PCSK9 inhibitors – from discovery of a single mutation to a groundbreaking therapy of lipid disorders in one decade

Jaworski, Krzysztof; Jankowski, Piotr; Kosior, Dariusz A.

doi:10.5114/aoms.2017.65239

Cited by 23 publications

(12 citation statements)

References 111 publications

(118 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The inhibition of PCSK9 (protein convertase subtilisin/kexin 9) is an efficient strategy for lowering cholesterol and low-density lipoprotein cholesterol (LDL-C) [32]. In a study by Momtazi-Borojeni et al, the anti-PCSK9 antibody was induced via a vaccine in mice inoculated with breast carcinoma cells.…”

Section: Cholesterol and Breast Cancer In Animal Studiesmentioning

confidence: 99%

Cholesterol, Oxysterols and LXRs in Breast Cancer Pathophysiology

Nazih

Bard

2020

IJMS

View full text Add to dashboard Cite

Breast cancer is the most frequent cancer among women. In 2018, it is estimated that 627,000 women died from breast cancer. This is approximately 15% of all cancer deaths among women (WHO 2018). Breast cancer is a multifactorial chronic disease. While important progress has been made to treat patients, many questions regarding aspects of this disease relating to carcinogenesis are still open. During carcinogenesis, cells exhibit cholesterol homeostasis deregulation. This results in an accumulation of intracellular cholesterol, which is required to sustain their high growth rate. Cholesterol efflux and influx are two metabolic pathways that are necessary to prevent cholesterol accumulation in the cells. Liver X receptors (LXRs) are nuclear receptors that, upon activation, induce the expression of ABC transporters, responsible for promoting cholesterol efflux, and the expression of IDOL (inducible degrader of low-density lipoprotein receptor), in charge of reducing cholesterol influx. Oxysterols, oxygenated derivatives of cholesterol formed through different pathways, have been discovered as LXR-specific ligands. Some oxysterols are involved in tumor formation while others are considered anti-tumor agents. In the present review, we discuss the involvement of cholesterol, oxysterols and LXRs in breast cancer pathophysiology, with an emphasis on the biological effects of LXR ligands.

show abstract

Section: Cholesterol and Breast Cancer In Animal Studiesmentioning

confidence: 99%

Cholesterol, Oxysterols and LXRs in Breast Cancer Pathophysiology

Nazih

Bard

2020

IJMS

View full text Add to dashboard Cite

show abstract

“…Consequently, there are not enough LDLRs to remove plasma LDL-C when the circulating level of PCSK9 is increased as a result of gain-of-function mutations [15], whereas low levels of plasma PCSK9, due to loss-of function mutations, will lead to more intact LDLRs which in turn take up more plasma LDL-C [15]. Therefore, PCSK9 inhibition has emerged as a therapeutic tool and is currently used as an effective LDL-lowering approach in hypercholesterolemic patients [16][17][18][19][20][21][22][23]. Although the safety of PCSK9 inhibitors in hypercholesterolemic conditions has been approved, there is scant information on the safety of PCSK9 inhibition in other conditions such as cancer.…”

Section: Introductionmentioning

confidence: 99%

Potential anti-tumor effect of a nanoliposomal antiPCSK9 vaccine in mice bearing colorectal cancer

Momtazi‐Borojeni¹,

Nik²,

Jaafari³

et al. 2019

aoms

View full text Add to dashboard Cite

Introduction: Inhibition of proprotein convertase subtilisin/kexin 9 (PCSK9) is an effective therapeutic tool for lowering low-density lipoprotein cholesterol (LDL-C). There is no available evidence on the efficacy and safety of PCSK9 inhibitors in non-cardiovascular diseases, particularly cancer. The present study aimed to evaluate the effect of PCSK9 inhibition on cancer endpoints in mice bearing colon carcinoma, using a nanoliposomal antiPCSK9 vaccine. Material and methods: The prepared nanoliposomal antiPCSK9 vaccine was subcutaneously inoculated in BALB/c mice four times with a biweekly interval. Two weeks after the last booster, the vaccinated and unvaccinated mice were subcutaneously inoculated with CT26 colon cancer cells into the right flank. After the tumor mass became palpable, the mice were randomly divided into three groups: (1) PBS (untreated control), (2) vaccine group, and (3) pegylated liposomal doxorubicin (PLD; positive control) group. Body weight, tumor size and survival of mice were monitored for 50 days. Results: The nanoliposomal antiPCSK9 vaccine could efficiently provoke specific antibodies against PCSK9 in BALB/c mice and thereby reduced the plasma level and function of PCSK9. Tumor volume was 77% and 87.7% lower (p < 0.0001) in the vaccinated mice when compared with Doxil (liposomal doxorubicin) and control mice, respectively. Tumor size analysis showed that time to reach the endpoint of the vaccine group (47 ±11 days) was slightly but not significantly higher than PLD (46 ±2.6 days) and the control (43 ±12 days) groups. The tumor growth rates in the vaccine and PLD groups were reduced by 9.3% and 7.3, respectively, when compared with the control group. The vaccinated mice survived slightly but not significantly longer than PLD and the control mice. The median survival of the vaccine, PLD and control groups were 51, 45, and 41 days, respectively. The vaccinated mice's life was prolonged by 24.4% as compared with the control mice, while it was increased by 9.8% in the PLD group. Preparation of immunogenic peptide The Immunogenic Fused PCSK9-Tetanus (IFPT) peptide with a purity grade of > 95% was synthe-Conclusions: Our results revealed that PCSK9 inhibition not only exerted no harmful effects but also could moderately inhibit tumor growth, and improve lifespan and survival in mice bearing colon cancer.

