Previously, I posted on the topic of cellular senescence, "zomby-like" cells that cannot divide but also do not die. They can become SASP cells, Senscent-Associated Secretory Phenotypes, that can promote the growth and progression of processes in other cells, including PC cells by secreting pro-inflammatory and other signaling factors.
This problem has been highlighted more and more recently as one of the mechanisms leading to treatment failures and resistances. (In the recent discussion of PEACE-1 thread for example.)
Here I want to highlight currently available treatments of senolytics, drugs and/or nutritional flavanoids with senolytic activities. These include: 1) Intermittent short courses of Dasatinib plus Quercetin. ( I take Dasatinib 100 mg daily for just 3 days combined with Quercetin 1000 to 1500 mg Quercetin for those three days. This I am repeating just once every two months. 2) Fisetin, another natural plant flavanoid with senolytic activiity. It is similar in structure and activity to Quercetin. I take it at 500 mg daily continuously, and increase this to 1000mg for a week after my Dasatinib + Quercetin 3-day cycles. Here is some of the science for your consideration:
I'm skeptical that that has anything to do with senescence in cancer cells. Just because they both use the adjective "senescent" does not mean they are at all the same thing. That link has nothing to do with cancer cells, it is only about fibroblasts. Senescence in cancer cells causes a number of genomic changes and the senescence-associated secretory phenotypes, which is pro-tumorogenic to nearby cells and promotes anti-oxidant effects that cripple immunological and chemo response. Senescence in fibroblasts has none of those effects.
I would not be taking dasatanib, which is very toxic and has been tested and found to have no benefit in prostate cancer. Quercetin, in moderation, probably won't harm you.
Indeed, a phase-3 RCT showed that “The addition of dasatinib to docetaxel did not improve overall survival for chemotherapy-naive men with metastatic castration-resistant prostate cancer. This study does not support the combination of dasatinib and docetaxel in this population of patients”.
Phase-3 is the highest level of evidence, but is about adding dasatinib to chemotherapy. The following phase 1/2 or 2 trials are on dasatinib alone, without docetaxel, and can have their own relevance. They are from chronic dasatinib treatment, as opposed to the intermittent treatment of dasatinib. The latter is used to target senescent cells which in principle would be enough if it works against senescent prostate cancer.
"Dasatinib was generally well tolerated and treatment-related adverse events were moderate. This study provides encouraging evidence of dasatinib activity in bone (reduction in bone alkaline phosphatase, my note) and reasonable tolerability in chemotherapy-naive patients with metastatic CRPC". researchgate.net/publicatio...
In a phase 2 trial of patients with metastatic castration-resistant prostate cancer, treatment with dasatinib 100 mg once daily reduced serum prostate-specific antigen (PSA) concentrations, led to tumour responses as defined by modified Response Evaluation Criteria in Solid Tumors (mRECIST), and decreased levels of the bone turnover markers urinary N-telopeptide (uNTx) and bone-specific alkaline phosphatase (BAP).21 (Link lost).
A phase 1/2 trial partly using dasatinib alone without docetaxel showed "Twenty-eight patients (61%) received single-agent dasatinib after docetaxel discontinuation and had stabilization of disease for an additional 1 to 12 months". ...."Treatment with dasatinib targeted both osteoclastic and osteoblastic components of bone disease, as shown by most patients having decreases in concentrations of uNTX and BAP"
Tall_Allens reply and skepticism are noted and appreciated. Let me confirm that these low-dose intermittent regimens have not been tested in PC trials. Their use is experimental and on SOC. And indeed a Phase III clinical trial of docetaxel chemotherapy with or without continuous dasatinib at 100mg daily showed no overall survival benefit but significant toxicity added with dasatinib. Continuous dasatinib carries significant risks! That is why I, use only the 3 day courses and repeat very infrequently rather than more. Fisetin clearly has very low potential for toxicity.
