Targeted drug delivery and cross-linking induced apoptosis with anti-CD37 based dual-ligand immunoliposomes in B chronic lymphocytic leukemia cells

Previously, we demonstrated that B-chronic lymphocytic leukemia (B-CLL) cells could be divided into 2 groups depending on the expression of CD38 by the malignant cells. The 2 groups differed in their signal-transducing capacities initiated by cross-linking of surface IgM; only in CD38-positive cells was an efficient signal delivered, invariably resulting in cell apoptosis. In this study, we investigated the effect of surface IgD cross-linking in 10 patients with CD38-positive B-CLL. Exposure of the malignant cells to goat antihuman δ-chain antibodies (Gaδ-ab) caused [Ca++]i mobilization and tyrosine kinase phosphorylation in a manner not different from that observed after goat antihuman μ-chain antibody (Gaμ-ab) treatment in vitro. However, Gaδ-ab-treated cells failed to undergo apoptosis and instead displayed prolonged survival in culture and differentiated into plasma cells when rIL2 was concomitantly present. Cross-linking of surface IgD failed to induce proliferation of the malignant cells in vitro. Moreover, treatment with Gaδ-ab did not prevent apoptosis of B-CLL cells induced by Gaμ-ab. Collectively, these experiments demonstrated that IgM and IgD expressed by the same cell may deliver opposite signals under particular circumstances and provide some clues for the understanding of the pathophysiology of B-CLL.

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BMS-936564 (MDX1338): A Fully Human Anti-CXCR4 Antibody Induces Apoptosis in an in Vitro Model of Stromal – Leukemia Cell Interaction for Chronic Lymphocytic Leukemia.

Blood ◽

10.1182/blood.v120.21.2887.2887 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2887-2887

Author(s):

Manoj Kumar Kashyap ◽

Deepak Kumar ◽

Harrison Jones Jones ◽

Michael Y. Choi ◽

Johanna Melo-Cardenas ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Stromal Cells ◽

Leukemia Cell ◽

Cell Interaction ◽

Lymphocytic Leukemia ◽

Leukemia Cells ◽

Drug Induced ◽

Induced Apoptosis ◽

Cells Cultured

Abstract Abstract 2887 Chronic lymphocytic leukemia (CLL) remains incurable despite advances in the biology and treatment of this disease. Current data support the notion that resistance to therapy is promoted by a “protective” tumor microenvironment in which non-leukemia cells produce factors that enhance the resistance of CLL cells to spontaneous or drug-induced apoptosis. One such factor is the chemokine CXCL12, which interacts with its receptor CXCR4 on CLL cells to promote cancer cell survival. To examine the therapeutic potential of blocking CXCL12-CXCR4 interactions, we studied the effect of BMS-936564, a fully human IgG4 anti-CXCR4 antibody, using an in vitro co-culture model of human bone marrow derived stomal-NKter cells – leukemia cell interaction. Such stromal-NKter cells secrete CXCL12 and enhance the resistance of CLL cells to apoptosis in vitro. We observed that primary CLL cells co-cultured with stromal-NKter cells had significantly greater viability than CLL cells cultured alone (20–60% above baseline at 48 hours). Moreover, CLL cells co-cultured with stromal cells had enhanced resistance to drug-induced apoptosis. We found that BMS-936564 antibody at concentrations of 2–200nM could enhance the rate of apoptosis of CLL cells cultured alone or in the presence of stromal cells. CLL cells that expressed unmutated IgVH genes or ZAP-70 appeared equally susceptible to treatment with BMS-936564 as did CLL cells that lack these adverse prognostic markers, as did CLL cells that harbored deletions in 17p13.2 and that were resistant to chemotherapeutic agents, such a fludarabine monophosphate. BMS-936564 antibody inhibited CXCL12 mediated F-Actin polymerization in CLL cells at lower concentrations (20–200nM) compared to AMD-3100 (Mozobil), a small molecule CXCR4 inhibitor (50–150μM). In addition, AMD-3100 did not induce apoptosis in CLL cells (10–300μM). In summary, we observed that the anti-CXCR4 antibody BMS-936564 inhibited CXCL12 mediated activation of the CXCR4 receptor in CLL cells and induced apoptosis in leukemia cells. The pro-apoptotic activity of BMS-936564 was observed in cells cultured alone or together with stromal cells suggesting that this antibody had direct cytotoxic effect on leukemia cells and that it can overcome the protective tumor microenvironment. More over, the activity of BMS-936564 was independent of the presence of poor prognostic factors such as del(17p) suggesting that its mechanism of action is P53 independent. These findings show evidence that the CXCR4-CXCL12 pathway is a valid therapeutic target in CLL and provide additional biological rationale for ongoing clinical trials in CLL and other hematological malignancies using BMS-936564. Disclosures: Kuhne: Bristol-Myers Squibb: Employment. Sabbatini:Bristol-Myers Squibb: Employment. Cohen:Bristol-Myers Squibb: Employment. Shelat:Bristol-Myers Squibb: Employment. Cardarelli:Bristol-Myers Squibb: Employment. Kipps:Abbott: Consultancy, Research Funding.

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PPI-G4 Glycodendrimers Upregulate TRAIL-Induced Apoptosis in Chronic Lymphocytic Leukemia Cells

Macromolecular Bioscience ◽

10.1002/mabi.201600169 ◽

2016 ◽

Vol 17 (5) ◽

pp. 1600169 ◽

Cited By ~ 9

Author(s):

Ida Franiak-Pietryga ◽

Kinga Ostrowska ◽

Henryk Maciejewski ◽

Dietmar Appelhans ◽

Małgorzata Misiewicz ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Lymphocytic Leukemia ◽

Leukemia Cells ◽

Induced Apoptosis

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Insights on magnetic spinel ferrites for targeted drug delivery and hyperthermia applications

Nanotechnology Reviews ◽

10.1515/ntrev-2022-0027 ◽

2022 ◽

Vol 11 (1) ◽

pp. 372-413

Author(s):

Mohamed Ibrahim Ahmed Abdel Maksoud ◽

Mohamed Mohamady Ghobashy ◽

Ahmad S. Kodous ◽

Ramy Amer Fahim ◽

Ahmed I. Osman ◽

...

Keyword(s):

Drug Delivery ◽

Cancer Therapy ◽

Targeted Drug Delivery ◽

Spinel Ferrite ◽

Spinel Ferrites ◽

Cancer Cell Proliferation ◽

Anticancer Properties ◽

Targeted Drug ◽

Induced Apoptosis ◽

Scientific Attention

Abstract Magnetic spinel ferrite nanoparticles (SFNPs) attract high scientific attention from researchers due to their broad area for biomedicine applications, comprising cancer magnetic hyperthermia and targeted drug delivery. Uniquely, its excellent performance, namely, tuning size and surface morphology, excellent magnetism, extraordinary magnetically heat induction, promising biocompatibility, and specific targeting capacity, is essential for their effective utilization in clinical diagnosis and therapeutics of diseases. This review emphasizes the anticancer properties of nanoparticles of spinel ferrites with extra focus on the most recent literature. A critical review is provided on the latest applications of SFNPs in cancer therapy. Based on the results obtained from this review, SFNPs have the indefinite ability in cancer therapy through two mechanisms: (1) hyperthermia, where SFNPs, used as a hyperthermia mediator, elevated the tumor cells heat post-exposure to an external magnetic field and radiosensitizer during cancer radiotherapy; and (2) targeted drug delivery of cytotoxic drugs in tumor treatment. SFNPs induced apoptosis and cell death of cancer cells and prevented cancer cell proliferation.

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