Overcoming tumor cell resistance to apoptosis with a natural product, GCS-100

描述（由申请人提供）：本提案的目的是研究来源于柑橘果胶的天然产物在克服半乳糖凝集素-3介导的对淋巴瘤细胞凋亡的抗性中的作用机制，并了解该天然产物与常规抗癌剂的相互作用。半乳糖凝集素-3（哺乳动物凝集素的半乳糖凝集素家族的成员）促进细胞存活，使得半乳糖凝集素-3过表达促进肿瘤细胞对细胞凋亡的抗性，并因此对许多常规化疗剂的抗性。半乳糖凝集素-3在称为弥漫性大B细胞淋巴瘤（DLBCL）的特定类型的淋巴瘤中高度过表达，并促进DLBCL细胞中的凋亡抗性。然而，半乳糖凝集素-3表达促进细胞凋亡抗性的机制尚不清楚。在各种转移性癌症动物模型中选择性抑制半乳糖凝集素-3介导的细胞-细胞相互作用的改性柑橘果胶已被开发为称为GCS-100的新型治疗化合物，其目前正在进行血液恶性肿瘤的临床试验。然而，关于这种果胶衍生的多糖抑制半乳糖凝集素-3的机制或这种天然产物与传统癌症疗法的相互作用的信息很少。这项R21申请的目标是进行临床前研究，以提高我们对GCS-100对淋巴瘤细胞作用机制的认识，使用人类淋巴瘤细胞系和原发性患者样本。具体而言，我们将1）鉴定半乳糖凝集素-3在B淋巴瘤细胞中的亚细胞定位，并确定GCS-100对半乳糖凝集素-3在这些细胞中的量和分布的影响; 2）表征半乳糖凝集素-3介导的B淋巴瘤细胞中的凋亡抗性的机制，并确定GCS-100如何拮抗半乳糖凝集素-3的抗凋亡作用; 3）研究半乳糖凝集素-3在原发性DLBCL患者样品中的细胞存活和疾病进展中的作用，以表征可受益于GCS-100的患者群体。了解GCS-100如何拮抗半乳糖凝集素-3的促生存功能也将有助于阐明半乳糖凝集素-3的表达如何使肿瘤细胞对凋亡产生抗性。因此，该R21应用程序对PA-06-400“癌症护理补充方法中的发展项目”具有高度响应性。公共卫生相关性：一组称为淋巴瘤的癌症需要新的疗法，因为许多患有这种疾病的患者对传统的癌症疗法没有反应。我们将研究一种来自柑橘果胶的天然产物治疗剂，用于使淋巴瘤细胞对常规癌症疗法的作用敏感的能力，从而潜在地增强对淋巴瘤患者的治疗和存活的反应。

DESCRIPTION (provided by applicant): The goal of this proposal is to investigate the mechanism of action of a natural product derived from citrus pectin in overcoming galectin-3 mediated resistance to apoptosis in lymphoma, and to understand the interaction of this natural product with conventional cancer agents. Galectin-3, a member of the galectin family of mammalian lectins, promotes cell survival, so that galectin-3 overexpression promotes tumor cell resistance to apoptosis and thus resistance to many conventional chemotherapeutic agents. Galectin-3 is highly overexpressed in a specific type of lymphoma, termed diffuse large B cell lymphoma (DLBCL) and promotes apoptosis resistance in DLBCL cells. However, the mechanism by which galectin-3 expression promotes apoptosis resistance is unknown. A modified citrus pectin that selectively inhibits galectin-3 mediated cell-cell interactions in various animal models of metastatic cancer has been developed as a novel therapeutic compound, termed GCS-100, that is currently in clinical trials for hematologic malignancies. However, there is little information on the mechanism by which this pectin-derived polysaccharide inhibits galectin-3, or the interaction of this natural product with conventional cancer therapies. The goal of this R21 application is to perform preclinical studies to advance our knowledge of the mechanism of action of GCS-100 on lymphoma cells, using both human lymphoma cell lines and primary patient samples. Specifically, we will 1) Identify the subcellular localization of galectin-3 in B lymphoma cells, and determine the effect of GCS-100 on the amount and distribution of galectin-3 in these cells; 2) Characterize the mechanism of galectin-3 mediated apoptosis resistance in B lymphoma cells and determine how GCS-100 antagonizes the anti-apoptotic action of galectin-3; 3) Investigate the role of galectin-3 in cell survival and disease progression in primary DLBCL patient samples, to characterize patient populations that could benefit from GCS-100. Understanding how GCS-100 antagonizes pro-survival functions of galectin-3 will also help to elucidate how galectin-3 expression makes tumor cells resistant to apoptosis. This R21 application is thus highly responsive to PA-06-400, "Developmental Projects in Complementary Approaches to Cancer Care". PUBLIC HEALTH RELEVANCE: Novel therapies are needed for a group of cancers termed lymphomas, as many patients with this disease fail to respond to conventional cancer therapies. We will investigate a natural product therapeutic, derived from citrus pectin, for the ability to sensitize lymphoma cells to the effects of conventional cancer therapies and thus potentially enhance the response to treatment and survival of lymphoma patients.