Inhibition of Cancer Stem Cells Promoted by Pimozide.

[pjoshea13]

New study below [1].

Pimozide is an antipsychotic drug [2].

"Over the past years, studies have described that users of antipsychotics are less likely to develop cancer than the population in general due to cytotoxic properties of this class of drugs on cancer cells. For this reason, Pimozide has been widely studied as a potential anticancer treatment, and satisfactory results in Melanoma, Central Nervous System Tumors, Osteosarcoma, Neuroblastoma, Myeloproliferative Neoplasms, Breast, Lung, Prostate, Ovarian, Colorectal, Pancreatic, and Hepatocellular Carcinoma have been showed. Moreover, advantages as clinical use approved by Food and Drug Administration (FDA), high clinical safety, low side effects, and reasonable price have stimulated the treatment with Pimozide instead of other agents." [1]

There has been a lot of interest in STAT3 in recent years - 550 PubMed hits for <prostate stat3> in twenty years!

From 2017 [3]:

"Mechanisms of castration-resistant prostate cancer (CRPC) are not well understood, thus hindering rational-based drug design. Activation of STAT3/5A, key components of the JAK/STAT pathway, is implicated in aggressive PC, yet their clinical relevance in CRPC remains elusive. Here, we evaluated the possible role of STAT3/5A in CRPC using immunological, quantitative mRNA expression profiling, and pharmacological methods. We observed a strong nuclear immunoreactivity for STAT3 and STAT5A in 93% (n=14/15) and 80% (n=12/15) of CRPC cases, respectively, compared with benign prostatic hyperplasia (BPH). We demonstrated that PC cells express varying levels of STAT3 and STAT5A transcripts. In addition, we demonstrate that pimozide, a psychotropic drug and an indirect inhibitor of STAT5, attenuated PC cells growth, and induced apoptosis in a dose-dependent manner. Furthermore, our analysis of the PC public data revealed that the STAT3/5A genes were frequently amplified in metastatic CRPC."

From 2016 [4]:

"Currently, drug discovery and development for clinical treatment of prostate cancer has received increased attention, specifically the STAT3 inhibitor. Our previous study reported that the neuroleptic drug pimozide had antitumor activity against hepatocellular carcinoma cells or stem-like cells through suppressing the STAT3 activity. In the present study we demonstrate that pimozide inhibits cell growth and cellular STAT3 activation in prostate cancer cells. Our results showed that pimozide inhibited prostate cancer cell proliferation in a dose- and time-dependent manner by inducing G1 phase cell cycle arrest, downregulated the ability of colony formation and sphere forming, as well as suppressed cells migration in both DU145 and LNCaP cells. Surprisingly, pimozide reduced the basal expression of phosphorylation STAT3 at tyrosine 705 and reversed the expression of phosphorylation of STAT3 induced by IL-6 addition, suggesting that pimozide can suppress cellular STAT3 activation. Thus, the antipsychotic agent pimozide may be a potential and novel therapeutic for patients with advanced prostate cancer."

From the new paper [1]:

"The action mechanism {of Pimozide} remains unclear, but three vias associated to cancer stem cell (CSC) hypothesis show that Pimozide: 1) blocks CSC features, as epithelial-to-mesenchymal transition (EMT), through inhibition of Wnt-β/catenin signaling; 2) acts as an inhibitor of Signal Transducer and Activator of Transcription (STAT-3 and 5), pathway which is activated and up-regulated in CSCs; 3) inhibits ubiquitine specific protease (USP1) and WD repeat-containing protein 48 (WDR48), that are proteins responsible to inhibit the differentiation and to maintain the cell in an undifferentiated state. Based on this perspective, the aim of this manuscript was to review the anti-neoplastic role of Pimozide during the tumorigenesis and its potential in revert the process of undifferentiation and proliferation of CSC through different vias."

-Patrick

[1] ncbi.nlm.nih.gov/pubmed/303...

[2] en.wikipedia.org/wiki/Pimozide

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

[4] ncbi.nlm.nih.gov/pubmed/265...

[snoraste]

with so much interest, i'm surprised there are no clinical trials for it. or is there?

[cesanon in reply to snoraste]

"Pimozide (sold under the brand name Orap) is an antipsychotic drug of the diphenylbutylpiperidine class. It was discovered at Janssen Pharmaceutica in 1963. It has a high potency compared to chlorpromazine (ratio 50-70:1)."

Looks like it is off patent. So there is little economic incentive for a pharmaceutical company to fund trials.

[sammamish]

Noted the apparent effect of forcing differentiation of ca cells, wonder if vitamin A might also do this?

[pjoshea13 in reply to sammamish]

Vitamin A? (Retinol)

From 2015:

"Carotenoids, retinol, tocopherols, and prostate cancer risk: pooled analysis of 15 studies."

"Overall prostate cancer risk was positively associated with retinol ..."

ncbi.nlm.nih.gov/pubmed/264...

-Patrick

[Hidden]

I used to have lorazepam available for occasional insomnia. My doctor recently denied my request for a refill. Thanks DEA for effectively criminalizing this class of drugs and scaring the wits out of doctors. BTW he prescribed trazadone, an antidepressant. I was taking only half a pill at bedtime. My libido was squashed lower than it was on ADT. Now I take a bit of an indica gummy or a half sominex tablet.

[HOPEFULSPOUSE in reply to Hidden]

My husband has starting taking a high-dose melatonin suppository that works over 12 hours. Works like a dream. Chose the suppository as sometimes he has nausea and can't keep a pill down. He also uses a melatonin patch sometimes (if we run out of the sup) and a melatonin patch. All this before we read about the anti-cancer effects of melatonin.

[HOPEFULSPOUSE in reply to HOPEFULSPOUSE]

P.S. Meant to say a melatonin patch and melatonin cream. Love the topicals.

[HOPEFULSPOUSE]

This is so interesting - will discuss with my husband's oncologist next week. Do you know anyone using this in their protocol?