Aspirin & radiation.

[pjoshea13]

New study. -Patrick

ncbi.nlm.nih.gov/pubmed/306...

Prostate. 2019 Jan 4. doi: 10.1002/pros.23755. [Epub ahead of print]

Salicylate enhances the response of prostate cancer to radiotherapy.

Broadfield LA1, Marcinko K1, Tsakiridis E1,2, Zacharidis PG1,2, Villani L1, Lally JSV1, Menjolian G3, Maharaj D3, Mathurin T3, Smoke M3, Farrell T4, Muti P2, Steinberg GR1, Tsakiridis T2,5,6.

Author information

Abstract

BACKGROUND:

Radiotherapy (RT) is a key therapeutic modality for prostate cancer (PrCa), but RT resistance necessitates dose-escalation, often causing bladder and rectal toxicity. Aspirin, a prodrug of salicylate (SAL), has been associated with improved RT response in clinical PrCa cases, but the potential mechanism mediating this effect is unknown. SAL activates the metabolic stress sensor AMP-activated protein kinase (AMPK), which inhibits de novo lipogenesis, and protein synthesis via inhibition of Acetyl-CoA Carboxylase (ACC), and the mammalian Target of Rapamycin (mTOR), respectively. RT also activates AMPK through a mechanism distinctly different from SAL. Therefore, combining these two therapies may have synergistic effects on suppressing PrCa. Here, we examined the potential of SAL to enhance the response of human PrCa cells and tumors to RT.

METHODS:

Androgen-insensitive (PC3) and -sensitive (LNCaP) PrCa cells were subjected to proliferation and clonogenic survival assays after treatment with clinically relevant doses of SAL and RT. Balb/c nude mice with PC3 xenografts were fed standard chow diet or chow diet supplemented with 2.5 g/kg salsalate (SAL pro-drug dimer) one week prior to a single dose of 0 or 10 Gy RT. Immunoblotting analysis of signaling events in the DNA repair and AMPK-mTOR pathways and lipogenesis were assessed in cells treated with SAL and RT.

RESULTS:

SAL inhibited proliferation and clonogenic survival in PrCa cells and enhanced the inhibition mediated by RT. Salsalate, added to diet, enhanced the anti-tumor effects of RT in PC3 tumor xenografts. RT activated genotoxic stress markers and the activity of mTOR pathway and AMPK and mediated inhibitory phosphorylation of ACC. Interestingly, SAL enhanced the effects of RT on AMPK and ACC but blocked markers of mTOR activation.

CONCLUSIONS:

Our results show that SAL can enhance RT responses in PrCa. Salsalate is a promising agent to investigate this concept in prospective clinical trials of PrCa in combination with RT.

© 2019 Wiley Periodicals, Inc.

KEYWORDS:

aspirin; cancer metabolism; mTORC1; prostate cancer; radiation therapy

PMID: 30609074 DOI: 10.1002/pros.23755

[NPfisherman]

Thanks again for the umpteenth time...good info for those getting radiation....glad I took my ASA when I had stereotactic ablation...

[Moespy in reply to NPfisherman]

Hi NDF, What dose of aspirin daily did you take during SBRT?

[NPfisherman in reply to Moespy]

I took 325 mg bid but the dose from Patrick's article is 2.5 g/ kg....thus your weight in pounds divided by 2.2 and multiplied by 2.5 mg will give the dose...always take enteric coated to protect your stomach or always take with food...

[Moespy in reply to NPfisherman]

Thank you! Much appreciated.

[dentaltwin in reply to NPfisherman]

Your dose is safer--note that dose in article is FOR MICE. For a 70 kg man, an equal dose would be over a half pound(!)

[NPfisherman in reply to dentaltwin]

How did I miss that?? Thank you dentaltwin...How many mg's in a half pound?? How much food to eat to cover that amount.??....LOL... I try and absorb info here, and read more and do it on Lupron and Zytiga "fog", which comes and goes....... still working too... Have a good evening...