show abstract

“…Early studies have shown that gain-of-function mutations in PCSK9 were causatively associated with increased plasma levels of LDL-C [19], while loss-of-function mutations were associated with hypocholesterolemia and a reduced risk of coronary artery disease [20][21][22]. This association has also been confirmed in proof-of-concept clinical trials [23][24][25][26][27][28][29][30]. Of note, it was recently reported that LDL-raising genetic variants of PCSK9 were associated with a higher risk of breast cancer, while LDL-lowering variants mimicking PCSK9 inhibitors were found to have significant association with a lower risk of breast cancer occurrence [16].…”

Section: Introductionmentioning

confidence: 88%

Effects of immunization against PCSK9 in an experimental model of breast cancer

Momtazi‐Borojeni¹,

Nik²,

Jaafari³

et al. 2019

aoms

View full text Add to dashboard Cite

Introduction: Inhibition of proprotein convertase subtilisin/kexin 9 (PCSK9) is an efficient strategy for lowering low-density lipoprotein cholesterol (LDL-C). There are, however, scant data on the efficacy and safety of PCSK9 inhibitors in non-cardiovascular diseases, particularly cancer. The present study aimed to evaluate the effect of PCSK9 inhibition using a nanoliposomal antiPCSK9 vaccine on cancer behavior and endpoints in mice bearing breast tumor. Material and methods: To induce antiPCSK9 antibody in vivo, a nanoliposomal antiPCSK9 vaccine absorbed on 0.4% alum adjuvant was used. To induce tumor, BALB/c mice were subcutaneously inoculated with 4T1 breast carcinoma cells. After the tumor mass was palpable (approximately 10 mm 3), the mice were randomly divided into four groups and subjected to different treatment protocols: (1) PBS (untreated control), (2) vaccine group, (3) combination of vaccine and Doxil, and (4) Doxil (positive control) group. Vaccine was subcutaneously administered to mice four times at 2-week intervals. Two weeks after the last administration, the vaccinated and non-vaccinated mice were subcutaneously inoculated with 4T1 breast carcinoma cells. To evaluate therapeutic efficacy, mouse body weight, tumor size, and survival were monitored every other day for 60 days. Results: The nanoliposomal antiPCSK9 vaccine was found to efficiently induce specific antibodies against PCSK9 in BALB/c mice, thereby decreasing plasma levels of PCSK9 and inhibiting its function. Tumor size analysis showed that time to reach endpoint (TTE) of the vaccine, combination, Doxil, and control groups was 47 ±10, 57 ±4, 60 ±4 and 39 ±9 days, respectively. Rate of tumor growth in vaccine, combination and Doxil groups was decreased by 21%, 48% and 53%, respectively, compared to the control group. Lifespan was increased by 4.2% in the vaccine group, compared with the Effects of immunization against PCSK9 in an experimental model of breast cancer Arch Med Sci 3, May / 2019 571 control group. Additionally, the survival in the combination and Doxil groups was significantly higher than the vaccine and control groups. Conclusions: Our results revealed that PCSK9 inhibition may moderately improve breast cancer outcomes while having no harmful effects in tumor-bearing mice.

show abstract

PCSK9 inhibitors – from discovery of a single mutation to a groundbreaking therapy of lipid disorders in one decade

Cited by 23 publications

References 111 publications

Cholesterol, Oxysterols and LXRs in Breast Cancer Pathophysiology

Cholesterol, Oxysterols and LXRs in Breast Cancer Pathophysiology

Potential anti-tumor effect of a nanoliposomal antiPCSK9 vaccine in mice bearing colorectal cancer

Effects of immunization against PCSK9 in an experimental model of breast cancer

Contact Info

Product

Resources

About