Hi does anyone knows why imatinib stopped working for me?after 4 month it stopped working for me
Hi Reve!
I think it should be quite clear that you had developed drug resistance against imatinib which is a common occurrence among POISers anyway. The reason why it worked is most probably due to immune suppression and inhibition of some cytokines like IL-8 as mentioned before.
The IL-8 production induced by TNF and H. pylori was also inhibited by protein tyrosine kinase (PTK) inhibitors and protein kinase C (PKC) inhibitors.
https://www.koreamed.org/SearchBasic.php?RID=2240437
Recently I have come to realize that my case is most probably caused by the state called senescence and I believe that SASP quite accurately describes the underlying issue. This state is practically incurable and increasing telomerase activity in such cells would only lead to cancer cell formation which is evidently undesirable. The only way to resolve senescence is to specifically kill off these cells through induction of apoptosis. So called senolytics like imatinib may just do that, however this may not work out so easily in real life as on paper. Unfortunately it could be possible that most of the cells in a tissue (e.g. prostate) have turned senescent in which case removal is nigh impossible. Senescence is also considered a necessity to retain tissue function and the removal of such tissue may lead to even greater loss of functional integrity on the whole than being simply malfunctional.
This is why I wish to know if you had experienced any permanent reduction in your symptoms or if POIS affects you just as it always had in the exact same way and intensity.
Regarding your original question imatinib induced drug resistance is a known problem in clinical practice. According to studies the problem stems from imatinib's ability to induce DNMTs which in the long run will cause hypermethylation and gene silencing. Due to this realization concomitant use of hypomethylating agents like histone deacetylase inhibitors (HDACi) are proposed as a possible countermeasure to avoid this development.
Imatinib-induced DNMT3A formed a complex with EZH2, which facilitated their binding to the PTEN promoter and induced DNA hypermethylation of this region, leading to downregulation of PTEN. Imatinib increased levels of both EZH2 and DNMT3A in leukemia cells, which probably caused global epigenetic aberrations and downregulated the expression of important genes involved in regulation of cell growth, apoptosis and drug metabolism, which could relate to acquisition of drug resistance.
The drug resistance against tyrosine kinase inhibitors could be overcome by treatment with an anti-epigenetic agent histone deacetylase inhibitor, highlighting a potential therapeutic strategy. In fact, we previously showed that histone deacetylase inhibitor successfully overcame imatinib resistance in EOL-1R cells in association with restoration of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) expression.
https://www.nature.com/articles/bcj201133.pdf?origin=ppub
Some prescription drugs are also being trialed for the same purpose with somewhat better known risks (e.g. neutropenia, thrombocytopenia).
Reversal of DNA methylation has been investigated as a target for cancer therapy. We have previously shown that decitabine, a hypomethylating agent, has single-agent clinical activity in CML including imatinib-resistant cases. In fact, a recent study showed that decitabine acts synergistically with imatinib in the treatment of CML cells in vitro.https://acsjournals.onlinelibrary.wiley.com/doi/full/10.1002/cncr.22470If you are interested several dietary supplement related HDAC inhibitors have been already discussed in the previous thread and some of them were also beneficial for POISers.
https://poiscenter.com/forums/index.php?topic=4061.msg43890#msg43890(ctrl+f: HDAC)
One concern though is that HDACi also inhibit hTERT and you should be aware of possible risks.
In another study, histone deacetylase inhibitors, which suppress hTERT expression in prostate cancer cells, also inhibited cell proliferation inhibition with no cell cycle arrest, apoptosis or cell differentiation. The results of our study show that imatinib inhibits proliferation by cell cycle arrest and not by apoptosis.
Two concerns have been mentioned regarding telomerase inhibition. Firstly, it may result in damage to normal stem cells. However, the length of telomeres in these cells compared to malignant cells may protect them from that apparent damage. Secondly, inhibiting TA might result in genomic instability, thereby leading to increased neoplasia.
https://www.nature.com/articles/6602592
Furthermore it is worth mentioning that both DNMTi (e.g. decitabine) and HDACi can restore ERbeta expression while ERbeta is also a known regulator of PTEN involved in imatinib induced drug resistance.
The most significant findings were that ERbeta down-regulates androgen receptor (AR) signaling and up-regulates the tumor suppressor phosphatase and tensin homolog (PTEN). The role of ERbeta in opposing AR signaling, proliferation, and inflammation suggests that ERbeta-selective agonists may be used to prevent progression of prostate cancer, prevent fibrosis and development of benign prostatic hyperplasia, and treat prostatitis.https://www.pnas.org/doi/full/10.1073/pnas.1702211114
