Targeting TRAIL Death Receptors in Triple-Negative Breast Cancers: Challenges and Strategies for Cancer Therapy

Kundu, Manjari; Greer, Yoshimi Endo; Dine, Jennifer; Lipkowitz, Stanley

doi:10.3390/cells11233717

Cited by 10 publications

(9 citation statements)

References 260 publications

(445 reference statements)

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“…S7D). To further con rm that the combinatorial treatment induced cell death, we quanti ed viability, cytotoxicity, and apoptosis induction with or without the pan-caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-uoromethyl ketone (Z-VAD-FMK) [44]. The combinatorial treatment suppressed cell viability and induced cytotoxicity as well as cleaved caspase-3/7 luminescence (Fig.…”

Section: Combinatorial Treatment Induces a Synergistic Anti-tumor Eff...mentioning

confidence: 97%

Targeting Metabolic Vulnerability by Combining NAMPT Inhibitors and Disulfiram for Treatment of Recurrent Ovarian Cancer

Lipkowitz,

Kudo,

Crooks

et al. 2024

Preprint

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Ovarian cancer (OV) has the highest mortality rate among gynecological cancers. As the OV progresses, tumor cells spread outside the ovaries to the peritoneal and abdominal cavities, forming cell clusters that float in the ascitic fluid caused by peritonitis carcinomatosa, leading to further dissemination and metastasis. These cell clusters are enriched with cancer stem cells (CSCs) which are responsible for treatment resistance, recurrence, and metastasis. Therefore, targeting CSCs is a potentially effective approach for treating OV. However, understanding how CSCs acquire treatment resistance and identifying targets against CSCs remains challenging. In this study, we demonstrate that 3D-spheroids of OV cell lines exhibit higher stemness than conventional adherent cells. Metabolomics profiling studies have revealed that 3D-spheroids maintain a high-energy state through increased glucose utilization in the citric acid cycle (TCA), efficient nucleotide phosphorylation, and elevated phosphocreatine as an energy buffer. We also found that nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme for NAD+ production, is highly expressed and is a potential therapeutic target against CSCs, while also serving as a prognostic indicator in OV. Moreover, we identified a previously unrecognized anti-tumor mechanism whereby disulfiram, an aldehyde dehydrogenase (ALDH) inhibitor, synergistically inhibited mitochondrial function when combined with NAMPT inhibitors. Finally, the combination of a NAMPT inhibitor and disulfiram showed significant anti-tumor effects and extended survival in an animal model. Our findings demonstrate the potential of spheroids as a preclinical model for targeting OV CSCs and also indicate that the combination of NAMPT inhibitors and disulfiram is a promising therapeutic strategy to overcome recurrent OV.

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Section: Combinatorial Treatment Induces a Synergistic Anti-tumor Eff...mentioning

confidence: 97%

Targeting Metabolic Vulnerability by Combining NAMPT Inhibitors and Disulfiram for Treatment of Recurrent Ovarian Cancer

Lipkowitz,

Kudo,

Crooks

et al. 2024

Preprint

Self Cite

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“…Because TRAIL selectively induces apoptosis in cancer cells, clinical trials were conducted to test the efficacy of TRAIL and agonist antibodies targeting death receptors in cancer patients (Table 1) [7,92]. Unlike most chemotherapeutic drugs, TRAIL ligand-based therapy causes apoptosis in tumor cells in a p53-independent manner [22].…”

Section: Targeting Trail and Trail Death Receptors For Cancer Therapiesmentioning

confidence: 99%

“…Unlike most chemotherapeutic drugs, TRAIL ligand-based therapy causes apoptosis in tumor cells in a p53-independent manner [22]. Therefore, several TRAIL-based cancer monotherapies and combinations have been tested in human clinical trials [7,92]. The earlier forms of TRAIL used were recombinant TRAIL (rTRAIL), which was purified with a poly-Histidine (His) or FLAG epitope (FLAG-TRAIL) tag in the NTC domain [93].…”