[dentaltwin in reply to NPfisherman]

A pound is 453.6 grams (thats 453,600 mg). Obviously that's a massive dose they're giving to the mice. Can't be easy on their stomachs.

[Hazard]

Just finished (2 days ago) 5 fractions of RT to left hip to treat painful bone mets. Probably too late to worry about aspirin?

[pjoshea13 in reply to Hazard]

Radiation continues to work for a while. Go for it.

-Patrick

[Break60]

Is this the same reason why taking celecoxib has also been shown to be effective?

[pjoshea13 in reply to Break60]

The following isn't a PCa study, but it will do.

cancerres.aacrjournals.org/...

-Patrick

[PhilipSZacarias]

Just a note: Taking aspirin is tricky during SBRT of the prostate. Although the radiation oncologist recommended that I stop taking aspirin during SBRT, I continued with aspirin except after the 5th and last dose because of excessive bleeding from the rectum (which happens in about 5% of cases, I was told). As soon as it subsided I resumed taking aspirin. Now a foam spacer is available, which should reduce the amount of radiation the rectum adjacent to the prostate receives, perhaps allowing aspirin to taken during treatment. Phil

[George71]

Patrick,

Would it be beneficial to take a half an aspirin a day while in radiation treatment or would it make the treatment more intense and damage healthy cells?

[pjoshea13 in reply to George71]

George,

Having read the 2014 paper, below [1], I wouldn't be that concerned:

"Aspirin use was also associated with reduced rates of distant metastases at 5 years (12.2% vs. 26.7% ...)."

"On subset analysis of patients with Gleason score (GS) 9–10 histology, aspirin resulted in improved 5-year OS (88% vs. 37% ...)"

-Patrick

[1] ncbi.nlm.nih.gov/pmc/articl...

[George71]

Patrick,

Thanks for the info.

I have another question -- I'm leaning toward salvage RT to pelvic lymph nodes plus 4 months ADT due to rising PSA (up from 0.4 to currently 0.6 over 14 months) --Currently only taking Avadart -- supplements and diet since surgery March 2016. PSA post surgery was 0.03 --- 4 of 10 lymph nodes positive from post pathology. None visible on PSMA scan done in 8/2018

My concern is taking ADT even for 4 months with the radiation -- It can start the morphing of the already Gleason 8 -9 PC cells. I was thinking if I do do RT with ADT that after the 4 months I could take a super Testosterone injection to shock any remaining PC -- since I will be stopping the ADT anyway (per radiation Dr.'s recommendation). It seems like a good time to take advantage of the situation.

I feel I have to try something better than what they have been doing for 40 years with little benefit.

I was reading a recent study of salvage IMRT to lymph nodes with and without ADT -- the overall 10 year survival only improved 2.6% . And these were patients with Gleason 7.

I would have thought it would have had a more curative or long lasting benefit.

researchgate.net/publicatio...

I'm curious what you would do? Any thoughts would be appreciated.

[George71 in reply to George71]

in the study, 33% had no evidence of disease @ a mean of 18 months, but apparently it wears off fairly soon -- if the bottom line is only 2.6% benefit in overall survival @ 10 years to do RT.

MO at M D Anderson said wait till it shows on scan and go from there -- even then -- he was saying wait till PSA reaches 10 and start some version of ADT.

They don't really have anything that works to any high degree or he would have recommended it. I don't qualify for any immunotherapy (no mutations)

I have been in no mans land for 3 years.

[pjoshea13 in reply to George71]

George,

I understand your frustration, but I'm not qualified to give the advice that you are looking for.

You mention the possibility of using T after the 4 months of ADT. Perhaps you could find someone familiar with, & sympathetic to, Sam Denmeade's BAT (Bipolar Androgen Therapy) approach. The T shock occurs at the beginning of the next month, for each month on ADT.

-Patrick