Multi-targeting TACE/ADAM17 and gamma-secretase of notch signalling pathway in TNBC via drug repurposing approach using Lomitapide

Sen, Plaboni; Kandasamy, Thirukumaran; Ghosh, Siddhartha Sankar

doi:10.1016/j.cellsig.2022.110529

Cited by 13 publications

(15 citation statements)

References 23 publications

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“…The Notch pathway potentiates various hallmarks of cancer such as angiogenesis, drug resistance, metastasis, invasion, and maintenance of CSCs, by possessing established cross talk with several downstream pathways and transcription factors. A recent study conducted by our group led us to the conclusion that inhibiting the Notch pathway in TNBC cells results in diminishing the aggressive characteristics of the TNBC cells . The study elucidates the comparative analysis of the dual-targeted drug Lomitapide along with the γ-secretase inhibitor LY411575 and the ADAM inhibitor TMI-1.…”

Section: Conclusion and Future Prospectivesmentioning

confidence: 98%

“…However, the in vitro assessment of TMI-1, a thiomorpholine sulfonamide hydroxamate bearing novel propargylic P1 group, endowed us with the efficacy of the compound in inhibiting the EMT, along with incorporating differentiated epithelial phenotype (CD44 + /CD24 + ). It also induced apoptosis and decreased the colony-forming ability and wound-healing properties of the TNBC cells …”

Section: Implications Of Notch In Cancermentioning

confidence: 99%

“…It also induced apoptosis and decreased the colony-forming ability and wound-healing properties of the TNBC cells. 129 Other Modes of Notch Inhibition. Abrogation of the Notch pathway has also been achieved using RNAi (ribonucleic acid interference) and shRNA (short-hairpin RNA).…”

Section: Modification Ofmentioning

confidence: 99%

“…A recent study conducted by our group led us to the conclusion that inhibiting the Notch pathway in TNBC cells results in diminishing the aggressive characteristics of the TNBC cells. 129 The study elucidates the comparative analysis of the dual-targeted drug Lomitapide along with the γsecretase inhibitor LY411575 and the ADAM inhibitor TMI-1. It was observed that, besides significant generation of ROS and inhibition of sphere formation by LY411575, TMI-1 exhibited no significant impact on the TNBC cells.…”

Section: ■ Conclusion and Future Prospectivesmentioning

confidence: 99%

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The Intricate Notch Signaling Dynamics in Therapeutic Realms of Cancer

Sen

Ghosh

2023

ACS Pharmacol. Transl. Sci.

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The Notch pathway is remarkably simple without the interventions of secondary messengers. It possesses a unique receptor−ligand interaction that imparts signaling upon cleavage of the receptor followed by the nuclear localization of its cleaved intracellular domain. It is found that the transcriptional regulator of the Notch pathway lies at the intersection of multiple signaling pathways that enhance the aggressiveness of cancer. The preclinical and clinical evidence supports the pro-oncogenic function of Notch signaling in various tumor subtypes. Owing to its oncogenic role, the Notch signaling pathway assists in enhanced tumorigenesis by facilitating angiogenesis, drug resistance, epithelial to mesenchymal transition, etc., which is also attributed to the poor outcome in patients. Therefore, it is extremely vital to discover a suitable inhibitor to downregulate the signal-transducing ability of Notch. The Notch inhibitory agents, such as receptor decoys, protease (ADAM and γ-secretase) inhibitors, and monoclonal/bispecific antibodies, are being investigated as candidate therapeutic agents. Studies conducted by our group exemplify the promising results in ablating tumorigenic aggressiveness by inhibiting the constituents of the Notch pathway. This review deals with the detailed mechanism of the Notch pathways and their implications in various malignancies. It also bestows us with the recent therapeutic advances concerning Notch signaling in the context of monotherapy and combination therapy.

