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

描述(申请人提供)：本提案的目的是研究从柑橘果胶中提取的一种天然产物在克服半乳糖凝集素-3介导的淋巴瘤细胞凋亡抵抗中的作用机制，并了解这种天然产物与传统抗癌药物的相互作用。Galectin-3是哺乳动物凝集素Galectin家族中的一员，可促进细胞存活，因此Galectin-3过表达可促进肿瘤细胞对凋亡的抵抗，从而对许多常规化疗药物产生耐药性。Galectin-3在一种特殊类型的淋巴瘤-弥漫性大B细胞淋巴瘤(DLBCL)中高表达，并促进DLBCL细胞的凋亡抵抗。然而，Galectin-3表达促进细胞凋亡抵抗的机制尚不清楚。一种修饰的柑橘果胶在各种转移癌动物模型中选择性地抑制Galectin-3介导的细胞-细胞相互作用，已被开发为一种新的治疗化合物，称为GCS-100，目前正在进行血液系统恶性肿瘤的临床试验。然而，关于这种果胶衍生的多糖抑制Galectin-3的机制，或者这种天然产物与传统癌症治疗方法的相互作用的信息很少。这一R21应用的目标是进行临床前研究，以促进我们对GCS-100对淋巴瘤细胞作用机制的了解，使用人类淋巴瘤细胞系和原发患者样本。具体地说，我们将1)确定Galectin-3在B淋巴瘤细胞中的亚细胞定位，并确定GCS-100对这些细胞中Galectin-3数量和分布的影响；2)表征Galectin-3介导的B淋巴瘤细胞凋亡抵抗的机制，并确定GCS-100如何拮抗Galectin-3的抗凋亡作用；3)研究Galectin-3在原代DLBCL患者样本细胞生存和疾病进展中的作用，以鉴定可从GCS-100受益的患者群体。了解GCS-100如何拮抗Galectin-3的促生存功能也将有助于阐明Galectin-3的表达如何使肿瘤细胞抵抗凋亡。因此，该R21应用程序对PA-06-400“癌症护理辅助方法中的开发项目”具有很高的响应性。公共卫生相关性：需要新的疗法来治疗一组被称为淋巴瘤的癌症，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。我们将研究一种从柑橘果胶中提取的天然治疗产品，以使淋巴瘤细胞对传统癌症治疗的效果敏感，从而潜在地提高淋巴瘤患者的治疗反应和存活率。

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.