welcome back mitochondria this is Dr Casey paver for another episode of cancer as a mitochondrial metabolic disease so we have covered a great deal at this point and we are now coming to the part of the micro series where we start to dive into melatonin's important role on cancer and this happens to be something that I've been looking very much forward to discussing because I know that for a lot of you a lot of the audience this is the aspect of Mel tonin that you're most interested in but as with vitamin D and with other things I don't want to only show one aspects of this molecule because there are so many amazing benefits of the molecule that we have covered in great detail but today we're going to talk about cancer and we're to talk about melatonin's various roles when it comes to prevention and treatment of cancer so let's get into it so the first paper that I want to go over is a paper about prevention and this paper is titled urinary six sulfoxy melatonin levels and risk of breast cancer and postmenopausal women and it's saying that increased melatonin levels were associated with a statistically significant lower risk of invasive breast cancer and postmenopausal women and it says this Association was strongest among never and past smokers so people who are basically never smoking in their life or who quit smoking and the odds ratio which is the risk of developing an invasive breast cancer was reduced by about 62% who had the highest levels of this melatonin metabolite in their urine and when they followed up four years later they found that the relationship was even stronger there was actually a 66% decreased risk of developing invasive breast cancer but they did not observe substantial variations in the relative Risk by hormone receptor status of breast cancer and what they're basically saying is you know essentially there are three major subtypes of breast cancer there is ER positive or estrogen receptor positive there's PR positive progesterone receptor positive and her two and what it's saying is that even though they had a much lower risk of developing cancers the ones who did there was no variations between whether it was ER or PR positive and what it's saying here is the results of this perspective study provide evidence for a statistically significant inverse association between melatonin levels as measured in overnight morning urine and invasive breast cancer risk in postmenopausal women pretty so let's dive in a little bit deeper to the proposed mechanisms of how melatonin exerts this not only chemo prevention but chemo therapeutic action against cancer so what it's saying here in this paper titled melatonin for the prevention and treatment of cancer is that epidemiological studies have indicated a possible oncostatic property of melatonin on different types of tumors besides experimental Studies have documented that melatonin could exert growth inhibition on some human tumor cells in vitro and in animal models the underlying mechanisms include antioxidant activity modulation of melatonin receptors mt1 and mt2 stimulation of apoptosis programed cell death regulation of pro survival signaling and tumor metabolism inhibition of angiogenesis forming new blood vessels around tumors metastases spreading of tumors throughout the body and induction of epigenetic alterations melatonin could be utilized as an adjunct of cancer therapies through reinforc ing the therapeutic effects and reducing the side effects of chemotherapies or radiation melatonin could be an excellent candidate for the prevention and treatment of several cancers including breast cancer prostate cancer gastric cancer and coloral cancer so let's dive in a little bit to this graph here and start to unpack the mechanisms of how melatonin acts and so it's going to have effects on apoptosis or programed cell death it's going to enhance cancer immunity it's going to directly interact with the m M T1 and mt2 melatonin receptors it's going to induce a cell cycle arrest so they're not having the uncontrolled growth of cancer it's going to affect epigenetic alterations that's going to include things like DNA methylation histone modification and micrornas it's going to modulate Pro survival signaling essentially things that pathologically keep cancer alive it's going to have blockades on energy metabolism we're going to talk about this in detail but lactic acid uptake aerobic glycolysis aka the warberg effect as well as other metabolites seen in cancer metabolism it's going to have antioxidant effect where it makes sense and it's going to help Block Invasion metastases and the building of new blood vessels around tumors the process called angiogenesis astounding how unbelievable and multifaceted this molecule is able to help the fight against cancer and this paper is titled melatonin mitochondria and the cancer cell and it says here that the long recognized fact that oxidative stress Within mitochondria is a Hallmark of mitochondrial dysfunction has stimulated the development of mitochondrial targeted antioxidant therapies melatonin should be included among the pharmacological agents able to modulate mitochondrial function in cancer given the number of relevant melatonin dependent effects are triggered by targeting mitochondrial function indeed melatonin May modulate the mitochondrial restate chain thus antagonizing the cancer highly glycolytic bioenergetic pathway in cancer cells and that is code word for going to antagonize the war effect which we'll see in great detail I really enjoyed the title of this paper it's called melatonin a full service anti-cancer agent inhibition of initiation progression and metastases and it's saying here that there is highly credible evidence that melatonin mitigates cancer at the initiation progression and metastases phases there are several facets of the research who have immediate application at the clinical level many Studies have shown that melatonin's co-administration improves the sensitivity of cancers to inhibition by chemotherapeutic drugs or conventional drugs so basically it's improving sensitivities to Conventional chemotherapies even more important are the findings that melatonin renders cancers previously totally resistant to treatment sensitive again to the same therapies so let's say you have a Cancer and you've been on conventional chemotherapy and you see progression or you maybe had some improvement at the beginning and now the cancer seems to be resistant to that chemotherapy melatonin can then resensitize cancer back to the therapies that