My post is meant as a way to consider possible senescent factors that may affect cancer patients. And it is a complex subject with many uncertainties. The following linked article takes the subject to greater depth. Note also the discussion of the effects of cellular senescence on frailty in the elderly.
Senescence and Cancer: A Review of Clinical Implications of Senescence and Senotherapies
12.2. Dasatinib Plus Quercetin
The combination of dasatinib (a tyrosine kinase inhibitor) plus quercetin (a flavonoid) (D + Q) may act in part via senescence induction, although this combination has quite wide-ranging cellular impacts. It reduces levels of senescent cells in a range of in vitro models and in mouse in vivo models [14,90]. That D + Q acts principally by senolytic effects for particular conditions, as opposed to effects on these other pathways, has been indicated in studies of, for example, osteoporosis. In mice with age-related osteoporosis, D + Q is as effective in restoring bone if administered once every few weeks as opposed to continuously despite D + Q having an elimination half-life of less than 11 h. Senescent cells take weeks to reappear. Thus, it seems very unlikely that in osteoporosis the beneficial effects of D + Q are due to mechanisms requiring continuous engagement of a classical biochemical target, such as occupancy of a receptor or inhibiting an enzyme, and senolytic “hit and run” effects are more plausible [102]. Consistent with this, in the case of frailty, which can be induced in younger healthy mice by transplanting senescent cells, a brief course of D + Q eliminates senescent cells and causes long term resolution of frailty [14]. Thus, the development of successful senolytics has more in common with developing antibiotics than the old fashioned one target-one drug-one disease drug development paradigm [103,104].
While D + Q has been shown to reduce levels of senescent cells in a range of in vitro models and in mouse in vivo models [14,90], to date there are few clinical trial data of its efficacy in the cancer setting, although some evidence in non-cancer settings. For example in pulmonary fibrosis, where it is thought that the secretome of senescent fibroblasts mediates fibrosis, Quercetin and Dasatinib reduce this effect in vivo [105]. In a cancer setting, it has been used to reduce radiation-induced skin ulceration in a mouse model by reducing senescent cells in the skin [75]. In human subjects, senescent cells may be implicated in the development of radiation-induced skin ulceration as shown recently by a study where p16 expression was associated with radiation-induced ulcers in human subjects [75]. This is potentially of great interest as radiation induced fibrosis and ulceration are a major cause of morbidity following radiotherapy in clinical practice.
12.3. Fisetin
Flavonoids are a group of naturally occurring chemicals found widely in fruit and vegetables and which are well known for their beneficial antioxidant properties. Studies looking at the senolytic properties of a range of flavonoids have found that fisetin is potent [106,107] and roughly twice as potent as quercetin, with an excellent toxicity profile in animal studies [108]. High levels are found in strawberries, apples, persimmons and lower levels in grapes and cucumbers [109]. It has been extensively investigated in vitro and in vivo, where it has wide ranging effects on a number of key pathways involved in cell cycle regulation, apoptosis, the suppression of inflammation, angiogenesis, and metastasis (reviewed in Kashjap at al. [109]). It has been investigated in studies of combined treatment with other anticancer agents to determine whether it may potentiate their effect. These studies are summarised in Table 4.
13. Impact of Frailty on Cancer Treatment and Outcomes
There is another way in which senolytics may impact on cancer outcomes—by enhancing resilience and reducing frailty. It is already recognised that long-term survivors of cancer have increased rates of frailty and reduced longevity, some of which are thought to be due to the direct and indirect induction of senescent cells by cancer therapies (chemotherapy and radiotherapy). A trial is currently running to assess the impact of senolytic therapy on stem cell transplant survivors using dasatinib and quercetin in a small number of patients and assessing the impact on frailty [126].
Another important patient group is the elderly with cancer. It is well recognized that treatments such as surgery and chemotherapy have a significant negative impact on physical function, with studies showing an increase in measures of frailty after treatment, which may never recover back to baseline levels. This loss of function is one of the reasons that older patients require longer hospital admission after surgery and sometimes require social care support in the longer term after surgery. This physical dysfunction is therefore a major burden on both the NHS and social care resources and is a research priority for the UK government. If use of senolytic therapies could reduce the frailty phenotype and enhance resilience, this would be a major advance in cancer therapies.