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Section: Conclusion and Future Prospectivesmentioning

confidence: 98%

Section: Implications Of Notch In Cancermentioning

confidence: 99%

Section: Modification Ofmentioning

confidence: 99%

Section: ■ Conclusion and Future Prospectivesmentioning

confidence: 99%

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The Intricate Notch Signaling Dynamics in Therapeutic Realms of Cancer

Sen

Ghosh

2023

ACS Pharmacol. Transl. Sci.

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“…One case series of six HoFH patients on long-term lomitapide therapy showed carotid intima-media thickness stabilization or regression [ 168 ]. In addition, recent studies emphasize the potential anti-cancer effects of lomitapide [ 169 , 170 ].…”

Section: Novel Ldl-c Lowering Drugsmentioning

confidence: 99%

Anti-Inflammatory Effects of Lipid-Lowering Drugs and Supplements—A Narrative Review

et al. 2023

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Cardiovascular diseases (CVD) are the leading cause of death worldwide. Since the establishment of the “lipid hypothesis”, according to which, cholesterol level is directly correlated to the risk of CVD, many different lipid-lowering agents have been introduced in clinical practice. A majority of these drugs, in addition to their lipid-lowering properties, may also exhibit some anti-inflammatory and immunomodulatory activities. This hypothesis was based on the observation that a decrease in lipid levels occurs along with a decrease in inflammation. Insufficient reduction in the inflammation during treatment with lipid-lowering drugs could be one of the explanations for treatment failure and recurrent CVD events. Thus, the aim of this narrative review was to evaluate the anti-inflammatory properties of currently available lipid-lowering medications including statins, ezetimibe, bile acid sequestrants (BAS), proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, fibrates, omega-3 fatty acids, and niacin, as well as dietary supplements and novel drugs used in modern times.

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Concurrent inhibition of IR, ITGB1, and CD36 perturbated the interconnected network of energy metabolism and epithelial‐to‐mesenchymal transition in breast cancer cells

Kandasamy,

Sarkar,

Sen

et al. 2024

J of Cellular Biochemistry

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Altered energy metabolism is an emerging hallmark of cancer and plays a pivotal in cell survival, proliferation, and biosynthesis. In a rapidly proliferating cancer, energy metabolism acts in synergism with epithelial‐to‐mesenchymal transition (EMT), enabling cancer stemness, dissemination, and metastasis. In this study, an interconnected functional network governing energy metabolism and EMT signaling pathways was targeted through the concurrent inhibition of IR, ITGB1, and CD36 activity. A novel multicomponent MD simulation approach was employed to portray the simultaneous inhibition of IR, ITGB1, and CD36 by a 2:1 combination of Pimozide and Ponatinib. Further, in‐vitro studies revealed the synergistic anticancer efficacy of drugs against monolayer as well as tumor spheroids of breast cancer cell lines (MCF‐7 and MDA‐MB‐231). In addition, the combination therapy exerted approximately 40% of the apoptotic population and more than 1.5‐ to 3‐fold reduction in the expression of ITGB1, IR, p‐IR, IRS‐1, and p‐AKT in MCF‐7 and MDA‐MB‐231 cell lines. Moreover, the reduction in fatty acid uptake, lipid droplet accumulation, cancer stemness, and migration properties were also observed. Thus, targeting IR, ITGB1, and CD36 in the interconnected network with the combination of Pimozide and Ponatinib represents a promising therapeutic approach for breast cancer.

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Multi-targeting TACE/ADAM17 and gamma-secretase of notch signalling pathway in TNBC via drug repurposing approach using Lomitapide

Cited by 13 publications

References 23 publications

The Intricate Notch Signaling Dynamics in Therapeutic Realms of Cancer

The Intricate Notch Signaling Dynamics in Therapeutic Realms of Cancer

Anti-Inflammatory Effects of Lipid-Lowering Drugs and Supplements—A Narrative Review

Concurrent inhibition of IR, ITGB1, and CD36 perturbated the interconnected network of energy metabolism and epithelial‐to‐mesenchymal transition in breast cancer cells

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