Welcome back mitochondriacs for another episode of cancer as a mitochondrial metabolic disease. So today we're going to be continuing our discussion and the journey into inhibitors of the critical glutamine cysteine antiporter named SLC7A11 or XCT aka the Achilles heel of cancer. Just as a reminder this is about video number 60 in the cancer as a mitochondrial metabolic disease. disease series. And if you're watching this channel for the first time in this particular video, welcome.
But that being said, it may be fairly difficult to start this series with this particular video. You may find benefit in watching this video, How Metabolic Therapy Checkmates Cancer, or even earlier in the series to get the necessary background information to fully maximize the value of this video. So without further ado, let's get into it.
So I'm going to start off by talking about this very exciting paper that was released in July of 2024, and it's titled Targeting Ferruptosis Regulators in Lung Cancer, Exploring Natural Products. And it says that lung cancer remains a formidable global health challenge, necessitating innovative therapeutic strategies for improved efficacy. This review explores the untapped potential of natural products and TCM.
traditional Chinese medicine in lung cancer therapy focusing on targeted ferruptosis regulators. Natural compounds such as curcumin and resveratrol exhibit diverse anti-cancer mechanisms, complementing TCM's holistic approach rooted in a 3,500-year history. Emphasizing the introduction of cell death, particularly ferruptosis, the review highlights the significance in overcoming challenges like resistance to conventional therapies.
Key ferruptosis regulators are explored in the context of natural products and TCM. The impact of these treatments on crucial pathways such as the antioxidant mechanisms, glutathione peroxidase 4, SLC7A11, and NRF2, iron metabolism regulators, and lipid and mitochondrial pathways is examined. The findings provide a comprehensive overview of how natural products and TCM modulate ferroptosis and lung cancer, offering valuable insights for the development of innovative side effect reduced therapeutic strategies.
This work holds promise for transforming the landscape of lung cancer treatment by integrating the rich resources of nature into conventional therapeutic paradigms. So this particular paper is looking at the process of phareptosis, and it is in particular looking at the various natural compounds that are available to us for therapeutic use. And I find this particular paper very exciting, and its graphics are graphics that I'm going to use over the next several videos to illustrate what part of the ferroptotic cell death process that each of these compounds has effects on.
So as we can see here, this is the overall process of ferroptosis and lipoperoxidation within a lung cancer model. And this is going to be fairly ubiquitous no matter what type of cancer we're dealing with. But in this particular paper and the next paper looking at lung cancer and subsequently colon cancer, you're going to see very similar graphics.
So what we have here is the SLC7A11 transporter, the glutamine cysteine antiporter, also known as XC. And it's going to be bringing in the necessary cysteine for the construction of glutathione. And then glutathione peroxidase is going to help in the reduction of lipid peroxidation and the prevention of feraptosis.
And then there are other involved pathways, such as the NRF2 pathway. which is going to help upregulate glutathione peroxidase. There's going to be the LOX or the lipoxygenase pathways, as well as CoQ10. This is kind of the overview of the ferreptotic process and how these cancer cells and how normal cells will prevent against this.
What is being shown here is how various natural compounds are having a direct effect or a direct inhibitory effect on this SLC7A11, which blocks cysteine uptake and ultimately blocks glutathione production, which ultimately leads to ferreptotic cell death. which is the goal. And then in this particular graphic, we see the iron side of things.
This is the other part of the ferreptotic process that is showing transferrin and other iron-binding proteins such as ferritin and how that leads to the Fenton reaction, which is a oxidative stress reaction with iron that allows for the lipid peroxidation and ferreptosis to occur. And so we see that there are several compounds that affect the transferrin. protein, as well as ferritin and some of these other more obscure proteins such as this NCOA4. And there are, as you can see, several natural compounds that we'll talk about that are responsible for making this process worse.
So just to be clear. We are looking at two separate major processes involved in ferreptosis. There is the antioxidant component part of it, which is involving glutamine, cysteine, glycine, glutathione, glutathione peroxidase, NRF2, etc., that pathway.
