http://www.labcanada.com/news/study-shows-diabetes-drug-helps-towards-immunity-against-cancer/1003535464/?&er=NA
3 cheers for met form in
my exhaustion, of my 5 year immunotherapy battle, well the kitchen sink approach has me living, and the sink gets bigger and bigger.
adding mpl and keytruda, there must be an enduring cure, lets look together.
I am certain of this breathe, the
I prayed
I went the cancer meeting, the very alternative one.
5516607_To_die_or_not_to_die_That_is_the_autophagic_question
http://www.eurekaselect.com/66536/article the full text on
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4163620/
DSICUSSION THE GOOD BIT, I MIGHT ACTUALLY GET TO USE THIS MPL, WITH KEYTRUDA. I GENTLE CHEMO ENHANCER WITH THE WORLDS BEST IMMUNOTHERAPIES.
Discussion
This study provides the first experimental evidence for the induction of autophagy by MPL in human ovarian cancer cells. Here, we have found that MPL-induced toxicity is manifested with features of autophagy (presented with deformation of cytoplasmic content and extensive vacuole formation) exerted through inhibition of mTOR/p70S6K signalling pathway . Several independent pieces of evidence support this conclusion.
Consequent to our recent described data on MPL-induced cleavage of PARP-1 and cell death, and the association of this marker with apoptosis (Submitted article), we anticipated that MPL may act as an apoptogenic agent. Published literature is divided as to whether PARP-1 cleavage is an event that precedes apoptotic cell death or is a marker of another distinct mechanism of cell death [21]. Our results however , did not show caspase-3 or caspase-8 activation in MPL-treated cells. Apoptotic features such as morphological changes in favour of apoptosis, increased level of Annexin-V+ or DNA fragmentation, were not detected. Additionally, MPL-induced antiproliferative effect was not prevented by pre-treatment with the pan-caspase inhibitor z-VAD-fmk, thus further confirming the induction of cell death is independent of the caspase-mediated apoptotic pathways. These results collectively suggest that cell death induced by MPL in ovarian cancer cell lines is not an apoptotic mediated event.
Instead, we conclusively found that cells treated with MPL undergo autophagy . Through LC3B localization studies, we were able to find that MPL treated cells present with typical autophagic morphology and biochemical signature. The autophagic effect of MPL was evident through drug induced expression of SQSTM1/p62 together with the conversion of LC3B-I to LC3B-II in a time and concentration dependent manner. SQSTM1/p62 protein interacts with LC3B-II [14,22] and is degraded in autophagolysosomes . Therefore, its reduction indicates increased autophagic degradation, whereas an increase of SQSTM1/p62 indicates incomplete autophagy [23]. On this line of thought, through accumulation of SQSTM1/p62 and LC3B-II, 10 µM MPL induces incomplete and non-productive autophagy while, higher concentration of MPL (25 µM) triggers active and complete autophagy (elevated LC3B-II along with degradation of other marker). The concept of “autophagic cell death” is commonly accepted based on the presence of autophagic features in dying cells and cell survival via suppression of autophagy [24,25]. Additionally, because autophagy may play a role as a cell survival pathway in response to therapeutic agents the induction of autophagy may work in favour of cancer cells [26]. Cell rescue experiments in which OVCAR-3 and A2780 cells were pre-treated with autophagy inhibitors like 3-MA resulted in decreasing cell viability compared with cells treated with MPL alone. Similar results were obtained in OVCAR-3 from experiments using wortmannin , an agent that inhibits the autophagic process at early stage [17]. The potentiated cell death through pre-treatment with autophagy inhibitors in cells treated with MPL indicates that other mechanisms of cell death may also be involved in MPL-induced cytotoxicity. Moreover, the specific end stage autophagy inhibitor, CQ targeting lysosomal proton pump did not influence the antiproliferative effect of MPL or the drug-induced morphologically changes.
The role of the mTOR , an atypical protein kinase as a positive regulator of protein synthesis, cell growth and proliferation has been well established. mTOR/p70S6K signalling is also known for its ability to halt and regulate cellular catabolic processes such as autophagy and it is frequently dysregulated in cancer and metabolic disorders [27,28]. Consistent with this, here we have described the negative effect of MPL on the mTOR/p70S6K pathway. Combined use of mTOR inhibitors (rapamycin and everolimus ) and MPL resulted in further suppression cell viability, suggesting that the inhibition of mTOR signalling may play a role in MPL-induced autophagy. We found that MPL markedly inhibits mTOR phosphorylation at Ser2448, which then prevents activation of the mTOR signalling. On this basis, inhibition of p70S6K and 4E-BP1 may be directly resulting from their upstream, inhibition of mTOR by MPL. Thus, the pharmacologic significance of MPL-induced inhibition of mTOR leads to vacuole formation and autophagy . This is justified by the solid evidence showing inhibition of apoptosis followed by the induction of autophagy. Additionally and in line with that, our results have shown that MPL induced inhibition of protein synthesis and the arrest of cell cycle . Together these observations explain inhibition of growth and proliferation seen in MPL-treated cells.
It is well established that induction of autophagy can provide therapeutic benefits and the modulators of autophagy may provide novel therapeutic tools and may ultimately lead to new therapeutic strategies in cancer. Current data suggest that depending on the context, there are various types of antineoplastic therapies which act through induction of autophagy. Anticancer agents (doxorubicin , temozolomide , etoposide ), histone deacetylase inhibitors, imatinib and anti-estrogen hormonal therapy have been shown to induce autophagy [29].
In conclusion, our studies provide the general mechanism behind the MPL-induced autophagy in ovarian cancer cells. Drug-induced autophagy is increasingly becoming a therapeutic strategy in the management of cancer patients. We provide proof-of-concept that MPL induces autophagy by suppressing mTOR/p70S6K pathway (Figure 6D). Studies to further explore the anticancer properties of MPL are currently in progress.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2914492/
Currently, the molecular mechanisms underlying the regulation of autophagy and the role of autophagy in cancer cells are not completely understood, but are beginning to be revealed. The reduced
Targeting the prodeath and prosurvival functions of autophagy as novel therapeutic strategies in cancer.
http://www.ncbi.nlm.nih.gov/pubmed/20224296/ a really good read~!
WHICH LEADS TOOO
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3076631/
In summary, this study demonstrates that KD inhibits mTOR pathway signaling in the brain and liver of healthy rats, and prevents late hippocampal mTOR activation after KA-induced SE. This mTOR inhibition may underlie some of the physiological effects of KD, including growth impairment, anticonvulsant actions, and potential antiepileptogenic effects. Further studies are necessary to prove a causal relationship between mTOR inhibition and antiepileptogenic actions of the KD.
SO IN A NUTSHELL, I AM STILL FOCUSSING ON METABOLIC TARGETS, HERE IS ANOTHER OFF LABLE DRUG THAT HAS THE POTENTIAL TO SYNERGISE WITH THE KD
TO MY GENIUSES
I am feeling very well, doing bloods today and pet scan tomorrow. You might find the articles interesting, I am starting MPL monapental
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4163620/ THE DRUG, MY PROF MORRIS ONE OF THE PIONEERS
This time with family precious and healing, despite the likehood of my divorce from wife.
Pete
DESPITE HIS CRITICS I FIND PROF MORRIS INSPIRING IN THE EXTREME, HE HIDES HIS LOVE AND CARE WELL BEHIND THE DOCTORS MASK. BUT NOONE DOES EXCELLENT MEDCINE WITHOUT LOVE, I SEE IT IN ALL MY DOCTORS.