Have you seen any evidence at all that senescent cells in cancer are the same thing as the senescent cells in the benign tissue of aging mice? It appears to be just a semantic confusion.
I haven't. This senescent cell targeted treatment sounds nice but as far as I can tell it doesn't apply to senescent cancer cells. There are numerous science articles on 72+hour fasting and clearing of senescent cells yet we have many examples 72+ hour fasting on this forum having no benefit. Some will claim it lowered their psa but I am skeptical since nearly all people fasting will increase fluid consumption which most likely have and impact on blood volume.
I agree. "Senolytic" is just an adjective to denote cells that don't divide. When applied to aging cells it means an entirely different cell type from cancer cells. Probably, they should have used a different adjective for cancer cells.
There could be a connection between the two. According to the view of a senolytics prophet, Dr Kirkland of the Mayo clinic, senescent cells resemble cancer cells that do not divide, including apoptosis resistance and metabolic shifts.
From one of the reports from his team: "As would be expected from their use as anticancer drugs, the senolytics D + Q (dasatinib + quercetin) and F (fisetin) delay death from cancers in mice [51, 52]. Over 50% of deaths in most mouse strains are caused by cancers, and D + Q and F delay deaths of old mice by up to 35 and 17%, respectively." doi.org/10.1111/joim.13141
Pre-clinical trials have limited evidence on their own, but in the case of D + Q (not fisetin yet) they are buttressed by two small clinical trials tentatively indicating efficacy albeit these did not target cancer but other diseases.
Dasatanib, a very toxic substance, has been tested with docetaxel and with abiraterone in humans with prostate cancer. It showed no efficacy with either. Yet treatment with docetaxel or with abiraterone are known to cause cancer senescent cells. So if it had any value in preventing cancer senescent cells, it would have increased overall survival. You are being confused by semantics.
But surely the three studies I referred to in my other response to you, showing efficacy in clinical trials from single-agent dasatinib on tumor response, reduced bone alkaline phosphate etc, has relevance?
They are not comparable. The phase 3 study is about docetaxel + dastainib vs docetaxel + placebo, which didn´t show efficacy from adding dasatinib. The phase 2 studies are for single-agent dasatinib, showing efficacy from dasatinib. Dasatinib can be effective on its own, but not provide additional benefit to chemo. Surely that is a possible interpretation?
The conversation here was about some mistaken notion that dasatanib (a very toxic substance) reduces cancer-senescent cells. Cancer-senescent cells are a cancer-protective mechanism that occurs when patients take chemo or hormone therapy. If if gets rid of such cells, chemo and hormone therapy would work better/longer if dasatanib were added to it. They do not.
If you are not using hormone therapy or chemo, there is no reason to be concerned with cancer senescent cells, and there is no reason to take dasatanib.
Actually there is. If Dasatinib can be judged to NOT be an inhibitor of existing (prostate) cancer, I will probably continue taking it together with Quercetin, for its potential anti-ageing effects and killing of non-cancer senescent cells.
That said, that senescent cancer cells, induced by chemo, hormone therapy or radiation, is a different type of cells from senescent cells caused by aging and at sites of diseases, is a most interesting proposition. The research literature largely describe aging-associated senescence as normal senescent cells, with cancer senescence called cancerous senescent cells / senescent tumor cells. There has not been any suggestion of senolytic drugs in principle being suspected of having lower efficacy against cancerous senescent cells the latter.
However, that phase 3 trial referred to on Dasatinib vs placebo combined with doceaxel is a strong pointer in this direction, although being from 2013, it did not include Quercetin; some senescent cells are only hit with the combination D+Q, either drug alone won´t do the job.
The second study, on dasatinib vs sunitinib, which target similar pathways, combined with abiraterone, I understand only shows that dastinib and sunitinib are equal under those circumstances.
