Molecular Mechanisms Underlying the Effects of Statins  in the Central Nervous System

McFarland, Amelia J.; Anoopkumar‐Dukie, Shailendra; Arora, Devinder; Grant, Gary; McDermott, Catherine; Perkins, Anthony V.; Davey, Andrew K.

doi:10.3390/ijms151120607

Cited by 160 publications

(148 citation statements)

References 168 publications

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“…This cell cycle arrest was accompanied by intrinsic apoptosis as demonstrated by diminished B-cell lymphoma 2 (Bcl-2) protein levels, increased cytosolic cytochrome c and active caspase 9 and caspase 3 levels. In human glioblastoma cells, previous studies have revealed that erivastatin, pitavastatin and fluvastatin are potent anti-proliferative agents (10,11). In addition, one clinical trial revealed that fluvastatin reduced tumour proliferation and increased apoptotic activity in high-grade, stage 0/1 breast cancer (12).…”

Section: Introductionmentioning

confidence: 99%

Combined pitavastatin and dacarbazine treatment activates apoptosis and autophagy resulting in synergistic cytotoxicity in melanoma cells

Al-Qatati

Aliwaini

2017

Oncol Lett

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Abstract. Melanoma is an aggressive skin cancer and its incidence is increasing faster than any other type of cancer. Whilst dacarbazine (DTIC) is the standard chemotherapy for metastatic melanoma, it has limited success. Statins, including pitavastatin, have been demonstrated to have a range of anticancer effects in a number of human cancer cell lines. The present study therefore explored the anti-cancer activity of combined DTIC and pitavastatin in A375 and WM115 human melanoma cells. Cell survival assays demonstrated that combined DTIC and pitavastatin treatment resulted in synergistic cell death. Cell cycle analyses further revealed that this combined treatment resulted in a G1 cell cycle arrest, as well as a sub-G1 population, indicative of apoptosis. Activation of apoptosis was confirmed by Annexin V-fluorescein isothiocyanate/propidium iodide double-staining and an increase in the levels of active caspase 3 and cleaved poly (ADP-ribose) polymerase. Furthermore, it was demonstrated that apoptosis occurs through the intrinsic pathway, evident from the release of cytochrome c. Finally, combined DTIC and pitavastatin treatment was demonstrated to also activate autophagy as part of a cell death mechanism. The present study provides novel evidence to suggest that the combined treatment of DTIC and pitavastatin may be effective in the treatment of melanoma. IntroductionMelanoma is a particularly aggressive skin cancer and its incidence is increasing faster than any other cancer worldwide (1). At present, the 10-year survival rate of patients diagnosed with advanced (stage IV) metastatic melanoma is <10% (2), which highlights the importance of early detection and treatment. The Food and Drug Administration approved the chemotherapeutic agent dacarbazine (DTIC) for the treatment of metastatic melanoma in 1975, and it remains the only licensed chemotherapeutic agent in use today (1). DTIC is a methylating agent which causes DNA damage, cell cycle arrest and apoptosis. Despite this, only 2% of all patients with metastatic melanoma receiving this treatment demonstrate a significant response and only 11.2% demonstrate a partial response (3). Resistance to DTIC has been associated with the upregulation of pro-survival signals and anti-apoptotic molecules in cancer cells. Despite its moderate effects, DTIC continues to be the standard treatment for metastatic melanoma as no other chemotherapeutic treatment has been demonstrated to have a significantly increased chance of survival when compared with DTIC (4,5). Provided the limited efficacy of the current metastatic melanoma chemotherapies in addition to the increasing incidence of melanoma cases, there appears to be a need for the development of more effective treatment strategies.Statins are a group of drugs commonly used for the reduction of cholesterol levels (6). They work by inhibiting 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, a critical enzyme in the mevalonate pathway, which is responsible for cholesterol synthesis (6,7). In addition, statins have been de...

