Welcome back, mitochondriacs, for another episode of Cancer as a Mitochondrial Metabolic Disease. I am happy to be back with you today to continue to discuss the inhibition of glutamine. And in the last video, when talking about Dawn, I wanted to present at least the poster child for the inhibition of glutamine as a drug, because it's something that is talked about a lot by Dr. Seyfried in particular. I wanted to cover it.
But I know a lot of you in the comments and via email have reached out to me asking me for more information on the natural glutamine inhibitors. And so that's what I plan to do over the next coming weeks is to provide you with as many of the natural glutamine inhibitors as I could find in the literature. And believe it or not, I was actually quite surprised with the large number that I was able to find, which is pretty amazing. And I just want to give a thanks out to some of you all who have given me tips, which led me to do some further deep dive and led me to be able to find several other glutamine inhibitors that were natural from plant compounds and phytonutrients.
So thank you for that. So let's get into it. So the first compound I want to talk about is a compound that is near and dear to my heart, and that is berberine. And I think that most people are aware of berberine, but I want to just give a little bit of a summary of what berberine actually is. So berberine...
is a plant metabolite belonging to the group of isoquinoline alkaloids with strong biologic and pharmacologic activity. Currently, berberine is receiving considerable interest due to its anti-cancer activity based on many biochemical pathways, especially its pro-apoptotic and anti-inflammatory activity. Therefore, a growing number of papers on berberine demands summarizing the knowledge and research trends. The efficacy of berberine in breast and colon cancer seems to be the most promising aspect.
So this is a natural compound and I first learned about berberine in the context of natural alternatives to things like metformin or other medications that are used in the treatment of diabetes. And it has profound effects on the glucose metabolism of cells, similar to metformin. It also has cholesterol effects as well. And that's kind of where I saw the majority of the education around berberine in my... own personal functional medicine training.
And we're going to hit berberine from a variety of angles because it has so many different important targets within cancer biology. But today we're going to specifically talk about it in regards to its effects on glutamine. So this paper is titled Berberine as a Potential Anti-Cancer Agent, a Comprehensive Review. And it says here, berberine, a potential bioactive agent, has remarkable health benefits. A substantial amount of research has been conducted to date to establish.
the anti-cancer potential of berberine. The present review consolidates salient information concerning the promising anti-cancer activity of this compound. The therapeutic efficacy of berberine has been reported in several studies regarding colon, breast, pancreatic, liver, oral, bone, cutaneous, prostate, intestinal, and thyroid cancers. Berberine prevents cancer cell proliferation by inducing apoptosis and controlling the cell cycle as well as autophagy. Berberine also hinders tumor cell invasion.
and metastases by down-regulating metastases-related proteins. Moreover, berberine is also beneficial in the early stages of cancer development by lowering epithelial mesenchymal transition protein expression. Despite its significance as a potential promising drug candidate, there are currently no pure berberine preparations approved for specific ailments.
Hence, this review highlights our current comprehensive knowledge of sources, extraction methods from kinetics and pharmacodynamic profiles of berberine, as well as the proposed mechanism of action. associated with its anti-cancer potential. And like I said, I'm going to cover berberine from a variety of pathways that it is responsible for influencing.
But just as an overview, you can see that it has inhibitory role on certain growth factors. It has a lot to do with the cell cycle. It has to do with other signaling cascades that are related to insulin, AMP kinase, BCL, et cetera, which ultimately ends up aiding in an inhibition of proliferation, cell cycle arrest of highly proliferative cells, inhibition of invasion into other tissues, and the induction of programmed cell death or apoptosis. And berberine has been shown to work on this SLC1A5 glutamine transporter, similar to several other medications and compounds that have been researched. And it says here that berberine inhibits growth of liver cancer cells by suppressing glutamine uptake.
And it further says berberine inhibited the proliferation of liver cancer cells. in vitro. Verbarine suppressed the glutamine uptake by inhibiting this SLC1A5 transporter.
The upregulation of SLC1A5 led to an increased glutamine uptake and improved tolerance to berberine. Berberine suppresses SLC1A5 expression by inhibiting CMIC. And we've talked about CMIC in the past as being one of the drivers of aberrant glutamine metabolism.
So as we talked about in a prior video, there are several known glutamine-only transporters as well as glutamine and other amino acid antiporters, where glutamine and another amino acid are transported in an opposite direction. And we're going to start to see how this comes together. But Berberine, as we talked about, focuses on this particular transporter, this SLC1A5, which is pretty exciting.
So before I can talk about the next compound under investigation, I want to talk to you about some of these transporters in a little bit more depth, because there are some certain vernacular that are used in the literature that makes it fairly difficult to understand exactly what's going on. So I want to talk about this LAT2. It's also known as SLC7A8.
And it says here that human LAT2 is mainly expressed in kidney, placenta, brain, and at a lower extent in spleen, skeletal muscle, small intestine, and lung. But it's also seen in prostate, ovaries, testis, and fetal liver, which seems like it's fairly well distributed throughout the body in various organs and tissues. And it says here that an upregulation of LAT2 expression by mTOR has been described in glomerular epithelial cells in the condition called glomerulonephritis.
mTOR integrates signals from inflammatory cytokines, stimulating LAT2 translocation to the plasma membrane. Increased surface LAT2 expression by DHT and EGF receptor involving the ERK1,2 signaling cascades has been described. So what is this actually telling us? Number one, this is fairly diverse throughout the human body and through multiple tissues. And it also completely ties in mTOR, inflammation, as well as other signaling molecules such as the hormone DHT and certain growth factor receptors and cascades.
So we can start to see how this is at least partly contributing to the cancer phenotype and the reliance on glutamine in particular, is that it will upregulate some of these glutamine transporters. And we can see here that the yellow is considered LAT2 and it is an amino acid. glutamine antiporter.
