Heparanase promotes tumor growth by cleaving HS chains of proteoglycan and releasing HS-bound angiogenic growth factors and facilitates tumor invasion and metastasis by degrading the ECM. HS mimetics, such as PG545, have been developed as antitumor agents and are designed to suppress angiogenesis and metastasis by inhibiting heparanase and competing for the HS-binding domain of angiogenic growth factors. However, how PG545 exerts its antitumor effect remains incompletely defined. Here, using murine models of lymphoma, we determined that the antitumor effects of PG545 are critically dependent on NK cell activation and that NK cell activation by PG545 requires TLR9. We demonstrate that PG545 does not activate TLR9 directly but instead enhances TLR9 activation through the elevation of the TLR9 ligand CpG in DCs. Specifically, PG545 treatment resulted in CpG accumulation in the lysosomal compartment of DCs, leading to enhanced production of IL-12, which is essential for PG545-mediated NK cell activation. Overall, these results reveal that PG545 activates NK cells and that this activation is critical for the antitumor effect of PG545. Moreover, our findings may have important implications for improving NK cell-based antitumor therapies.

    Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Heparitin Sulfate; Humans; Interleukin-12; Killer Cells, Natural; Lymphocyte Activation; Lymphoma; Lysosomes; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Myeloid Differentiation Factor 88; Oligodeoxyribonucleotides; Saponins; Toll-Like Receptor 9

2016
Heparanase-neutralizing antibodies attenuate lymphoma tumor growth and metastasis.
    Proceedings of the National Academy of Sciences of the United States of America, 2016, Jan-19, Volume: 113, Issue:3

    Heparanase is an endoglycosidase that cleaves heparan sulfate side chains of proteoglycans, resulting in disassembly of the extracellular matrix underlying endothelial and epithelial cells and associating with enhanced cell invasion and metastasis. Heparanase expression is induced in carcinomas and sarcomas, often associating with enhanced tumor metastasis and poor prognosis. In contrast, the function of heparanase in hematological malignancies (except myeloma) was not investigated in depth. Here, we provide evidence that heparanase is expressed by human follicular and diffused non-Hodgkin's B-lymphomas, and that heparanase inhibitors restrain the growth of tumor xenografts produced by lymphoma cell lines. Furthermore, we describe, for the first time to our knowledge, the development and characterization of heparanase-neutralizing monoclonal antibodies that inhibit cell invasion and tumor metastasis, the hallmark of heparanase activity. Using luciferase-labeled Raji lymphoma cells, we show that the heparanase-neutralizing monoclonal antibodies profoundly inhibit tumor load in the mouse bones, associating with reduced cell proliferation and angiogenesis. Notably, we found that Raji cells lack intrinsic heparanase activity, but tumor xenografts produced by this cell line exhibit typical heparanase activity, likely contributed by host cells composing the tumor microenvironment. Thus, the neutralizing monoclonal antibodies attenuate lymphoma growth by targeting heparanase in the tumor microenvironment.

    Topics: Animals; Antibodies, Monoclonal; Antibodies, Neutralizing; Cell Proliferation; Glucuronidase; HEK293 Cells; Humans; Luciferases; Lymphoma; Mice, Inbred BALB C; Mice, Inbred NOD; Mice, SCID; Molecular Weight; Neoplasm Metastasis; Recombinant Proteins; Saponins; Tumor Burden; Tumor Microenvironment; Xenograft Model Antitumor Assays

2016