In a recent overview "Senolytics for cancer therapy: Is all that glitters really gold?", ncbi.nlm.nih.gov/labs/pmc/a... is emphasized the lack of universality for any individual senolytic amongst different therapy-induced senescent tumor cell models. Sometime they work but often not, depending on cell lineage and if the senescence is induced by aging, by cancer therapy, by cancer itself etc.
“Although it might be tempting to propose the use of alternative senolytics in the clinic, the cancer field has yet to provide unequivocal pre-clinical support for any senolytic as an adjuvant therapy. There is far too little literature relating to the ability of other compounds, such as D+Q (Dasatinib + Quercetin), piperlongumine, and fisetin to act as senolytics in the context of chemotherapy-induced senescence, and what is currently available is not particularly promising. For example, as opposed to its success in the context of aging-related processes, D+Q failed to kill senescent liver cells, and each drug alone failed to kill senescent ovarian cancer cells[50, 150]”. . Piperlongumine, while showing modest senolytic activity in olaparib-treated ovarian cancer [50], failed to kill senescent prostate cells [145]. Fisetin failed to kill senescent ovarian cancer cells [50], and, in our hands, was also largely ineffective against senescent lung, head and neck, and prostate cancer cells(unpublished data). Thus, similar to navitoclax, the senolytic activity of these agents may prove to be highly dependent on the cell lineage and senescence-inducing agents used”.
Cancer is underrepresented among the pre-clinical and clinical trials on senolytics, possibly indicting a lack of support for this among the researchers. There is a clinical trial targeting frailty in long-term survivors of cancer, which is thought to be caused by induction of senescent cells by cancer therapies.
On the other hand, there are those phase 2 studies, mentioned elsewhere on this thread, indicating efficacy of single-agent dasatinib on prostate cancer. And a smattering of other indications. E.g. the efficacy of dasatinib on brain and non-small cell lung cancer being enhanced by rapamycin/everolimus, a substance that some of us use.
Everolimus improves the efficacy of dasatinib in PDGFRα-driven glioma. J Clin Invest. 2020; 130:5313–25. doi.org/10.1172/JCI133310. [PubMed].
Rapamycin Enhances the Anti-Cancer Effect of Dasatinib by Suppressing Src/PI3K/mTOR Pathway in NSCLC Cells. PLoS One. 2015; 10:e0129663. doi.org/10.1371/journal.pon.... [PubMed].
I believe the jury is still out, but as of now it seems uncertain if D + Q has any anti PCa effect.
The evidence is stronger for D+Q exerting anti-ageing effects by killing non-cancer senescent cells.
Anti-aging compounds may have particular relevance for PCa, From sciencedirect.com/science/a... …”it appears that cancer survivors experience increased multi-morbidity and frailty and reduced lifespan compared to the general population [3,4]. Taken together, these data suggest an acceleration of ageing in cancer survivors [4], as such, exploring the use of identified anti-ageing compounds in cancer survivors is of interest”.
To my surprise, I have a side-effect from a 3-5 day dosing of D, a temporarily sharply lowered lymphocyte count, that I plan to make a separate post on. With the anti-cancer effect highly uncertain, it does raise the bar for using it as an anti-aging drug, still the latter is enticing.I appreciate your challenging the anti-pc effect!
Unless it is damaging your bone marrow. Myelosuppression is a known side effect. It is usually temporary, but cancer can damage bone marrow too and the combined effect may be serious.
MateoBeach, what is your take on D+Q after the input from TA? I dived into the issue in a reply to him. The evidence goes both ways on PCa but on the whole doesn´t look too good. The anti-aging effects of D+Q look much better, and this makes their use a no-brainer for me , if it weren´t, in my case, for the surprising temporarily sharply reduced lymphocyte count I found on the two series of counts that I have done. Am inclined to continue, but will closely monitor next time as well.
