Repurposing antidepressant sertraline as a pharmacological drug to target prostate cancer stem cells: dual activation of apoptosis and autophagy signaling by deregulating redox balance
Somaiah Chinnapaka, Velavan Bakthavachalam, and Gnanasekar Munirathinam
Additional article information
Abstract
Cancer stem cells play a major role in tumor initiation, progression, and tumor relapse of prostate cancer (PCa). Recent studies suggest that Translationally Controlled Tumor Protein (TCTP) is a critical survival factor of stem cells including cancer stem cells. Here, we aimed to determine whether the TCTP inhibitor sertraline (STL) could target prostate cancer stem cells (PCSC). In colony formation, spheroidogenesis, angiogenesis, and wound healing assays STL showed a robust inhibition of tumorigenic (colony growth), angiogenic (endothelial tube formation) and metastatic (wound healing and migration) potential of PCSC. Interestingly, antioxidants such as N-acetyl cysteine (NAC), Glutathione (GSH) and catalase effectively blocked the cytotoxicity effect of STL on PCSC implicating oxidative stress as the underlying anti-PCSC targeting mechanism. Cell cycle analysis showed a robust G0 arrest in PCSC exposed to STL. Notably, STL induced both apoptosis and autophagy by activating free radical generation, hydrogen peroxide formation (H2O2), lipid peroxidation (LPO) and depleted the levels of glutathione (GSH). Moreover, surface marker expression analysis using confocal revealed that STL significantly down regulates the expression levels of aldehyde dehydrogenase 1 (ALDH1) and cluster of differentiation 44 (CD44) stem cell markers. Furthermore, in western blot analysis, STL treatment applied in a dose-dependent manner, caused a marked decrease in TCTP, phospho TCTP, anti-apoptotic markers survivin and cellular inhibitor of apoptosis protein 1 (cIAP1) expression as well as a significant increase in cleaved caspase3 and cleaved Poly [ADP-ribose] polymerase 1 (PARP-1) expression. Of note, STL also significantly down regulated the stem cell markers (ALDH1 and CD44) and epithelial to mesenchymal transition (EMT) markers such as transcription factor 8 (TCF8) and lymphoid enhancer-binding factor-1 (LEF1) expression levels. Concurrently, STL increased the levels of autophagy markers such as light chain (LC3), Beclin1 and autophagy-related gene (ATG5). Taken together, our study suggests that STL could be an effective therapeutic agent in eliminating prostate cancer stem cells.
"Furthermore, MTT cell viability assay was performed to identify the role of iron in the cytotoxic effects of STL. Our data revealed that STL exerted synergic effect in the presence of FS and iron chelators such as DFO"
Hi. My husband has depresssion and mood swings which we feel is in major part due to treatment - currently Decapeptyl and Zytigia (never had mental health issues before) but of course having an advanced cancer diagnosis s a pretty depressing fact in itself, so its hard to know the true 'cause'. He tried psychological tx for 2 years with little lasting effect. Now is on Sertraline. Not a massive improvement, but possibly a bit of relief. Still high mood swings and fatigue though. There is a highly regarded Cochrane Review of the impact of antidepressants in people with cancer - which shows a poor level of evidence for effectivity I am sorry to say.
What is shocking is that there are so few high quality studies of this issue of depression - which we all know is a major aspect of QOL for people living with cancer.
So, if there is a possibility that the sertraline might just possibly be helping in some other celluar way - well, that makes me feel a bit better this morning!!
Make sure he gets an adequate dose. Usual max is 200 mg and nonpsychiatrists are often unwilling to go that high. Side effects are usually not a problem, except of course decreased sex drive and impotence. There is a risk of precipitating mania if the patient has bipolar. By and large very well tolerated. Ranked just below Lexapro in efficacy.
I am on Zytiga + Lupron and apart from very annoying hot flushes evening fatigue and breast development, I am in good shape and have a high QOL. I live in Mexico where generic Sertraline is cheap and OTC. Is there any reason why I shouldn’t give Sertraline a try for a month?
In addition to my SOC meds, I follow the Care Oncology protocol and use four other drugs off label (metformin, doxycycline, atorvastatin and Mebednazole) plus home made full extract cannabis oil.
If I go ahead with this experiment., what would this group recommend as dependent variables?
The WebMD contraindications are listed below. Nevertheless in my opinion you should run it past an oncologist. If you are with COC their oncologist would probably be more open minded to such things.
Conditions:
a disorder with excess antidiuretic hormone called syndrome of inappropriate antidiuretic hormone
low amount of sodium in the blood
an increased risk of bleeding
manic behavior
a form of mania that has a lower severity of symptoms
manic-depression
suicidal thoughts
serotonin syndrome
a type of disorder with high serotonin levels
closed angle glaucoma
liver problems
bleeding from stomach
esophagus or duodenum
seizures
weight loss
CYP2C19 poor metabolizer
risk of angle-closure glaucoma due to narrow angle of anterior chamber of eye
Reading the original article I find it very impressive how they detailed all their lab procedures. Still they are showing how they poisoned the stem cells in a flask via ROS. They did not use a control line of non cancerous human cell lines and that sertraline would not kill those too. Good science though. Would like to see what happens in animal models with therapeutic levels of sertraline next. Not sure that unregulated ROS oxidative stress is something I want in my body on a long term basis. Though I am on fluoxetine at low dose.
Had my R/V with a psychologiste specialist in depression due to cancer and other health problems. Talk for over an hour answering her questions. Cry a lot.
I am VERY limited physically since 1994 and with the time it got worse.
I have to use a walker to walk half a kilometer twice a day than I have to use my pump of Ventolin to help me catch my breath. Fighting to breath exhauste you and I already have a chronic anemia due to my Lymphoma.
I have been in Tai chi classes where some people do it sitting down. Also it can help to go through the motions in your mind. I often do this when I want to go to sleep after going to the toilet in the middle of the night.
So sorry for such severity of challenges that have you suffering and depressed. The sertraline can take a few weeks to fully work. Otherwise, all that we can do is to do all that we can. Every day.
Regarding Feldenkrais, I recommend the book Relaxercise by David Zemach-Bersin, Kaethe Zemach- Bersin and Mark Reese. You can do nearly all of the movements sitting down. They make me feel great.
Any waist twisting is a no no. When I said I am limited, I meant it.I went to 3 different Pain Clinics (18 months each) and the last one almost kill me.
And that was before my emphysema.
So now I tried to relax in my 3,000.00$ bed which I set at the zero-G position and I read a LOT. A book every 2 days. These sci-fic books help me to forget a little bit my pain. I am on Fentanyl 87 mcg/hr patches every 3 days. I am waiting for a response from Medical Canabis to see if oil or muffin or any NON-SMOKING canabis. My PG prescribed it almost a month ago.
Don't give up on the Feldenkrais technique just yet. It's not about stretching but neurophysiology.
From the book "Relaxercise exercises are easy to do. They involve hardly any muscular effort, are safe and effective, and take only fifteen to thirty minutes to do. Best of all , the results and rewards are immediate. With Relaxercise you can begin to feel better right away."
Ideally get some one-to-one appointments with a trained Feldenkrais teacher. I would be very surprised if a number of one-to-ones could not improve your situation.
Are you supposed to take something in south to zoloft, in order to get the anti cancer effect? The article said “taken together” but it doesn’t say what to take it with.
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