#146

I wouldn’t be so sure about that. Atorvastatin has a lower incidence of diabetes compared to rosuvastatin, and if we speculate this could be off-target effects in muscles relating to HMGCR inhibition for the latter reducing the glucose sink.

1 Like
#147

I believe lipophilic Statins are better at penetrating the brain’s BBB, so would be better to control cancers in the brain. On the other hand, depleting cholesterol (particularly Desmosterol) in the brain can cause “brain fog”, which is less likely with non-lipophilic statins like rosuvastatin, though they still penetrate the BBB, just somewhat less. I would not use lipophilic statins just for brain cancer prevention if I had any symptoms of “brain fog”.

In the rest of the body there is probably no obvious difference between different statins in effect on intra-cellular cholesterol and hence no difference in effect on cancer prevention.

1 Like
#148

If you can measure serum desmosterol that is correlated with brain desmosterol.
I don’t think there is any recent evidence establishing the claim that some statins penetrate the BBB differently, if you have any I’d like to take a look at it.

If you can’t measure serum desmosterol then you cna use other things than statins.

1 Like
#149

Bempepoic Acid also lowers intra-cellular cholesterol, but mainly in the liver since it is a pro-drug that requires a liver enzyme to be converted into the active form.

Ezetimibe just lowers LDL cholesterol in blood by blocking absorption from food, but all cells that need more cholesterol can absorb LDL cholesterol from the blood, and if internal cholesterol synthesis in cancer cells is shut down with Statin + Bempedoic Acid, cancer cells can still get cholesterol from LDL in the blood. However the additional benefit on top of Statin + Bempedoic Acid is probably small both for reducing LDL cholesterol and intra-cellular cholesterol in cancer cells.

1 Like
#150

I agree that there is little evidence that Rosuvastin is better than Atorvastin at not reducing desmosterol : I would not use any Statin if I had symptoms of brain fog, unless I actually had cancer. Fortunately most people only get brain fog for a few weeks after starting on high dose statins and the brain somehow adapts.

2 Likes
#151

Do you have any evidence showing that brain desmosterol changes levels is related to possible brain fog side effect? The turnover for brain cholesterol is very long and most is synthesized early in life.

No it’s from cholesterol that’s dumped to be reabsorbed by the body.

1 Like
#152

Thanks for color

Not sure if in practice Bemp or Eze will lower cell cholesterol through the body than PCSK9i will

They seem to mostly impact the the blood levels

@AnUser outside of statins do you think the others would have a meaningful impact on cell levels (and hence potentially help prevent cancer)?

#153

I don’t understand the question.

#154

Tananth said:

That roughly only seems to potentially be correct for statins

(A) do you think the effect of statins is likely to be material enough outside of the blood and through the bodies cells to have an impact on cancer?

(B) even if (A) is true, do you think one would expect Bempedoic Acid and Eze to have a similar effect? (I don’t because most of their effect is just via the blood, not what each cell does with its own cholesterol synthesis)

1 Like
#155

I would recommend searching for clinical trials and see if whatever you searched for show potential for prevention.

1 Like
#156

According to the website I linked, Bempedoic Acid has an anti-cancer effect (as an ACLYL inhibitor), independent of its effect on cholesterol. Second BA further lowers LDL cholesterol (beyond what is achievable with Statins alone) which indirectly prevents cancer cells from getting much cholesterol from the blood. Finally, BA lowers intra-cellular cholesterol inside the liver, so would help with liver cancer, or metastatic liver lesions.

Ezetimibe only indirectly helps fight cancer by further lowering LDL cholesterol. Unfortunately, there is no way to eliminate all cholesterol in cancer cells, since there will always be some LDL cholesterol in the blood that cancer cells can draw on, but the lower the LDL cholesterol, the better.

5 Likes
#157

Thanks guys. Was interested in understanding the pathways and logic. Still not sure why PCSK9i should be less “ex ante” logical to help vs Ezetimibe. But no worries. Not need to spend more time on this for my sake.