And then we're looking at this pathway, which is responsible for the actual iron sequestration and protection against oxidative stress with iron to help prevent ferreptosis. and we're looking at natural compounds that have effects on both of these pathways. This next paper is titled Targeting Ferruptosis Regulators by Natural Products and Colorectal Cancer, and it says colorectal cancer poses a significant global health challenge, ranking as the third most diagnosed cancer and the second leading cause of cancer-related deaths.
Despite advancement in treatment, challenges such as delayed diagnosis, multidrug resistance, and limited therapeutic effectiveness persist. emphasizing the need for innovative approaches. This review explores the potential of natural products, nutraceuticals, and phytochemicals for targeting ferreptosis-related regulators as a novel strategy in CRC.
Ferreptosis, a form of regulated cell death characterized by iron-dependent lethal lipid peroxide accumulation, holds substantial importance in CRC progression and therapy resistance. Natural products known for their diverse bioactive effects and favorable safety profiles emerge. as promising candidates to induce ferroptosis in CRC cells. Exploring amino acid, iron, lipid metabolism regulators, and oxidative stress regulators reveals promising avenues for inducing cell death in CRC.
This comprehensive review provides insights into the multifaceted effects of natural products on proteins integral to ferroptosis regulation, including glutathione peroxidase 4, SLC7A11, ASCL4, NCOA4, and hemoxygenase 1. By eliciting the intricate mechanisms through which natural products modulate these programs, this review lays the foundation for a promising therapeutic strategy in colorectal cancer. And just like the last study had its own graphics, this has very similar graphics showing a bunch of natural products which affect this SLC7A11 protein, this glutamine cysteine antiporter, which has the exact same mechanisms of protecting against lipid peroxidation and ferreptosis, a couple of other different. inhibitors of the glutathione peroxidase 4 enzyme, and then other things that modulate lipoxygenases, NRF2, and other proteins related to CoQ10 that help protect against ferroptosis.
I think this highlights a very important topic to discuss, and that is the use of antioxidants such as NAC, glutathione, vitamin C, and coenzyme Q10 when dealing with cancer. Because... although these are likely showing benefit in a lot of other conditions and in preventive medicine, they're likely going to cause harm when dealing with cancer.
And that is because these cancer cells, remember, they come from us and they are hijacking some of the most important pathways that protect against oxidative stress, in particular, the NRF2 pathway, glutathione, et cetera, but also things like vitamin C in low doses and coenzyme Q10. So be very careful and please discuss these supplements with your own integrative oncologist or functional integrative practitioner to help mitigate and prevent any harm that can be being done. And then again, we see here the very similar graphic for colorectal cancer and how we have the transferrin protein, we have ferritin, this NCOA4, hemoxygenase 1, and how they all interact to either accelerate or prevent the Fenton reaction.
which leads to lipid peroxidation and feraptosis. And we can see there are natural compounds that have been shown to affect all of these steps and enhance the process of feraptosis in this colorectal cancer model. And the first natural product that I'm going to talk about during this particular video is the role of capsaicin, the compound found in chili peppers that induces feraptosis in non-small cell lung cancer by regulating this SLC7A11. glutathione peroxidase for signaling in vitro. And it says here that capsaicin increased total iron levels and ferrous ion levels in these non-small cell lung cancer cells in contrast to the control group, whereas the level of glutathione was reduced in contrast with the control group.
Besides, the mRNA and protein levels of this SLC7811, that glutamine cysteine antiporter, and glutathione peroxidase were decreased significantly in those treated with capsaicin in contrast to the control group. Our study indicated that capsaicin inhibited the proliferation of these non-small cell lung cancer cells and induced ferroctosis by inactivating this SLC7A11 glutathione peroxidase 4 signaling. Capsaicin could be used as a potential anti-cancer agent in the treatment of non-small cell lung cancer. And what I'm going to do is very similar to what we've done in the past is I'm going to show where each of these compounds work. So we see here capsaicin is blocking or inhibiting this SLC7A11 antiporter, which is going to lead to a decrease in cysteine uptake and a decrease in glutathione, which is going to lead to excess lipid peroxidation and feraptosis, which is favorable for these lung cancer cells.