were working previously astounding melatonin also inhibits molecular processes associated with metastases by limiting the entrance of cancer cells into the vascular system and preventing them from establishing secondary growth at distant sites remember metastases at the end of the day are in general what leads to the demise of a cancer patient so if melatonin has a profound effect on both Invasion into other tissues and metastases that's amazing this is of particular importance since cancer metastases often significantly contributes to the death of the patient exactly another area of that deserves additional consideration is related to the capacity of melatonin and reducing the toxic consequences of anti-cancer drugs while increasing their efficacy although this information has been available for more than a decade it has not been adequately exploited at the clinical level basically the researchers are finding these amazing things with melatonin but it's not being translated to the bedside where the patient needs it the most all right this next paper is titled melatonin and cancer treatment current knowledge and future opportunities melatonin is a pleotrophic molecule with numerous biologic activ activities that I think we have hammered pretty hard since the beginning of this micro series is that melatonin has diverse actions on multiple systems including mitochondria now we're seeing its diverse actions upon cancer as a whole epidemiological and experimental Studies have documented that melatonin could inhibit different types of cancer in vitro and in Vivo results show the Improvement of melatonin in different anti-cancer mechanism including apoptosis induction cell proliferation inhibition reduction in tumor growth and metasteses reduction in the side effects associated with chemotherapy radiotherapy or radiation decrease drug resistance in cancer therapy and augmentation of the therapeutic effects of conventional anti-cancer therapies I think this is underscores that this molecule plays an important role in whatever type of treatment plan that you decide to employ if you want to be conventionally treated with chemotherapy radiation surgery Etc melatonin deserves to be part of that treatment strategy because it augments that and minimizes side effects if you want to use it as an important tool for your mitochondrial metabolic therapies such as the Press pulse that Dr CED has proposed I think that it definitely is an important tool to use for those therapies as well and you'll see exactly in the later slides why that is so let's talk a little bit about some of the mechanisms that we've covered so far that melatonin has important roles within melatonin because it's a Circ hormone has a lot to do with the cell cycle and the clock genes we have not had a chance to talk about the clock genes in detail and we will in future videos but needless to say it's going to have a profound effect on the circadian clock genes and the clock genes are located in every cell of your body now the major clock genes are set through this supermatic nucleus in the brain but those signals are going to get distributed throughout the body to the various peripheral clock genes and melatonin has direct effect on those peripheral clock genes it's also going to have Direct effects on progrowth Pathways such as akt here and cic which is going to help modulate the cell cycle decrease proliferation increase apoptosis and as you can see here in the bottom right hand corner it's going to actually increase reactive oxygen species Within These cancer cells remember this is an exact 180 of what it does to the healthy cells where it provides potent antioxidant protection and this is just another amazing graphic showing that melatonin has so many diverse actions upon the entire cancer process let's start going clockwise it affects the genetic stability it affects the redo regulation it affects epigenetic regulation it affects apoptosis metabolic disregulation Invasion and metastases our ability to fight cancer through using our own immune system it modulates pro- Survival Systems used by cancer it is related to telr maintenance it regulates angiogenesis the iic tumor micro environment and again the cell cycle what is not covered in blue boxes is it reverses cancer and sensitivity to treatment and it can synergize with radio and chemotherapy and you may be asking how is that possible well the mechanisms are fairly diverse number one it's going to have an effect on the glycolysis utilization by cancer cells which is their the backbone of how they make energy how they make their antioxidant response systems through glutathione so it's going to make them more sensitive to chemotherapy and radiation it's also going to increase reactive oxygen species within cancer cells which is going to act in Synergy with radiotherapy and chemotherapy which a lot of times uses an increase in reactive oxygen species within cancer cells the issue is that those type of therapies do not distinguish between healthy cells and good cells whereas melatonin does I think that I'll end on this slide because it's an amazing slide if we can follow it through so we have a normal or a cancer cell and you're exposed to chemotherapy radiation some insult that can damage that cell and Lead it to trying to become transformed into a cancer cell and you start to see changes in the DNA and chromatin the cell kind of shrivels up a little bit you start to see membrane blubbing and we see kind of two major actions that melatonin takes at this point in the cancer process either melatonin can completely restore the cancer cell or the normal cell that's trying to convert into into a cancer cell you see a complete restoration of that or if it's too far gone and it's not possible to be saved melatonin will then initiate apoptosis program cell death so that it can be eaten by phagocytes or macrofagos or different parts of the immune system to get rid of that cancer cell I think that at this point you're starting to see that melatonin is a critical component to maintain your health and prevent disease but also in the fight against cancer we've started to dig in into the more pleotrophic or multiple biologic mechanisms in which cancer is halted in its tracks by melatonin however I think the most exciting part of this story of this melatonin story comes in the next video when we start talking about melatonin's direct actions against the warberg effect and metabolic reprogramming if you like videos like this please like share subscribe until next time