TA did not seem to be well versed in the basic science of what is known and not known regarding senolytics and senostatics for cancer associated including treatment emergent SCs vs other age related and degenerative SCs. (Possibly because there are no human RCTs yet, which is his forte?) The article linked below is excellent to lay out what is known. I believe you provided that link. TA does not reference things like the “bystander effect” etc. I am currently of the opinion that SCs and SASP are very important and am not inclined to wait for clinical trials to be completed. Yes, D+Q has toxic potential, so do all cancer drugs. And for dasatinib it looks like one dosing cycle is enough to last for months. If I were you with depressed lymphocytes, I would not repeat it for at least 3-4 months. And then at half dose of 50mg for just three consecutive days along with quercetin and consider adding fisetin.One thing seems clear and is proposed in the article: senescence is part of the mechanism for maximum effectiveness of chemotherapy and
probably for RT. It should not be used during chemotherapy. But some months after when the chemo has done what it can, then post-chemotherapy (secondary adjunctive) may well be beneficial for remaining treatment induced senescent cells. That’s my take. I am continuing with it going forward, but keeping vigilant.
Thanks! Might you have any reference to a dosing cycle being enough to last for months? In humans? Kirkland says it takes from 10 days to 6 weeks from initiation to attainment of a completed state of cellular senescence "at least in cell culture".
50 mg seems safer, but 100 mg was used in the two clinical trials and, if it has any relevance, that is also the starting dose for myeloid leukemia, increased to 140 mg if inadequate response.
But minimum effective dose (rather than maximum tolerated dose to toxicity) is not established. Since you had a significant adverse effect at 100mg/day. I would decrease the dose to 50mg for you as an individual. "Toxicity is in the dosage". Many would stay away altogether. But I , like you, are intrigued by the pre-clinical body of evidence at this juncture. I chose the 3 day 100/1000 mg followed a month later by repeating it as that was used in some longevity programs. I get labs next week to see if any measurable adverse effects. However I do not have a way to assay senescent cells.
Here is excerpt with descriptions of human trials (from that same article). It also explains (elsewhere) the mechanisms whereby infrequent intermittent dosing can be effective.
"The first-in-human trial of senolytics was of D + Q
for patients with IPF [70] (N = 14 patients with
stable IPF) in an open-label study of intermittent
D + Q (3 days/week over 3 weeks). Physical function
was evaluated by testing 6-minute walk distance,
4-metre gait speed and chair-stands time.
These assessments were significantly and clinically
meaningfully improved by D + Q (P < 0.05). Furthermore,
correlations were found between change
in function and change in SASP-related pro-inflammatory
cytokines, matrix-remodelling proteases
and micro-RNAs (23/48 markers;
r ≥ 0.50). This pilot study supports the feasibility
of further clinical trials using senolytics. It provided
initial evidence that senolytics can alleviate
physical dysfunction in IPF, supporting evaluation
of D + Q in larger randomized, controlled trials for
senescence-associated diseases.
Several clinical trials of senolytics are currently
underway or planned (Table 3). These include
Phase I or II trials of D + Q for IPF, age-related
osteoporosis, age-related frailty, frailty in bone
marrow transplant survivors with an accelerated
ageing-like syndrome, frailty in childhood cancer
survivors in their late 30’s and 40’s also with an
accelerated ageing-like syndrome, the ongoing trial
"Transplantation of the enriched senescent population into castrated, syngeneic mice confirmed that senescent cells escape the growth arrest and form castration-resistant tumors in vivo."
You can't do that kind of study on men (or dogs, these days), so mice it must be.
"Outgrowth from senescence was associated with increased expression of constitutively active androgen receptor splice variants, a common mechanism of resistance to ADT.
"Finally, the selective elimination of senescent PCa cells following ADT in vitro by the senolytic navitoclax (ABT-263) interfered with the development of androgen-independent outgrowth."
"Furthermore, it is feasible that senolytic therapy to eliminate senescent PCa cells could delay disease recurrence and/or progression to androgen independence."