And this AA is signifying an amino acid, which is getting removed from the cell while glutamine is being uptaked into the cell. And so I gave you that background because this LAT2 has been shown to be found in several different types of cancer. And it says here in this paper that LAT2 regulates glutamine-dependent mTOR activation to promote glycolysis and chemoresistance in pancreatic cancer.
It says that reprogrammed energy metabolism has become an emerging hallmark of cancer. In recent years, transporters have been reported to be amino acid sensors involved in controlling mTOR recruitment and activation, which is crucial for the growth of both normal and tumor cells. And it says the results of a survival analysis indicated that high expressions of both LAT2 and LDHB predicted a poor prognosis in patients with pancreatic cancer. Furthermore, we found that LAT2 can promote proliferation, inhibit apoptosis, activate glycolysis.
and alter glutamine metabolism to activate mTOR in vitro and in vivo. And you may be asking yourself, why am I going down this path of this LAT2 cascade? And the reason is because the next compound that I want to talk about, curcumin, happens to work upon that mechanism, or at least that is one of the ways that it works on cancer metabolism.
And I just want to give you a background of what curcumin is for those who don't know. So curcumin is an active polyphenolic pigment. obtained from the rhizomes of curcuma longa, or the turmeric plant.
Curcumin is typically used for its antioxidant, anti-inflammatory, wound healing, and anti-carcinogenesis qualities that halt the onset or progression of cancer. And then it later says that curcumin decreases tumor cell growth and increases apoptosis by upregulating the expression of activity of p53, attenuating the regulation of anti-apoptosis PI3K signaling. and MAP kinases to boost endogenous ROS generation and overexpression of anti-apoptosis genes such as BCL-2.
And so we're going to cover similar to berberine curcumin in multiple ways. But today, I wanted to particularly talk about glutamine in this glutamine micro series. So let's zoom out a little bit.
Now that we've talked about LAT2 and we know what that is and how important it can be for certain cancers, let's talk about how curcumin inhibits glutamine. uptake into cells. And it says in this paper, curcumin synergistically enhances the efficacy of gemcitabine against gemcitabine-resistant curcumin.
cholangiocarcinoma, which is a gallbladder tumor, but it can also be gallbladder ductal tumor as well, via the targeting of LAT2 glutamine pathway. And it says, in conclusion, curcumin synergistically enhances gemcitabine, which is a type of chemotherapy efficacy against gemcitabine-resistant cholangiocarcinoma by induction of apoptosis, partly by inhibiting the LAT2 glutamine pathway. And in this diagram, we see that curcumin plus gemcitabine is going to block this LAT2 glutamine pathway. which is going to induce cell cycle arrest, induce apoptosis, and inhibit cell proliferation.
And it's also shown here that the decreased amount of glutamine is not able to get converted to glutamate, which then is going to block its ability to upregulate glutathione synthesis. Other amino acid synthesis block its ability to enter into the TCA cycle and be used for not only aberrant energy production through a broken mitochondria, but also fatty acid and nucleotide synthesis as seen in diagrams such as this, we see that the TCA cycle's glutamine utilization is heavily feeding lipid or fatty acid synthesis as well as nucleotide DNA and RNA synthesis as well. So the last compound that I want to talk about in this video is another well-known compound called silibeninin. And silibeninin is a mixture of essentially flavonoids extracted from the milk thistle plant and has often been used to in the treatment of acute and chronic liver disorders caused by toxins, drugs, alcohol, hepatitis, gallbladder disorders for its antioxidant and hepatoprotective properties.
And it says in this paper titled, Silibenin, a potential old drug for cancer therapy. It says further research suggests that Sili Marin may function diversely and may serve as a novel therapy for cancer therapy, such as lung cancer, prostatic cancer, colon cancer, breast cancer, bladder cancer, and hepatocellular carcinoma or liver cancer by regulating. cancer cells, growth, proliferation, apoptosis, angiogenesis, and many other mechanisms. And I get this as a background because I want to talk about the main topic that we're talking about today, the inhibition of glutamine pathways, both uptake and utilization.
And what it says here in this paper titled, Silly Benin Suppresses Glioblastoma, a Deadly Form of Brain Cancer, Cell Growth, Invasion, Stemness, and Glutamine Metabolism by this SLC1A5 pathway. And ultimately, this paper suggests that silibenin, this flavonoid mixture found in milk thistle, plays an important antitumor role in the GBM process, which may be achieved by inhibiting this important glutamine uptake pathway, SLC1A5. And I always find that it's the most helpful to show this on a picture. So very similar to what berberine does is silibenin or siliamarin or milk thistle happens to act. on the same transporter is a glutamine-only uptake transporter that brings glutamine in so that it can be further used by aberrant metabolism of cancer cells.
So what have we covered today? I just gave three additional tools that we have potentially in our tool bag for the inhibition of glutamine uptake. We talked about berberine, curcumin, and we talked about milk thistle or silabinin, a flavonoid extract from silymarin or milk thistle.
And these are studied compounds that have likely profound anti-cancer effects, but maybe we didn't understand exactly how these compounds are acting. And although most of these compounds have pleiotrophic effects where they are affecting dozens of chemical pathways, I do think that given the importance on the reliance of glucose and glutamine, I do believe that it's glutamine uptake inhibition. to be one of the most important mechanisms by which these compounds likely work.
And one of the other things that I wanted to mention is that when I first started going through a lot of this literature, I was fairly disheartened by a graphic like this because as you can see here, the majority of the purple bubbles with different chemical names are things that are not attainable for most people to get their hands on. However, things like milk thistle or berberine. or curcumin or EGCG, as we'll talk about in the next video, are things that are readily available, are known to be safe, and likely have diverse roles on these pathologic processes.
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