And again, using the kind of classic graphic here, we have this SLC7A11 that is what is being blocked by capsaicin. So the next compound we're going to talk about today is sulforaphane. And sulforaphane is an amazing chemical that has pleiotrophic effects on cancer. Definitely more and out of the scope of this particular video because there's so many different mechanisms in which it works upon.
But we're going to talk about today is sulforaphane's actions on this SLC7A11. So this paper is titled... Effective ferreptotic small cell lung cancer death from SLC7811 inhibition by sulforaphane. And it says here that following the addition of sulforaphane to the cell culture, cell growth was significantly inhibited and cell death was shown in small cell lung cancer and multi-drug resistant cells. The ferreptotic effects of sulforaphane were confirmed following culture with a ferreptosis inhibitor, ferrostat-1 and deferoxamine.
iron levels were elevated, which resulted in the accumulation of lipid reactive oxygen species. And later it says, in conclusion, the present study demonstrated that sulforaphane-induced cell death was mediated by feraptosis and inhibition of the mRNA and protein expression levels of SLC7A11 in small cell lung cancer cells. The anti-cancer effect of sulforaphane may provide novel options for small cell lung cancer treatment. And unfortunately, this graphic is somewhat blocked by my face here, but what's behind? Curtain number one here on my face is basically showing sulforaphane blocking SLC7A11.
The antiporter leads to a decrease in cysteine, a subsequent decrease in glutathione, and elevation in lipid reactive oxygen species, which when combined with iron is going to lead to ferroptotic cell death. And going back to the graphic we have seen in the past, sulforaphane again blocking SLC7A11 and ultimately leading to ferroptosis. And lastly, on the classic graphic, sulforaphane is blocking SLC7A11.
Very encouraging. So the last compound that we're going to talk about today is going to be resveratrol. And I bring up resveratrol again because we've talked about resveratrol in particular with glutamine in the past. I'm going to show graphics regarding that again. But resveratrol seems to have multiple mechanisms in which it blocks glutamine uptake by cancer cells.
And this particular paper is titled Effect and mechanism of resveratrol on ferreptosis-mediated P53-SLC7A11 in oral squamous cell carcinoma. And it says here that medium to low-dose resveratrol had no toxic effect on these human oral keratinocyte cells. While high-dose resveratrol markedly reduced cell viability, resveratrol significantly suppressed the viability of this oral squamous cell carcinoma cells.
Resveratrol inhibited oral squamous cell carcinoma cell colony. formation, migration, invasion, and induced G1 phase arrest. Resveratrol caused the translocation of P53 protein to the nucleus, obviously increased iron content, reactive oxygen species levels, and LDH release.
And LDH release would be another name for cell death because when LDH is released, it shows that the cell is releasing intracellular components into the extracellular areas. It also showed decreased glutathione content and glutathione peroxidase. protein expression and induced feraptosis.
And it says conclusion that resveratrol accelerated feraptosis and inhibited malignant behaviors of oral squamous cell carcinoma cells by regulating the p53 SLC7A11 axis. And just going back to our kind of classic graphics here, resveratrol right here is blocking SLC7A11, which is lowering glutathione and cysteine and increasing lipid peroxidation and feraptosis. And going back here, resveratrol blocks this SLC7A11 antiporter.
And remember, from a prior video, SLC1A5 is also blocked by resveratrol. So with resveratrol, we're getting kind of a double whammy in terms of glutamine inhibition. I hope that you're starting to see the therapeutic potential of these nutraceuticals and polyphenols that are found in first and foremost foods, natural foods, but also in very safe and readily available nutraceutical supplements.
I think that we are starting to see that we have a lot more at our disposal when it comes to glutamine inhibition with natural compounds that we may have been led to believe. I think a lot of us, including my own self, thought that we pretty much had EGCG as the only natural glutamine inhibitor, and we're starting to see that that is far from the truth. So be encouraged.
There's still a lot more left to share. when it comes to natural glutamine inhibitors. If you like videos like this, please like, share it with folks that you love and care about who need this information. And until next time.