#158

I am still taking PCSK9i (Praluent) + Ezitimibe, since I don’t like the “brain-fog” I was experiencing with Atorvastin. I plan to continue on Praluent, as long as I don’t have cancer, but might add a small dose (5mg per day or every other day) of Atorvastin to hedge my bets.

It is indeed unclear if PCSK9i actually have a net negative effect on cancer growth since the benefit of lower LDL cholesterol (leaving less for newly divided cancer cells to suck up) should roughly cancel the effect of higher intra-cellular cholesterol, if existing cancer cells are not gaining more intra-cellular cholesterol than other cells. Given that PCSK9i acts more strongly on liver cells than most other cells in the body, most LDL cholesterol should be removed by liver cells, so except for liver cancer PCSK9i might actually still provide a net protection again most cancer cells. And you might even end up with net protection against liver cancer if you combine Bempedoic Acid (which primarily lowers cholesterol production in liver cells) with PCSK9i, which might be a good strategy for those intolerant to Statins.

1 Like
#159

On the statin chemoprevention question: I have not made a thorough review of the literature, but from a bit of a dig there is evidence that statins improve survival in patients with existing cancers of various kinds, including colon, prostate, breast, and lung — so not just the liver. But it’s quite inconsistent and of variable methodological quality. Here is a summary of previous studies by an observational study that did find a protective effect against colon cancer:

Few epidemiologic studies have investigated the effect of statin use after diagnosis on cancer-specific mortality in patients with colorectal cancer. Although our main finding (fully adjusted HR, 0.71; 95% CI, 0.61 to 0.84) is consistent with a Scottish study of 308 patients with colorectal cancer, which observed a nonsignificant 58% reduction in colorectal cancer-specific mortality in statin users after diagnosis (HR, 0.42; 95% CI, 0.17 to 1.05),9 their findings may be subject to immortal time bias.16 This bias occurs because individuals who survive longer are more likely to receive a medication and, consequently, the medication erroneously seems protective.16 Lakha et al9 used Cox regression models and therefore, to account for immortal time bias, medication use should be investigated with time-varying covariates,16 but this is not mentioned. Our main finding is consistent with a recent American study by Mace et al10 of 407 patients with rectal cancer who were undergoing chemoradiotherapy, which observed a marked but nonsignificant reduction in cancer-specific mortality in patients using statins both before and after surgery (HR, 0.62; 95% CI, 0.32 to 1.18). Finally, another American study by Ng et al11 used observational data from a trial investigating chemotherapy regimens (statin use was not randomly assigned) and found no association between statin use and cancer recurrence (adjusted HR, 1.14; 95% CI, 0.77 to 1.69). Although there is some overlap in the CIs from our study and in the study by Ng et al,11 inconsistency in the estimates could reflect the different methodologies used.
https://ascopubs.org/doi/10.1200/JCO.2013.54.4569

Regardless, the key thing seems to be the intracellular cholesterol synthesis pathway, and in particular two intermediates (geranylgeranyl pyrophosphate and farnesyl pyrophosphate) that stimulate Ras and related oncogenic pathways. So non-statin drug classes (except maybe Bemp in the liver) aren’t going to do it, if there is a real ‘it’ to do.

And there’s next to nothing in primary prevention, this (in a very high-risk group) being one of the few.

3 Likes
#160

Atorvastatin failed to prevent cancer deaths in the ITP though perhaps combining it with either acarbose or a SGLT2 inhibitor could yield slightly higher lifespan extension than either by themselves.

