When fasting, avoiding sugar or using Fenbendazole, Flubendazole, Mebendazole, Berberine, Green Tea etc, tumor cells will start to scavenge nutrients by breaking down cells to recycle them as fuels, survive microenvironmental stress and to increase growth and aggressiveness (source) in a process known as Autophagy.
It’s normally a good thing to activate autophagy to prevent tumors, however, with established tumors, it’s one of the ways they get fuel when the glucose is being restricted so Autophagy is an innevitable reality when restricting calories, and so blocking Autophagy becomes an important strategy to add to Fat and Glutamine blocking, and that’s why we have developed AUTOPHIB™.
Some of the Autophagy-related pathways are:
BECLIN1, mTOR, LC3, ATG5-7, ULK1, FOXO, PI3k/AKT
Even though many of our favourite anti-tumor supplements which inhibit mTOR and PI3k/AKT such as Curcumin, Green Tea, Metformin, Berberine, Quercetin & Fenbendazole activate Autophagy we still need to use them but need a mechanism to override their ability to activate Autophagy.
Autophagy is an essential survival pathway during nutrient or growth factor deprivation, and genetic studies demonstrate that it contributes to some forms of tumors in mice. However, because autophagy supplies amino acids through protein degradation, it does not serve as a source of net protein synthesis. It is also potently suppressed by mTORC1.
Additionally as we re-instate P53 Tumor Suppressor function and it’s response to stress with Fenbendazole, Flubendazole and Mebendazole we also activate Autophagy via (DRAM)29, Sestrin230, Bcl-2-associated X protein (Bax) and p53-upregulated modulator of apoptosis (PUMA)31 (source).
There are an abundant amount of Autophagy-activating nutraceutical agents but very few which actually block this process, which is one reason that Autophagy is normally very active. Fortunately work in the area of Neural inflammation has identified a number of quite potent autophagy-blockers. These also can have the very useful side effects of reducing pain.
AUTOPHIB™ is a capsule formula containing three ingredients shown to inhibit Autophagy and also reduce neuropathic & spinal pain; Palmitoylethanolamide (PEA) , Luteolin (Pagoda flower) and Capsaicin from Capsicum.
Palmitoylethanolamide (PEA) is a biologically active, endogenous lipid that is widely distributed throughout the body’s tissues and is synthesised on demand (Gabrielsson 2016). It was first isolated in 1957 as an anti-inflammatory component in egg yolks and is found in many foods such as Edamame beans. PEA has been studied extensively for its anti-inflammatory, neuroprotective and analgesic properties since the 1970’s.* (Hesselink 2013)
When combined, PEA and luteolin show enhanced anti-inflammatory, anti-oxidant and neuroprotective properties. This combination has been shown to reduce pro-inflammatory cytokines (TNF-alpha, IL-1 beta, IL-6) and chemokines (MIP-1 alpha, MIP-2) significantly more than PEA or luteolin alone. Additionally, PEA with luteolin was shown to reduce oxidative and nitrosative damage more effectively than PEA or luteolin alone.* (Impellizzeri 2018) . Additionally, it has been found that the combination of PEA and Luteolin in a 10:1 ratio the expression of Akt/mTOR signaling pathways increases and can inhibit autophagy.
With AUTOPHIB™ we have combined this combination with another Autophagy inhibitor; Capsaicin.
Capsaicin inhibits autophagy by activating the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/ and mammalian target of rapamycin (mTOR) [source] .
Capsaicin induces apoptosis in tumor cells by intracellular calcium increase, reactive oxygen species generation, disruption of mitochondrial membrane transition potential, and activation of transcription factors such as NF-kB and STATS and also reduces resistance to chemotherapeutic treatments.
Autophagy initiation is controlled by the ULK kinase complex and the PI13-kinase complex containing Beclin-1, which integrate stress signals from the mTOR complex 1 (mTORC1).
When mTORC1 activity is inhibited such as by AMPK activators Metformin, Berberine, Green Tea and Curcumin, the ULK (serine/threonine-protein kinase) and the Beclin-1 complex translocate to the initiation site ATG13 (autophagy-related protein) which triggers the self-eating autophagic process. This machinery is also co-opted by various herpes viruses such as Kaposi sarcoma.
In 2016 Yoshinori Ohsumi was awarded the nobel peace prize for identifying gene versions involved in uncontrolled autophagy ( which are mutated in many breast and ovarian tumors) and loss of two others from the brains of mice causes neurodegeneration. In fact, there are now a variety of human neurological diseases where autophagy has been implicated, including Alzheimer’s and Parkinson’s.
Human ovarian cancer cells are highly sensitive to challenge with autophagy-targeting agents. Tumor cells with impacted autophagy are marked by accumulation of the yellow gene marker, which disappears as the cells die.
The Viral Association with Autophagy
Autophagy may suppress carcinogenesis owing to its key role in the first line of defense against viral and bacterial infection (Deretic et al, 2013). Indeed, several potentially carcinogenic pathogens potently activate autophagy upon infection. These pathogens include hepatitis B virus (which promotes hepatocellular carcinoma), human herpesvirus 8 (which causes Kaposi’s sarcoma and contributes to the pathogenesis of primary effusion lymphoma and multicentric Castleman’s disease), human papillomavirus type 16 and 18 (HPV‐16 and HPV‐18, which cause cervical carcinoma), Epstein–Barr virus and Helicobacter pylori (both of which are associated with gastric carcinoma), Streptococcus bovis (which causes colorectal carcinoma), Salmonella enterica (which is associated with an increased incidence of Crohn’s disease, hence sustaining colorectal carcinogenesis, and gallbladder carcinoma), as well as Chlamydia pneumoniae (an etiological determinant in some forms of lung cancer) (Nakagawa et al, 2004; Travassos et al, 2010; Yasir et al, 2011; Conway et al, 2013; Griffin et al, 2013; Zhang et al, 2014).
AUTOPHIB™ may be used as an adjuvant to standard care, and as part of a metabolic fuel-blocking approach along with FASNHIB™, GLUTAHIB™ to inhibit metabolic fuel supply and later with MEBENGRAV™ to activate caspases similar to the press-pulse strategy made famous by Dr Thomas Seyfried and NICLOSTEM™ to help eradicate stem cells.[To better understand these concepts, See our MFI Strategy here – Werone Private Herbal Health Trust Members only]
These 3 main metabolic fuel pathways exploited by Tumors are the targets for using Re-purposed drugs such as Metformin, Doxycyline, Dipyridamole, Niclosamide, Aspirin and a statin to inhibit these pathways which drive the TCA cycle within each Tumor cell with the aim of to weakening it over time. MBZ also interferes with VEGFR kinase by competing with ATP which is the energy used within the TCA Cycle of every cell.
Take 2 x caps with water after food in the morning, 2 x caps noon and 2 x caps after food at night or as directed by a health professional. May be suitable as an adjuvant. AUTOPHIB™ may best be supported with FASNHIB™ for Fatty Acid inhibition & GLUTAHIB™ metabolic fuel supply inhibiting formulas, CURCUBOS™, CURCUMEL™, EGAMMA™, OMEGA DHA™, and a ZERO Sugar/Fat Diet with regular cruciferous vegetables (SULFORAPHANE). The 120 or 180 capsule versions may be more suitable for this. For synthetic chemotherapeutic versions consider: METFORMIN, LD/ASPIRIN and/or STATIN, & DIPYRIDAMOLE & MILDRONATE .
Palmitoylethanolamide with Luteolin Decreases Autophagy
Capsaicin Inhibits Chemotherapeutic/5-FU-induced Autophagy
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