Section: Targeting Trail and Trail Death Receptors For Cancer Therapiesmentioning

confidence: 99%

“…rTRAIL combined with chemotherapy has been shown to improve clinical outcomes in Phase III clinical studies for patients with advanced NSCLC [7,97]. Furthermore, TRAIL-based therapy can be combined with immunotherapy (NCT02991196), biological treatment (NCT00400764, NCT00508625), and targeted therapy (NCT01258608, NCT00315757) to improve overall survival (OS) in a variety of cancers [7,92].…”

Section: Targeting Trail and Trail Death Receptors For Cancer Therapiesmentioning

confidence: 99%

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The Role of TRAIL in Apoptosis and Immunosurveillance in Cancer

Pimentel

Zhou

2023

Cancers

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Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily that selectively induces apoptosis in tumor cells without harming normal cells, making it an attractive agent for cancer therapy. TRAIL induces apoptosis by binding to and activating its death receptors DR4 and DR5. Several TRAIL-based treatments have been developed, including recombinant forms of TRAIL and its death receptor agonist antibodies, but the efficacy of TRAIL-based therapies in clinical trials is modest. In addition to inducing cancer cell apoptosis, TRAIL is expressed in immune cells and plays a critical role in tumor surveillance. Emerging evidence indicates that the TRAIL pathway may interact with immune checkpoint proteins, including programmed death-ligand 1 (PD-L1), to modulate PD-L1-based tumor immunotherapies. Therefore, understanding the interaction between TRAIL and the immune checkpoint PD-L1 will lead to the development of new strategies to improve TRAIL- and PD-L1-based therapies. This review discusses recent findings on TRAIL-based therapy, resistance, and its involvement in tumor immunosurveillance.

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“…Conversely, other studies have demonstrated that MSCs can induce TNBC cell apoptosis or autophagy through the transfection and synthesis of miRNAs, or by inhibiting bone marrow-derived MSCs [18]. In addition, MSCs can express tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), which can trigger apoptosis in TNBC cells [21]. MSCs can also inhibit the expression of cyclin D1, a key regulator of cell cycle progression [22][23][24].…”

Section: Context-dependent Effects Of Msc-tnbc Interactions On Prolif...mentioning

confidence: 99%

From Interaction to Intervention: How Mesenchymal Stem Cells Affect and Target Triple-Negative Breast Cancer

Shum

et al. 2023

Biomedicines

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Triple-negative breast cancer (TNBC) lacks estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 expressions, making targeted therapies ineffective. Mesenchymal stem cells (MSCs) have emerged as a promising approach for TNBC treatment by modulating the tumor microenvironment (TME) and interacting with cancer cells. This review aims to comprehensively overview the role of MSCs in TNBC treatment, including their mechanisms of action and application strategies. We analyze the interactions between MSC and TNBC cells, including the impact of MSCs on TNBC cell proliferation, migration, invasion, metastasis, angiogenesis, and drug resistance, along with the signaling pathways and molecular mechanisms involved. We also explore the impact of MSCs on other components of the TME, such as immune and stromal cells, and the underlying mechanisms. The review discusses the application strategies of MSCs in TNBC treatment, including their use as cell or drug carriers and the advantages and limitations of different types and sources of MSCs in terms of safety and efficacy. Finally, we discuss the challenges and prospects of MSCs in TNBC treatment and propose potential solutions or improvement methods. Overall, this review provides valuable insights into the potential of MSCs as a novel therapeutic approach for TNBC treatment.

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Targeting TRAIL Death Receptors in Triple-Negative Breast Cancers: Challenges and Strategies for Cancer Therapy

Cited by 10 publications

References 260 publications

Targeting Metabolic Vulnerability by Combining NAMPT Inhibitors and Disulfiram for Treatment of Recurrent Ovarian Cancer

Targeting Metabolic Vulnerability by Combining NAMPT Inhibitors and Disulfiram for Treatment of Recurrent Ovarian Cancer

The Role of TRAIL in Apoptosis and Immunosurveillance in Cancer

From Interaction to Intervention: How Mesenchymal Stem Cells Affect and Target Triple-Negative Breast Cancer

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