4 Likes
#161

The long pre-cancerous state of colorectal cancer (CRC) provides an opportunity to prevent the occurrence and development of CRC. The detoxification of CRC food-borne carcinogenic heterocyclic amines is highly dependent on UDP glucuronosyltransferase 1A (UGT1A)-mediated glucuronidation. Sulforaphane (SFN), a phytochemical, possesses antioxidant, anti-inflammatory and anticarcinogenic effects on the prevention of CRC. Previous studies revealed that SFN upregulates the expression of UGT1A. The aim of the present study was to investigate the regulatory mechanism of SFN-induced UGT1A upregulation and provide novel understanding on the basic research and chemoprevention of CRC. In the present study, the viability and proliferation of CRC cells (HT-29 and SW480) treated with SFN were assessed by MTT, colony formation and EdU assays. Flow cytometry was used to detect the cell cycle arrest and apoptosis of cells treated with different concentrations of SFN. The motility of cells was determined by wound healing and Transwell assays. Nuclear factor, erythroid 2 like 2 (Nrf2) short hairpin RNA (shRNA) and negative control shRNA lentiviruses were used for cell transfection. Reverse transcription-quantitative polymerase chain reaction and western blotting were employed to verify the role of Nrf2 in SFN-induced UGT1A. HT-29 and SW480 cells were divided into a control, an SFN and a PD98059 [an extracellular signal-regulated kinase (ERK) inhibitor] + SFN group. Western blotting detected the protein levels of Nrf2 and UGT1A. Intracellular levels of reactive oxygen species (ROS) were detected using a reactive oxygen assay kit. The results revealed that SFN inhibits cell proliferation and colony formation, promotes apoptosis, and reduces the migratory ability of CRC cells. The phosphorylation of ERK induced by SFN promoted Nrf2 accumulation. Furthermore, a significant increase in the levels of UGT1A was observed, which coincided with SFN-induced upregulation of Nrf2 levels in nuclear fractions. Pretreatment with PD58059 reversed the SFN-induced subcellular translocation of Nrf2 and the expression of UGT1A. In addition, SFN-induced high levels of ROS in CRC cells may be associated with the ERK signaling pathway. Collectively, these results indicated that SFN inhibited the proliferation of CRC cells and upregulated the expression of UGT1A in CRC cells via the ERK/Nrf2 signaling pathway.

Colon cancer (CC) is one of the most common and deadly cancers worldwide. Oncologists are facing challenges such as development of drug resistance and lack of suitable drug options for CC treatment. Flavonoids are a group of natural compounds found in fruits, vegetables, and other plant-based foods. According to research, they have a potential role in the prevention and treatment of cancer. Apigenin is a flavonoid that is present in many fruits and vegetables. It has been used as a natural antioxidant for a long time and has been considered due to its anticancer effects and low toxicity. The results of this review study show that apigenin has potential anticancer effects on CC cells through various mechanisms. In this comprehensive review, we present the cellular targets and signaling pathways of apigenin indicated to date in in vivo and in vitro CC models. Among the most important modulated pathways, Wnt/β-catenin, PI3K/AKT/mTOR, MAPK/ERK, JNK, STAT3, Bcl-xL and Mcl-1, PKM2, and NF-kB have been described. Furthermore, apigenin suppresses the cell cycle in G2/M phase in CC cells. In CC cells, apigenin-induced apoptosis is increased by inhibiting the formation of autophagy. According to the results of this study, apigenin appears to have the potential to be a promising agent for CC therapy, but more research is required in the field of pharmacology and pharmacokinetics to establish the apigenin effects and its dosage for clinical studies.

1 Like
#162

Great post, I found this case report of a hepatocellular carcinoma interesting when I did some research on cyproheptadine;

#163

Good catch about the anticancer mechanism of statins being related to Geranylgeraniol(GG): I was considering supplementing with statin plus GG (a precursor of CoQ10), but that would completely eliminate the primary anti cancer mechanism of statins!

Hopefully, just using CoQ10 with statin will still preserve the anti-cancer benefit.

7 Likes
#164
6 Likes
#165

Peter Attia weighs in on colonoscopies and colon cancer screening tests.

Verdict: A colonoscopy is superior

And I agree. I’d probably be dead without them.

3 Likes