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Section: Introductionmentioning

confidence: 99%

Combined pitavastatin and dacarbazine treatment activates apoptosis and autophagy resulting in synergistic cytotoxicity in melanoma cells

Al-Qatati

Aliwaini

2017

Oncol Lett

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“…Zahamowanie wątrobowej syntezy cholesterolu zwiększa obwodowy klirens tego steroidu, co zmniejsza stężenie frakcji LDL, do czego przyczynia się również zahamowanie wątrobowej produkcji apolipoproteiny B100, wchodzącej w skład LDL. Statyny zwiększają także stężenie frakcji HDL oraz wykazują inne korzystne efekty sercowo-naczyniowe, niezależne od ich wpływu na parametry lipidowe, jak poprawa integralności śródbłonka naczyniowego, zmniejszanie i kontrolowanie reakcji zapalnej w świetle naczynia, hamowanie proliferacji mię-śniówki gładkiej i procesu remodelingu naczyniowego [57,58]. Wzrastająca liczba doniesień sugeruje, iż część z tych efektów (zmniejszenie produkcji apoB100, wzrost HDL) jest mediowana przez agonistyczny wpływ statyn na PPAR-α, co ponadto wyjaśnia obserwowany, analogiczny do fi bratów, wpływ wybranych związków z tej klasy (simwastatyna, prawastatyna, ceriwastatyna) na obniżanie stężenia trójglicerydów [59,60].…”

Section: Wpływ Na Ppar Jako Dodatkowy Aspekt Farmakodynamiki Sartanówunclassified

Agoniści receptorów aktywowanych proliferatorami eroksysomów w farmakoterapii. Obecne znaczenie i perspektywy zastosowania

Dobrek¹

2017

PiS

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“…Within liver cells, ATV disrupts cholesterol biosynthesis by blocking 3-hydroxy-3-methylglutaryl-coenzyme A reductase, which reduces the amount of cholesterol released into the blood. As a consequence, low-density lipoprotein cholesterol uptake by liver cells increases and blood cholesterol levels diminish (6). However, in clinical trials of ATV, pharmacokinetic parameters including maximum plasma concentration (C max ), time to reach C max (T max ), area under the plasma concentration-time curve (AUC) from time 0 to the time of last measurement (AUC 0-t ), AUC from time 0 extrapolated to infinity (AUC 0-∞ ), apparent clearance of the fraction dose absorbed (Cl/F), elimination rate constant in the terminal drug phase (Ke) and the half-life in the terminal drug phase (T 1/2 ) are variable (7).…”

Section: Introductionmentioning

confidence: 99%

Effect of AGTR1 and BDKRB2 gene polymorphisms on atorvastatin metabolism in a Mexican population

et al. 2017

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Abstract. Discrepancies in the response to drugs are partially due to polymorphisms in genes involved in drug metabolism and transport. The frequency, pattern and impact of these polymorphisms vary among populations. In the present study, the pharmacokinetics and pharmacogenetics of atorvastatin (ATV) in a Mexican population were investigated. The study cohort exhibited differing ATV metabolizing phenotypes, and in subsequent allelic discrimination assays, single nucleotide polymorphisms in the angiotensinogen, angiotensin II type 1 receptor (AGTR1) and bradykinin B2 receptor (BDKRB2) genes were genotyped and their effects on the pharmacokinetic parameters of ATV were assessed. Additionally, association studies were performed to test for a correlation between metabolizing phenotypes and genetic variants. It was observed that carriers of the genotypes A/C and C/T in AGTR1 and BDKRB2 had higher area under the plasma concentration-time curve values from time 0 to the time of the last measurement and from time 0 extrapolated to infinity, and lower values of clearance of the fraction dose absorbed compared with homozygous carriers (P<0.05). Only the C/C genotype of BDKRB2 was associated with the fast metabolizer phenotype. These data suggest that AGTR1 and BDKRB2 are involved in ATV pharmacokinetics; a novel finding that requires confirmation in further studies.

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Molecular Mechanisms Underlying the Effects of Statins in the Central Nervous System

Cited by 160 publications

References 168 publications

Combined pitavastatin and dacarbazine treatment activates apoptosis and autophagy resulting in synergistic cytotoxicity in melanoma cells

Combined pitavastatin and dacarbazine treatment activates apoptosis and autophagy resulting in synergistic cytotoxicity in melanoma cells

Agoniści receptorów aktywowanych proliferatorami eroksysomów w farmakoterapii. Obecne znaczenie i perspektywy zastosowania

Effect of AGTR1 and BDKRB2 gene polymorphisms on atorvastatin metabolism in a Mexican population

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