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（由申请人提供）：本提案的总体目标是靶向肿瘤相关透明质酸-透明质酸酶（HA-HAase）系统，以开发前列腺癌（CaP）的新型治疗药物。HA是促进肿瘤生长和转移的糖胺聚糖，HAase是将HA降解成血管生成片段的糖苷内切酶。HYAL 1是由CaP细胞分泌的肿瘤来源的HAase。CaP组织中HA-HYAL 1的联合表达是预测CaP进展的独立预后指标。通过反义cDNA转染阻断CaP细胞中的HYAL 1表达，减少异种移植物中的肿瘤生长、侵袭和血管形成。硫酸化HA（sHA）聚合物和小sHA寡糖是HYAL 1活性的有效抑制剂，其通过引起细胞周期停滞来抑制CaP细胞生长并抑制CaP异种移植物的生长。这些药物降低黏着斑激酶的活化，下调雄激素受体水平和活性。4-甲基伞形酮（4-MU），用作治疗肝脏营养的膳食补充剂，抑制HA合成。通过阻断细胞周围HA形成，4-MU通过半胱天冬酶-8活化诱导CaP细胞凋亡并抑制CaP异种移植物的生长。sHA和4-MU都是口服生物可利用的，对雄激素依赖性和非依赖性CaP细胞都有活性，并且在长期治疗后没有显示出组织学或全身毒性。在拟议项目中待检验的主要假设是，sHA和4-MU（单独或组合）将消除CaP生长及其进展。将在体外评价sHA化合物抑制细胞生长和侵袭的功效。将在3种CaP异种移植模型（即，原位肿瘤植入、诱导转移和骨内生长模型）。还将研究sHA对HA-HYAL 1介导的细胞内信号传导的影响（目的1）。将在体外研究4-MU在控制CaP细胞生长、侵袭和运动中的作用。如上所述，将在三种CaP异种移植模型中检查单独或与sHA组合的4-MU对肿瘤生长和转移的抑制。还将研究4-MU诱导细胞凋亡和消除HA介导的细胞内信号传导的机制（目的2）。将在两种CaP转基因模型中研究sHA和4-MU单独或组合作为CaP生长和转移的阶段特异性治疗的功效（目的3）。相关性：这是第一项提出评估HA-HYAL 1系统抑制剂作为治疗CaP的治疗药物的研究。如果证明有效，sHA化合物和4-MU将成为一类新型的基于糖胺聚糖的靶向特异性抗肿瘤药物。