Enhanced cytotoxicity of an anti-transferrin receptor IgG3-avidin fusion protein in combination with gambogic acid against human malignant hematopoietic cells: functional relevance of iron, the receptor, and reactive oxygen species

被引：37

作者：

Ortiz-Sanchez, E. ^{[1
]}

Daniels, T. R. ^{[1
]}

Helguera, G. ^{[1
]}

Martinez-Maza, O. ^{[2
,3
,4
]}

Bonavida, B. ^{[3
,4
]}

Penichet, M. L. ^{[1
,3
,4
]}

机构：

[1] Univ Calif Los Angeles, Dept Surg, Div Surg Oncol, David Geffen Sch Med, Los Angeles, CA 90095 USA

[2] Univ Calif Los Angeles, David Geffen Sch Med, Dept Obstet & Gynecol, Los Angeles, CA 90095 USA

[3] Univ Calif Los Angeles, David Geffen Sch Med, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90095 USA

[4] Univ Calif Los Angeles, David Geffen Sch Med, Dept Microbiol Mol Genet & Immunol, Los Angeles, CA 90095 USA

来源：

LEUKEMIA | 2009年 / 23卷 / 01期

关键词：

TfR; iron; antibody fusion protein; gambogic acid; hematopoietic malignances; ROS; HUMAN-BONE-MARROW; NF-KAPPA-B; TRANSCRIPTASE MESSENGER-RNA; HUMAN TRANSFERRIN RECEPTOR; SIGNALING PATHWAY; INDUCED APOPTOSIS; CANCER-CELLS; MONOCLONAL-ANTIBODIES; PHENOTYPIC ANALYSIS; TISSUE DISTRIBUTION;

D O I：

10.1038/leu.2008.270

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

The human transferrin receptor (hTfR) is a target for cancer immunotherapy due to its overexpression on the surface of cancer cells. We previously developed an antibody-avidin fusion protein that targets hTfR (anti-hTfR IgG3-Av) and exhibits intrinsic cytotoxicity against certain malignant cells. Gambogic acid (GA), a drug that also binds hTfR, induces cytotoxicity in several malignant cell lines. We now report that anti-hTfR IgG3-Av and GA induce cytotoxicity in a new broader panel of hematopoietic malignant cell lines. Our results show that the effect of anti-hTfR IgG3-Av is iron-dependent whereas that of GA is iron-independent in all cells tested. In addition, we observed that GA exerts a TfR-independent cytotoxicity. We also found that GA increases the generation of reactive oxygen species that may play a role in the cytotoxicity induced by this drug. Additive cytotoxicity was observed by simultaneous combination treatment with these drugs and synergy by using anti-hTfR IgG3-Av as a chemosensitizing agent. In addition, we found a concentration of GA that is toxic to malignant hematopoietic cells but not to human hematopoietic progenitor cells. Our results suggest that these two compounds may be effective, alone or in combination, for the treatment of human hematopoietic malignancies.

引用

页码：59 / 70

页数：12

共 54 条

[31] H2O2 AND ANTIOXIDANTS HAVE OPPOSITE EFFECTS ON ACTIVATION OF NF-KAPPA-B AND AP-1 IN INTACT-CELLS - AP-1 AS SECONDARY ANTIOXIDANT-RESPONSIVE FACTOR [J].