Inhibition of NF-κB and Akt pathways by an antibody-avidin fusion protein sensitizes malignant B-cells to cisplatin-induced apoptosis

Bonavida,

doi:10.3892/ijo_00000615

Cited by 5 publications

(2 citation statements)

References 23 publications

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“…Interestingly, targeting the TfR1 can also be a strategy to overcome resistance to anti-cancer agents ( 91 ). In fact, treatment of malignant B cells resistant to cisplatin with ch128.1Av lead to the inhibition of the NF-κB and AKT pathways, resulting in the resensitization of these malignant cells to the cytotoxic effects of cisplatin ( 154 ).…”

Section: Targeting Tfr1 For Cancer Therapymentioning

confidence: 99%

“…Surprisingly, ch128.1Av was also found to have intrinsic anti-proliferative/pro-apoptotic activity in vitro against several human hematopoietic cancer cells, including MM cells (KMS-11, MM.1S, 8226/S, OCI-My5, and primary MM cells isolated from patients), APL cells (HL-60), Burkitt lymphoma (BL) cells (Ramos, Raji, and HS-Sultan), B-lymphoblastoid cell lines (ARH-77 and IM-9), TCL (Jurkat), and erythroleukemic cells (K562) (96,152). These cytotoxic effects could be enhanced through the combination with other anti-cancer agents including gambogic acid (a xanthone isolated from a plant used in traditional Chinese medicine), the HXR9 peptide that prevents HOX gene transcription, and the chemotherapeutic cisplatin (152)(153)(154). Interestingly, targeting the TfR1 can also be a strategy to overcome resistance to anti-cancer agents (91).…”

Section: Mouse/human Chimeric Anti-human/rat Tfr1 Antibodiesmentioning

confidence: 99%

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Antibodies Targeting the Transferrin Receptor 1 (TfR1) as Direct Anti-cancer Agents

et al. 2021

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The transferrin receptor 1 (TfR1), also known as cluster of differentiation 71 (CD71), is a type II transmembrane glycoprotein that binds transferrin (Tf) and performs a critical role in cellular iron uptake through the interaction with iron-bound Tf. Iron is required for multiple cellular processes and is essential for DNA synthesis and, thus, cellular proliferation. Due to its central role in cancer cell pathology, malignant cells often overexpress TfR1 and this increased expression can be associated with poor prognosis in different types of cancer. The elevated levels of TfR1 expression on malignant cells, together with its extracellular accessibility, ability to internalize, and central role in cancer cell pathology make this receptor an attractive target for antibody-mediated therapy. The TfR1 can be targeted by antibodies for cancer therapy in two distinct ways: (1) indirectly through the use of antibodies conjugated to anti-cancer agents that are internalized by receptor-mediated endocytosis or (2) directly through the use of antibodies that disrupt the function of the receptor and/or induce Fc effector functions, such as antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cell-mediated phagocytosis (ADCP), or complement-dependent cytotoxicity (CDC). Although TfR1 has been used extensively as a target for antibody-mediated cancer therapy over the years, interest continues to increase for both targeting the receptor for delivery purposes and for its use as direct anti-cancer agents. This review focuses on the developments in the use of antibodies targeting TfR1 as direct anti-tumor agents.

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Section: Targeting Tfr1 For Cancer Therapymentioning

confidence: 99%

Section: Mouse/human Chimeric Anti-human/rat Tfr1 Antibodiesmentioning

confidence: 99%

Antibodies Targeting the Transferrin Receptor 1 (TfR1) as Direct Anti-cancer Agents

et al. 2021

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Deferasirox-induced iron depletion promotes BclxL downregulation and death of proximal tubular cells

Martín‐Sánchez

Gallegos-Villalobos

Fontecha‐Barriuso

et al. 2017

Sci Rep

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Iron deficiency has been associated with kidney injury. Deferasirox is an oral iron chelator used to treat blood transfusion-related iron overload. Nephrotoxicity is the most serious and common adverse effect of deferasirox and may present as an acute or chronic kidney disease. However, scarce data are available on the molecular mechanisms of nephrotoxicity. We explored the therapeutic modulation of deferasirox-induced proximal tubular cell death in culture. Deferasirox induced dose-dependent tubular cell death and AnexxinV/7AAD staining showed features of apoptosis and necrosis. However, despite inhibiting caspase-3 activation, the pan-caspase inhibitor zVAD-fmk failed to prevent deferasirox-induced cell death. Moreover, zVAD increased deferasirox-induced cell death, a feature sometimes found in necroptosis. Electron microscopy identified mitochondrial injury and features of necrosis. However, neither necrostatin-1 nor RIP3 knockdown prevented deferasirox-induced cell death. Deferasirox caused BclxL depletion and BclxL overexpression was protective. Preventing iron depletion protected from BclxL downregulation and deferasirox cytotoxicity. In conclusion, deferasirox promoted iron depletion-dependent cell death characterized by BclxL downregulation. BclxL overexpression was protective, suggesting a role for BclxL downregulation in iron depletion-induced cell death. This information may be used to develop novel nephroprotective strategies. Furthermore, it supports the concept that monitoring kidney tissue iron depletion may decrease the risk of deferasirox nephrotoxicity.

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Delivery of Intracellular-Acting Biologics in Pro-Apoptotic Therapies

Li¹,

Nelson²,

Evans³

et al. 2011

Current Pharmaceutical Design

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The recent elucidation of molecular regulators of apoptosis and their roles in cellular oncogenesis has motivated the development of biomacromolecular anticancer therapeutics that can activate intracellular apoptotic signaling pathways. Pharmaceutical scientists have employed a variety of classes of biologics toward this goal, including antisense oligodeoxynucleotides, small interfering RNA, proteins, antibodies, and peptides. However, stability in the in vivo environment, tumor-specific biodistribution, cell internalization, and localization to the intracellular microenvironment where the targeted molecule is localized pose significant challenges that limit the ability to directly apply intracellular-acting, pro-apoptotic biologics for therapeutic use. Thus, approaches to improve the pharmaceutical properties of therapeutic biomacromolecules are of great significance and have included chemically modifying the bioactive molecule itself or formulation with auxiliary compounds. Recently, promising advances in delivery of pro-apoptotic biomacromolecular agents have been made using tools such as peptide “stapling”, cell penetrating peptides, fusogenic peptides, liposomes, nanoparticles, smart polymers, and synergistic combinations of these components. This review will discuss the molecular mediators of cellular apoptosis, the respective mechanisms by which these mediators are dysregulated in cellular oncogenesis, the history and development of both nucleic-acid and amino-acid based drugs, and techniques to achieve intracellular delivery of these biologics. Finally, recent applications where pro-apoptotic functionality has been achieved through delivery of intracellular-acting biomacromolecular drugs will be highlighted.

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Inhibition of NF-κB and Akt pathways by an antibody-avidin fusion protein sensitizes malignant B-cells to cisplatin-induced apoptosis

Cited by 5 publications

References 23 publications

Antibodies Targeting the Transferrin Receptor 1 (TfR1) as Direct Anti-cancer Agents

Antibodies Targeting the Transferrin Receptor 1 (TfR1) as Direct Anti-cancer Agents

Deferasirox-induced iron depletion promotes BclxL downregulation and death of proximal tubular cells

Delivery of Intracellular-Acting Biologics in Pro-Apoptotic Therapies

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