Glycosaminoglycan-based inhibitors for treatment of prostate cancer

用于治疗前列腺癌的糖胺聚糖抑制剂

• 批准号: 7265404
• 负责人: Vinata B Lokeshwar
• 金额: $ 26.05万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7265404
• 关键词: 7-hydroxycoumarin; Anchorage-Independent Growth; Androgen Receptor; Androgens; Apoptosis; Appendix; B-Lymphocytes; Bioavailable; Blood Circulation; Cancer Model; Cell Cycle Arrest; Cells; Characteristics; Class; Complementary DNA; DU145; Dose; Endoglycosidases; Enzymes; Event; Focal Adhesion Kinase 1; G2/M Arrest; Glycosaminoglycans; Growth; Health; Histologic; Hyaluronic Acid; Hyaluronidase; Immunohistochemistry; Implant; In Vitro; Induction of Apoptosis; Infiltration; Inorganic Sulfates; LNCaP; Laboratories; Lead; Liver; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Modeling; Molecular; Neoplasm Metastasis; Nude Mice; Oligonucleotides; Oligosaccharides; Oral; Oral Administration; PSA level; Patients; Polymers; Property; SPAM1 gene; Signal Transduction; Specimen; Staging; Staining method; Stains; System; Testing; Therapeutic; Therapeutic Agents; Tissues; Toxic effect; Transfection; Transgenic Model; Transgenic Organisms; Tumor-Derived; Umbelliferones; Unspecified or Sulfate Ion Sulfates; Vascularization; Xenograft Model; Xenograft procedure; angiogenesis; antitumor drug; base; cancer cell; caspase-8; cell growth; cell motility; dietary supplements; follow-up; improved; in vivo; inhibitor/antagonist; neoplastic cell; novel; novel therapeutics; prognostic; tumor; tumor growth; tumor progression

DESCRIPTION (provided by applicant): The overall objective of this proposal is to target the tumor-associated hyaluronic acid-hyaluronidase (HA-HAase) system to develop novel therapeutics for prostate cancer (CaP). HA is a glycosaminoglycan that promotes tumor growth and metastasis and HAase is an endoglycosidase that degrades HA into angiogenic fragments. HYAL1 is a tumor-derived HAase, secreted by CaP cells. Combined HA-HYAL1 expression in CaP tissues is an independent prognostic indicator for predicting CaP progression. Blocking HYAL1 expression in CaP cells, by antisense cDNA transfection, decreases tumor growth, invasion and vascularization in xenografts. Sulfated HA (sHA) polymer and small sHA oligosaccharides are potent inhibitors of HYAL1 activity which inhibit CaP cell growth by causing cell-cycle arrest and inhibit the growth of CaP xenografts. These agents decrease activation of focal adhesion kinase and down regulate androgen receptor levels and activity. 4-methyl-umbelliferone (4-MU), used as a dietary supplement for the treatment of liver aliments, inhibits HA synthesis. By blocking pericellular HA formation, 4-MU induces apoptosis in CaP cells by caspase-8 activation and inhibits the growth of CaP xenografts. Both sHA and 4-MU are orally bioavailable, active against both androgen dependent and independent CaP cells and show no histologic or systemic toxicity upon long-term treatment. The main hypothesis to be tested in the proposed project is that, sHA and 4-MU, either alone or in combination, will abrogate CaP growth and its progression. The efficacy of sHA compounds to inhibit cell growth and invasion will be evaluated in vitro. Inhibition of tumor growth, metastasis and angiogenesis will be examined in 3 CaP xenograft models (i.e., orthotopic tumor implant, induced metastasis and intra-osseous growth models). Effect of sHA on HA-HYAL1 mediated intracellular signaling will also be investigated (Aim 1). Effect of 4-MU in controlling CaP cell growth, invasion and motility will be investigated in vitro. Inhibition of tumor growth and metastasis by 4-MU, either alone or in combination with sHA, will be examined in the three CaP xenograft models, as described above. Mechanism of 4-MU induced apoptosis and abrogation of HA- mediated intracellular signaling will also be investigated (Aim 2). Efficacy of sHA and 4-MU, either alone or in combination, as stage-specific treatments for CaP growth and metastasis will be investigated in two transgenic models of CaP (Aim 3). Relevance: This is the first study that proposes to evaluate inhibitors of the HA-HYAL1 system as therapeutic agents for the treatment of CaP. If proven efficacious, sHA compounds and 4-MU will be a novel class of glycosaminoglycan-based target-specific anti-tumor drugs.

描述(申请人提供)：这项提案的总体目标是针对肿瘤相关的透明质酸-透明质酸酶(HA-HASE)系统，以开发前列腺癌(CAP)的新疗法。HA是一种促进肿瘤生长和转移的糖胺聚糖，HAase是一种内切糖苷酶，可将HA降解为血管生成片段。HYAL1是一种肿瘤来源的HAase，由CAP细胞分泌。HA-HYAL1在CAP组织中的联合表达是预测CAP进展的独立预后指标。通过反义c DNA转染法阻断HYAL1在CAP细胞中的表达，可减少异种移植瘤的生长、侵袭和血管生成。硫酸盐化的HA聚合物和小分子HA寡糖是HYAL1活性的有效抑制剂，它通过导致细胞周期停滞来抑制CAP细胞的生长，并抑制CAP异种移植瘤的生长。这些药物减少粘着斑激酶的激活，并下调雄激素受体的水平和活性。4-甲基伞形酮(4-MU)可抑制HA的合成，作为治疗肝脏营养的膳食补充剂。4-MU通过阻断细胞周围HA的形成，通过激活caspase-8诱导CAP细胞凋亡，抑制CAP异种移植瘤的生长。SHA和4-MU均为口服生物利用型，对雄激素依赖和非雄激素依赖的CAP细胞均有抑制作用，长期治疗后无组织学或全身毒性。在拟议的项目中要检验的主要假设是，SHA和4-MU单独或联合使用将取消上限增长及其进展。SHA化合物抑制细胞生长和侵袭的效果将在体外进行评估。在3种CAP异种移植模型(即原位肿瘤移植模型、诱导转移模型和骨内生长模型)中观察对肿瘤生长、转移和血管生成的抑制作用。沙门氏菌对HA-HYAL1介导的细胞内信号的影响也将被研究(目标1)。4-MU在体外对CAP细胞的生长、侵袭和运动的控制作用将被研究。如上所述，4-MU单独或与SHA联合使用对肿瘤生长和转移的抑制作用将在三种帽异种移植模型中进行检测。4-MU诱导细胞凋亡和取消HA介导的细胞内信号转导的机制也将被研究(目标2)。在CAP的两个转基因模型中，将研究单独或联合使用SHA和4-MU作为针对CAP生长和转移的阶段特异性治疗的有效性(目标3)。相关性：这是第一项建议评估HA-HYAL1系统抑制剂作为治疗CAP的药物的研究。如果被证明是有效的，SHA化合物和4-MU将成为一类新型的基于糖胺聚糖的靶向抗肿瘤药物。