Recall the 1995 paper from Edward Giovannucci, that used data from a (much-maligned) food-frequency questionnaire sent to 47,894 participants in the Health Professionals Follow-up Study in 1986.
"Between 1986 and 1992, 812 new cases of prostate cancer, including 773 non-stage A1 cases, were documented."
"Of 46 vegetables and fruits or related products, four were significantly associated with lower prostate cancer risk; of the four--tomato sauce .., tomatoes .., and pizza .., but not strawberries--were primary sources of lycopene."
So that started the lycopene craze. I figgured that if pizza was on the list, the protection was probably not due to a "healthy" lifestyle factor. That wouldn't impress TA, but I was born in England, where a proper "full English" breakfast includes a fried tomato, so I was convinced.
But I kept asking myself 'what about the strawberries?. The most active polyphenol is fisetin. The paper did not set off a strawberry craze (it is one of the 'dirty dozen') & there was no fisetin supplement to be had.
But PCa-fisetin studies were done - (& seemingly ignored.)
Finally, a supplement appeared. Even now, there are only a few, & they contain Novusetin:
Ah yes, the classic English breakfast. Remembering that from early season bike race training on Mallorca where everyone stays in British package tourist hotels. In addition to a cooked half tomato, there is a scoop of cold canned beans, a bland white sausage and an optional cold hard boiled egg. Add a cup of tea and slice of white toast and you are ready to face the London Spring weather. So they say.
I vaguely remember my first full breakfast in a London hotel in the 1960's. I went for the mixed grill, which was basically the Full Englsh, but there was a lamb chop & some kidneys. The fried half tomato, of course. Compote & cereal too, with copious amounts of coffee & toast with preserves. One can maybe handle that until age 26 & I don't regret it.
A boiled egg? I never heard of such a thing in the full English.
Another time in London I went for the kippers. Why shouldn't one dine at breakfast? As Nalakrats once said: "Breakfast like a king", the important meal of the day.
Those who had central heating & ne longer needed the calories had already converted to cornflakes. Sad!
Those days are closer to Dickens' time than ours. In the Pickwick papers, the breakfast at an inn would be a table full of food plus the inevitable cold mutton.
Yes, my hotel stays in London in the seventies featured breakfasts exactly as you describe. Although different, I found most German and Dutch breakfasts matched the English calories on my most recent visits ten or fifteen years ago.
Thanks for the question "Novusetin" IS fisetin. It is a brand name for fisetin supplement by the Cyvex Nutrition Company. They formerly called this same product "Cognisetin". Same thing. Just their brand name for fisetin. That is why it is not on the labels of fisetin supplements from other companies. I like and take the Vitablossom liposomal fisetin.
Thank you for those links. The second one is a great overview. The intervention trial in the third link will be very interesting. Also shows how research interest in senolytics is rising strongly.
I got my Dasatinib cheap from a source in India that I judge as trustworthy. I was 98 % certain it was the right stuff now 100 % after a certain temporary side effect occurred that is compatible with dasatinib, will post on the latter. There are even more trustworthy sources. Next time I will choose D made by the largest generic company in India, Dr Reddy´s.
MateoBeach, what is your thinking behind using fisetin daily? What I have seen about fisetin is that is to be taken with long intervals, say monthly or bimonthly, at high doses on a few consecutive days, to deal with senescent cells. Similar to dasatinib + quercetin.
Good question PB. Senolytics only require intermittent clearing as SCs are slow to re-accumulate. Every three months for a few days appears sufficient. So that is what I have done with dasatinib + quercetin. Actually I did the three day regimen and repeated it one month later as was done in one human trial. Expect not to repeat it for three more months.If using fisetin instead, perhaps 3-4 days at 1,000 mg could be effective. I don’t know since they use different pathways as senolytics. So I combined both since fisetin appears completely non toxic. Now I’ve decided to continue fisetin at lower dose 500 mg ongoing, along with my 500 of quercetin daily, as it seems to have so much positive potential as a flavonoid photochemical.
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