The evolving landscape of PCSK9 inhibition in cancer

Oza, Palak P.; Kashfi, Khosrow

doi:10.1016/j.ejphar.2023.175721

Cited by 14 publications

(5 citation statements)

References 280 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It has been observed that the inhibition or deficiency of PCSK9 can yield therapeutic benefits in cancer treatment, by not only curbing tumorigenesis but also enhancing anti-tumor immunity. 440 , 441 Encouragingly, several therapeutic strategies designed to directly inhibit PCSK9 have already been rigorously explored in the context of hyperlipidemia management. This rigorous investigation resulted in the approval of three mAbs and one siRNA agent that can obstruct both intracellular and extracellular PCSK9 function.…”

Section: Pcsk9 As a Potential Target For Multiple Disordersmentioning

confidence: 99%

Targeting proprotein convertase subtilisin/kexin type 9 (PCSK9): from bench to bedside

Bao,

Liang,

Chang

et al. 2024

Sig Transduct Target Ther

View full text Add to dashboard Cite

Proprotein convertase subtilisin/kexin type 9 (PCSK9) has evolved as a pivotal enzyme in lipid metabolism and a revolutionary therapeutic target for hypercholesterolemia and its related cardiovascular diseases (CVD). This comprehensive review delineates the intricate roles and wide-ranging implications of PCSK9, extending beyond CVD to emphasize its significance in diverse physiological and pathological states, including liver diseases, infectious diseases, autoimmune disorders, and notably, cancer. Our exploration offers insights into the interaction between PCSK9 and low-density lipoprotein receptors (LDLRs), elucidating its substantial impact on cholesterol homeostasis and cardiovascular health. It also details the evolution of PCSK9-targeted therapies, translating foundational bench discoveries into bedside applications for optimized patient care. The advent and clinical approval of innovative PCSK9 inhibitory therapies (PCSK9-iTs), including three monoclonal antibodies (Evolocumab, Alirocumab, and Tafolecimab) and one small interfering RNA (siRNA, Inclisiran), have marked a significant breakthrough in cardiovascular medicine. These therapies have demonstrated unparalleled efficacy in mitigating hypercholesterolemia, reducing cardiovascular risks, and have showcased profound value in clinical applications, offering novel therapeutic avenues and a promising future in personalized medicine for cardiovascular disorders. Furthermore, emerging research, inclusive of our findings, unveils PCSK9’s potential role as a pivotal indicator for cancer prognosis and its prospective application as a transformative target for cancer treatment. This review also highlights PCSK9’s aberrant expression in various cancer forms, its association with cancer prognosis, and its crucial roles in carcinogenesis and cancer immunity. In conclusion, this synthesized review integrates existing knowledge and novel insights on PCSK9, providing a holistic perspective on its transformative impact in reshaping therapeutic paradigms across various disorders. It emphasizes the clinical value and effect of PCSK9-iT, underscoring its potential in advancing the landscape of biomedical research and its capabilities in heralding new eras in personalized medicine.

show abstract

Section: Pcsk9 As a Potential Target For Multiple Disordersmentioning

confidence: 99%

Targeting proprotein convertase subtilisin/kexin type 9 (PCSK9): from bench to bedside

Bao,

Liang,

Chang

et al. 2024

Sig Transduct Target Ther

View full text Add to dashboard Cite

show abstract

“…The use of PCSK9 small interfering RNA (PCSK9i) also enhanced the efficacy of immune therapy targeted at the checkpoint protein PD-1 [248]. Additionally, PCSK9 inhibition has demonstrated the potential to induce cancer cell apoptosis through several pathways, increase the efficacy of a class of existing anticancer therapies, and boost the host immune response to cancer [249]. Hence, a novel application of PCSK9 inhibitors in cancer and metastasis could be considered.…”

Section: Role Of Pcsk9 In Cancermentioning

confidence: 99%

“…In several studies, PCSK9 siRNA was shown to effectively suppress the proliferation and invasion of tumor cells. Hence, a novel application of PCSK9 inhibitors/silencers in cancer and metastasis could be considered [249].…”

Section: Pcsk9 Inhibitorsmentioning

confidence: 99%

Atherosclerosis, Diabetes Mellitus, and Cancer: Common Epidemiology, Shared Mechanisms, and Future Management

Katsi

Papakonstantinou

Tsioufis

2023

IJMS

View full text Add to dashboard Cite

The involvement of cardiovascular disease in cancer onset and development represents a contemporary interest in basic science. It has been recognized, from the most recent research, that metabolic syndrome-related conditions, ranging from atherosclerosis to diabetes, elicit many pathways regulating lipid metabolism and lipid signaling that are also linked to the same framework of multiple potential mechanisms for inducing cancer. Otherwise, dyslipidemia and endothelial cell dysfunction in atherosclerosis may present common or even interdependent changes, similar to oncogenic molecules elevated in many forms of cancer. However, whether endothelial cell dysfunction in atherosclerotic disease provides signals that promote the pre-clinical onset and proliferation of malignant cells is an issue that requires further understanding, even though more questions are presented with every answer. Here, we highlight the molecular mechanisms that point to a causal link between lipid metabolism and glucose homeostasis in metabolic syndrome-related atherosclerotic disease with the development of cancer. The knowledge of these breakthrough mechanisms may pave the way for the application of new therapeutic targets and for implementing interventions in clinical practice.

show abstract

“…The inhibition of PCSK9 caused apoptosis in cancer models in vitro [ 112 , 113 ]. The pathways of the increased apoptosis due to PCSK9 inhibition are mitochondrial signalling pathways and the activation of endoplasmic reticulum stress [ 114 ]. The effect of the downregulation is not universal, in a mice model of melanoma, the inhibition of PCSK9 did not demonstrate growth reduction or a better prognosis [ 115 ].…”

Section: Other Possible Implications Of Pcsk9 Inhibitorsmentioning

confidence: 99%

The Anti-Thrombotic Effects of PCSK9 Inhibitors

Péč,

Benko,

Jurica

et al. 2023

Pharmaceuticals

View full text Add to dashboard Cite

Atherosclerosis is the primary process that underlies cardiovascular disease. The connection between LDL cholesterol and the formation of atherosclerotic plaques is established by solid evidence. PCSK9 inhibitors have proven to be a valuable and practical resource for lowering the LDL cholesterol of many patients in recent years. Their inhibitory effect on atherosclerosis progression seems to be driven not just by lipid metabolism modification but also by LDL-independent mechanisms. We review the effect of PCSK9 inhibitors on various mechanisms involving platelet activation, inflammation, endothelial dysfunction, and the resultant clot formation. The main effectors of PCSK9 activation of platelets are CD36 receptors, lipoprotein(a), oxidised LDL particles, tissue factor, and factor VIII. Many more molecules are under investigation, and this area of research is growing rapidly.

show abstract

The evolving landscape of PCSK9 inhibition in cancer

Cited by 14 publications

References 280 publications

Targeting proprotein convertase subtilisin/kexin type 9 (PCSK9): from bench to bedside

Targeting proprotein convertase subtilisin/kexin type 9 (PCSK9): from bench to bedside

Atherosclerosis, Diabetes Mellitus, and Cancer: Common Epidemiology, Shared Mechanisms, and Future Management

The Anti-Thrombotic Effects of PCSK9 Inhibitors

Contact Info

Product

Resources

About