Chauhan Dharminder, Li Guilan, Podar Klaus, Hideshima Teru, Neri Paola, He Deli, Mitsiades Nicholas, Richardson Paul, Chang Yan, Schindler Joanne, Carver Bradley, Anderson Kenneth C
The Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
Cancer Res. 2005 Sep 15;65(18):8350-8. doi: 10.1158/0008-5472.CAN-05-0163.
Human multiple myeloma is a presently incurable hematologic malignancy, and novel biologically based therapies are urgently needed. GCS-100 is a polysaccharide derived from citrus pectin in clinical development for the treatment of cancer. Here we show that GCS-100 induces apoptosis in various multiple myeloma cell lines, including those resistant to dexamethasone, melphalan, or doxorubicin. Examination of purified patient multiple myeloma cells showed similar results. Specifically, GCS-100 decreases viability of bortezomib/PS-341-resistant multiple myeloma patient cells. Importantly, GCS-100 inhibits multiple myeloma cell growth induced by adhesion to bone marrow stromal cells; overcome the growth advantage conferred by antiapoptotic protein Bcl-2, heat shock protein-27, and nuclear factor-kappaB; and blocks vascular endothelial growth factor-induced migration of multiple myeloma cells. GCS-100-induced apoptosis is associated with activation of caspase-8 and caspase-3 followed by proteolytic cleavage of poly(ADP-ribose) polymerase enzyme. Combined with dexamethasone, GCS-100 induces additive anti-multiple myeloma cytotoxicity associated with mitochondrial apoptotic signaling via release of cytochrome c and Smac followed by activation of caspase-3. Moreover, GCS-100 + dexamethasone-induced apoptosis in multiple myeloma cells is accompanied by a marked inhibition of an antiapoptotic protein Galectin-3, without significant alteration in Bcl-2 expression. Collectively, these findings provide the framework for clinical evaluation of GCS-100, either alone or in combination with dexamethasone, to inhibit tumor growth, overcome drug resistance, and improve outcome for patients with this universally fatal hematologic malignancy.
人类多发性骨髓瘤是一种目前无法治愈的血液系统恶性肿瘤，迫切需要新型的生物疗法。GCS - 100是一种从柑橘果胶中提取的多糖，目前正处于癌症治疗的临床开发阶段。在此我们表明，GCS - 100可诱导多种多发性骨髓瘤细胞系发生凋亡，包括那些对地塞米松、美法仑或阿霉素耐药的细胞系。对纯化的患者多发性骨髓瘤细胞的检测也显示了类似结果。具体而言，GCS - 100可降低硼替佐米/PS - 341耐药的多发性骨髓瘤患者细胞的活力。重要的是，GCS - 100可抑制因黏附于骨髓基质细胞而诱导的多发性骨髓瘤细胞生长；克服抗凋亡蛋白Bcl - 2、热休克蛋白 - 27和核因子 - κB所赋予的生长优势；并阻断血管内皮生长因子诱导的多发性骨髓瘤细胞迁移。GCS - 100诱导的凋亡与半胱天冬酶 - 8和半胱天冬酶 - 3的激活相关，随后是聚（ADP - 核糖）聚合酶的蛋白水解切割。与地塞米松联合使用时，GCS - 100通过细胞色素c和Smac的释放诱导与线粒体凋亡信号相关的附加抗多发性骨髓瘤细胞毒性，随后激活半胱天冬酶 - 3。此外，GCS - 100 +地塞米松诱导的多发性骨髓瘤细胞凋亡伴随着抗凋亡蛋白半乳凝素 - 3的显著抑制，而Bcl - 2表达无明显改变。总的来说，这些发现为单独或与地塞米松联合使用GCS - 100进行临床评估提供了框架，以抑制肿瘤生长、克服耐药性并改善这种普遍致命的血液系统恶性肿瘤患者的预后。
