Based on these studies, do you think it's best to use simvastatin as your choice of statins? I'm using Crestor 5 mg plus 5mg Zetia and my ldl has gone down to a level, which puts me at risk of infection. Plus, my brain isnt functioning nearly as well as it used to. My current ldl is 27. This probably was caused by the Nubeqa causing a buildup of Crestor in my system (one of the potential, negative interactions). I'm not sure if I'll try Simvastatin again or just go with 2.5mg of crestor and 2.5 of zetia per day, to see if that can raise the ldl closer to 70-90.
I can't get the graphs to embed on this post.
You can see them here:
3. Results
3.1. Differential Effects of 3 Different Hydrophilic and Lipophilic Statins with or without Enzalutamide on Prostate Cancer Cells
We first investigated the short-term effects of three different statins on various PCa cell lines, representing different stages of the disease: androgen-sensitive LNCaP cells, androgen-insensitive PC-3 cells and two cell lines mimicking castration resistance (LNCaPabl, 22Rv1). We selected three widely prescribed statins (simvastatin, atorvastatin and rosuvastatin) because of their different pharmaceutical characteristics as reviewed by Althanoon [18]. Simvastatin and atorvastatin are lipophilic pro drugs, which are metabolized through cytochrome P450 CYP4A5, whereas rosuvastatin is hydrophilic and does not need an additional activation step. In addition, atorvastatin and rosuvastatin both use the organic anion transporting polypeptide OATP1P1 for cellular uptake [18].
Cell viability was determined after treatment of cells with rising concentrations of each statin ranging from 0.1 to 5 µM over 3 days. We tested these concentrations as they were commonly used in preclinical trials on statins in PCa [23,24]. Of note, a previous pharmacological study showed that even high doses of lovastatin that are required to reach plasma bioactivity levels in this µM range are well-tolerated [25].
Simvastatin demonstrated the strongest growth inhibitory effect of all three statins, followed by atorvastatin and rosuvastatin, which in fact did not express any significant inhibition on the investigated cell lines (Figure 1A). At a concentration of 1 µM, simvastatin accomplished a >50% reduction of cell growth representing the IC50, whereas atorvastatin reached the IC50 mark at a concentration of 3 µM in the same cell lines. Responsiveness to the three statins also strongly differed among the cell lines. Simvastatin and atorvastatin had the strongest growth-inhibitory effect in androgen-insensitive PC-3 cells, followed by LNCaP cells, which mimic hormone-sensitive PCa. The two castration-resistant cell lines, LNCaPabl and 22Rv1, on the other hand, were clearly less sensitive to statin treatment. Representative images of each cell line after treatment with the most effective dose of 5 µM are shown in Figure 1B.
Biomedicines 11 00029 g001a 550Biomedicines 11 00029 g001b 550Figure 1. Growth-inhibitory effects of statins on different PCa cell lines. (A) Four different PCa cell lines (LNCaP, LNCaPabl, 22Rv1, PC-3) were treated with increasing concentrations of simvastatin (sim), atorvastatin (ato), and rosuvastatin (rosu) in the absence or presence of 5 µM enzalutamide (enza) over 72 h. Cell viability was assessed with a colorimetric CellTiter 96® Aqueous one solution cell proliferation assay and expressed as percentage of mock control (DMSO) that was set 100%. (B) Representative images were taken after 72 h of treatment with 5 µM of the indicated statin (100× magnification). (C) Induction of apoptosis was assessed after treatment of cells with 5 µM of each statin through a caspase 3/7 assay. Caspase 3/7 activity was expressed as percentage of mock control that was set 100%. Data are represented as mean ± SEM. (** p < 0.01, *** p < 0.001).
Corresponding with the effect obtained on cell viability, simvastatin significantly induced apoptosis in LNCaP and PC-3 cells and to a much lesser extend in LNCaPabl and 22Rv1 cells (Figure 1C). Atorvastatin, by contrast, only induced apoptosis in PC-3 cells whereas rosuvastatin did not induce apoptosis in any of the cell lines (Figure 1A,B).
In combination with 5 µM of the anti-androgen enzalutamide, there was a weak increase in growth inhibition of androgen-sensitive LNCaP cells compared to statins alone, particularly at lower concentrations between 2 and 4 µM (Figure 1A), whereas there was no apparent additive effect of statins and enzalutamide in PC-3 cells. In castration-resistant LNCaPabl cells, enzalutamide combined with atorvastatin resulted in the most prominent growth inhibition. Notably, simvastatin and also rosuvastatin were able to increase the effect of enzalutamide in 22Rv1 cells. These data suggest that statins may in fact be able to enhance the tumor growth inhibitory effect of enzalutamide, however, depending on the type of statin and the tumor cell line.
3.2. Differential Effects of Statins on the Expression of HMGCR
One of the possible explanations for the differential effects of statins observed in PCa cells is the transcriptional upregulation of enzymes of the mevalonate pathway by sterol regulatory element binding protein 2 (SREBP2), a feedback mechanism that is activated by statin treatment. Previous studies have demonstrated that AR-negative PC-3 cells lack SREBP2 expression and are therefore highly responsive to statins [26]. Therefore, we next investigated changes in HMGCR expression after treatment of our 4 PCa cell lines with the three different statins through qPCR. As depicted in Figure 2A, simvastatin treatment induced an upregulation of HMGCR in AR-positive LNCaP, LNCaPabl and 22Rv1 cells but not in AR-negative PC-3 cells, confirming previously published results [26]. Similarly, HMGCS1 was significantly upregulated by simvastatin in LNCaP, LNCaPabl and 22Rv1 cells but did not affect the expression in PC-3 cells (Figure 2B). Treatment with atorvastatin and rosuvastatin, by contrast, increased the expression of HMGCR and HMGCS1 in all 4 cell lines, including PC-3 cells, indicating that a lack of response to the different statins cannot solely be explained by the SREBP2 mediated feedback mechanism.
Biomedicines 11 00029 g002 550Figure 2. Expression of HMGCR (A) and HMGCS1 (B) after treatment with statins (5 µM) was determined via real-time qPCR and normalized to the housekeeping gene hydroxybilane synthase (HMBS). Data are represented as mean ± SEM. (* p < 0.05, ** p < 0.01, *** p < 0.001).
Statin use and mortality risk in men on ADT.
Glutamine blockade to starve tumors, Using bacteria in the microbiome to attack cancer, 2 articles on finding dormant cancer cells in bone
