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Tumor Engraftment in a Xenograft Mouse Model of Human Mantle Cell Lymphoma
Published on: March 30, 2018
Triterpenoids display single agent anti-tumor activity in a transgenic mouse model of chronic lymphocytic leukemia
Christina L Kress1, Marina Konopleva, Vanesa Martínez-García
1Burnham Institute for Medical Research, La Jolla, California, United States of America.
Background:
The synthetic triterpenoid 2-Cyano-3,12-Dioxooleana-1,9-Dien-28-Oic Acid (CDDO) and derivatives display anti-tumor activity against a variety of cultured tumor cell lines and in mouse xenografts. In this report, we have studied the effects of CDDO and its imidazolide derivative (CDDO-Im) on chronic lymphocytic leukemia (CLL), using patients' CLL cells and a mouse model of CLL and small B cell lymphoma (SBL).
Principal Findings:
CDDO and CDDO-Im efficiently induced apoptosis of malignant human and mouse B-cells ex vivo, although CDDO-Im was over 10-fold more potent than CDDO. Treating mice with CLL/SBL with liposome-formulated CDDO or CDDO-Im resulted in significant reductions of B cells in blood, spleen and lung. CDDO-Im was shown to be more potent than CDDO, while treatment with empty liposomes had no impact on disease. CDDO-Im treatment initially resulted in an increase of circulating B cells, which correlates with a reduction in resident lymphocytes in spleen, and lungs, suggesting that CDDO-Im induces mobilization of tumor cells from lymphoid organs and infiltrated tissues into the circulation. Analysis of blood cells recovered from treated mice also showed that CDDO-Im is a potent inducer of tumor cells death in vivo. Furthermore, CDDO-Im efficiently eradicated mouse CLL/SBL cells but had little effect on the viability of normal B and T cells in vivo.
Significance:
The presented data demonstrate that triterpenoids CDDO and CDDO-Im reduce leukemia and lymphoma burden in vivo in a transgenic mouse model of CLL/SBL, and support the clinical testing of CDDO-based synthetic triterpenoids in patients with CLL.
Insights
Synthetic triterpenoids, 2-Cyano-3,12-Dioxooleana-1,9-Dien-28-Oic Acid (CDDO) and CDDO-Im, effectively reduced leukemia and lymphoma in a mouse model. These compounds show promise for clinical trials in chronic lymphocytic leukemia (CLL) patients.
Area of Science:
- Oncology
- Immunology
- Pharmacology
Background:
- Synthetic triterpenoids, including 2-Cyano-3,12-Dioxooleana-1,9-Dien-28-Oic Acid (CDDO) and its derivatives, exhibit anti-tumor properties.
- Previous studies demonstrated efficacy against various tumor cell lines and in mouse xenografts.
Purpose of the Study:
- To investigate the effects of CDDO and its imidazolide derivative (CDDO-Im) on chronic lymphocytic leukemia (CLL) and small B cell lymphoma (SBL).
- Utilized patient-derived CLL cells and a relevant mouse model for comprehensive analysis.
Main Methods:
- Ex vivo apoptosis assays on human and mouse B-cells treated with CDDO and CDDO-Im.
- In vivo studies involving liposome-formulated CDDO or CDDO-Im treatment in a mouse model of CLL/SBL.
- Analysis of B-cell reduction in blood, spleen, and lung, alongside assessment of tumor cell death in circulation.
Main Results:
- CDDO-Im demonstrated over 10-fold greater potency than CDDO in inducing B-cell apoptosis ex vivo.
- Liposome-formulated CDDO and CDDO-Im significantly reduced B-cell counts in blood, spleen, and lung of treated mice.
- CDDO-Im treatment led to increased circulating B cells, suggesting mobilization from lymphoid organs, and effectively eradicated mouse CLL/SBL cells with minimal impact on normal B and T cells.
Conclusions:
- Triterpenoids CDDO and CDDO-Im effectively reduce leukemia and lymphoma burden in vivo.
- The findings support the clinical investigation of CDDO-based synthetic triterpenoids for treating CLL.
