Chemotherapy/Radiation For Breast Cancer Treatment

TreasureVibe

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[1] Bingham, S. "Effect of white versus red meat on endogenous N-nitrosation in the human colon and further evidence of a dose response." The Journal of nutrition (2002)

The main suspect behind red meat-induced colon carcinogenesis is the N-nitroso functional group (R–N–N=O), which can be formed on any biomolecule having a terminal amide or imine—i.e. urea, arginine, lysine—and appears to arise from nitrite or nitrogen dioxide. This study had shown very significant increases in N-nitroso compounds after red meat consumption that hadn't been observed after pork- or chicken-eating (but they hadn't checked for prostaglandin E₂).

'Although red meat resulted in the expected increase in endogenous N-nitrosation in this study, the same amount of white meat had no effect in 10 of 12 volunteers;' ―Bindham
[2] Cross, A. "Haem, not protein or inorganic iron, is responsible for endogenous intestinal N-nitrosation arising from red meat." Cancer Research (2003)

The same Cambridge researchers followed-up with a very simply yet powerful study design aiming to elucidate some finer details. They had fed white meat, red meat, eggs, lentils, etc., to a group of limeys English men who'd served as their own controls. Consistent with both epidemiological observation and the N-nitroso hypothesis of colon carcinogenesis, they had found that only those who'd consumed red meat had increased levels of N-nitrosation. This had been a consistent, dose-dependent effect not observed among those eating an isoproteomic amount of anything else.

'Nitric oxide has also been shown to react directly with hemoglobin and myoglobin to produce N-nitroso compounds.' ―Cross

They had also done trials using either simple inorganic iron or that complexed inside a porphyrin ring, or what is called 'haem' by the English. They had found that inorganic iron had done little towards N-nitrosation, but heme–iron had a considerable effect. From this study any logical person is forced to conclude that the heme–iron complex is unique in its ability to catalyze N-nitroso formation.

The total nitrogen consumed has little effect, so it really could be the heme–Fe³⁺ binding to endogenous nitric oxide normally produced from eNOS...

What type of iron do tumors accumulate?

[Cardiotoxicity of lindane, a gamma isomer of hexachlorocyclohexane].

It seems to affect calcium homeostasis of many tissues. The similarity between lindane and inositol (1, 4, 5) phosphate (IP3) suggested that lindane releases Ca2+ from IP3-sensitive intracellular stores in macrophages and myometrial cells. Ca2+ release from reticulum endoplasmic, mitochondria and other Ca2+ stores has been reported in cat kidney cells. Lindane altered energetic metabolism of hepatic mitochondria and the inositol-phosphate synthesis in neuronal cells. However, lindane does not compete with the IP3 receptor. Lindane produces a Ca2+ influx in mice peritoneal macrophage cells responsible for the Ca2+ induced Ca2+ release produced by phospholipase C via IP3 pathway and resulting in a maintained increase of the free cytosolic Ca2+ concentration. Lindane decreased the membrane erythrocyte and cerebral cell concentration of phosphatidyl inositol PI, PIP and PIP2 in rats repetitively exposed to lindane for 3 or 6 months. Lindane induces oxidative stress; it modifies the activity of the scavenger enzymes. This effect is involved in the inhibition of intercellular gap junctions. Modifications of the electrocardiogram (ECG), sinusal rhythm alteration and negative and dysphasic variations of T wave, similar to those produced by hyperkaliemia, have been reported after lindane absorption. During acute lindane poisoning, the activities of serum transaminases (SGOT, SGTP), and lactate deshydrogenase (LDH) increase. Lindane produces histological alterations of cardiac tissues and a cardio-vascular dystrophy (contracture, degenerescence and necrosis) mainly in the left ventricular wall and a hypertrophy of the left ventricle.

source: [Cardiotoxicity of lindane, a gamma isomer of hexachlorocyclohexane]. - PubMed - NCBI

What do you think, does the same go for IP3? I am actually thinking of contacting Dr. Vucenik and Dr. Shamsuddin about this.

Also see:

The cardiac IP3 receptor: Uncovering the role of “the other” calcium release channel

And this: Phytate reduces age-related cardiovascular calcification. - PubMed - NCBI
and Protection of ischemic heart from reperfusion injury by myo-inositol hexaphosphate, a natural antioxidant. - PubMed - NCBI

And Epiphany: Modulation of IP3 receptors in Autism – Pancreatitis and Caffeine?

And: Original article: Caffeine protects against experimental acute pancreatitis by inhibition of inositol 1,4,5-trisphosphate receptor-mediated Ca2+ release

And:

(Oxytocin is a potent uterine stimulator whose clinical use in labor and delivery is well documented. Researchers have shown that oxytocin's clinical effectiveness is due to the activation of phospholipase C to produce inositol-1,4,5-triphosphate which releases calcium from intracellular stores and stimulates uterine contractions. The activation of the phosphatidylinositol signaling system by calcium agonists is also supported by the work of other researchers).

Source: Inositol, IP3 and IP6

This also is kind of confusing, genistein and quercetin lower IP3 in tumors, causing differentiation apoptosis. I thought IP3 was good? Or is this book not correct:

Principles of Orthomolecularism

Also very specific and informative:

Intracellular Signaling Mediators in the Circulatory and Ventilatory Systems

And this is also significant:

Huntington's disease[edit]
Huntington's disease occurs when the cytosolic protein Huntingtin (Htt) has an additional 35 glutamine residues added to its amino terminal region. This modified form of Htt is called Httexp. Httexp makes Type 1 IP3receptors more sensitive to IP3, which leads to the release of too much Ca2+ from the ER. The release of Ca2+ from the ER causes an increase in the cytosolic and mitochondrial concentrations of Ca2+. This increase in Ca2+ is thought to be the cause of GABAergic MSN degradation.[15]

Source: Inositol trisphosphate - Wikipedia

Heart disease is a major complication in Huntington's Disease according to Huntington's disease - Wikipedia

The second greatest risk is heart disease, which causes almost a quarter of fatalities of those with HD.[17]

Another good source on the specific matter:

Intracellular Calcium
 
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Travis

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Bonnett, R. "Reactions of nitrous acid and nitric oxide with porphyrins and haems. Nitrosylhaems as nitrosating agents." Journal of the Chemical Society (1975)

'We conclude that for haem systems attack by nitrosating species may occur at both the porphyrinate ligand (mesopositions and vinyl groups) and at the metal, and that the nitrosylhaem system formed by reaction at the metal may itself function, directly or indirectly, as a nitrosating agent under favourable conditions. We thank the Ministry of Agriculture, Fisheries and Food for support.' ―Bonnett

Wade, R. "Redox reactivity of iron (III) porphyrins and heme proteins with nitric oxide. Nitrosyl transfer to carbon, oxygen, nitrogen and sulfur." Chemical research in toxicology (1990)

'Sir: Nitrosamines are well-known carcinogens (1). They are reported to be denitrosated by mammalian cytochrome P-450 (2-11), and the nitrosyl adduct of the P-450 heme has been detected (2). As a part of our study of these and related reactions, we expected high-spin hemes to readily cleave the N-N bond of nitrosamines to generate the enormously stable heme-NO adducts (12-1 7):' ―Wade

Results from this study strongly imply that endogenous nitric oxide (ṄO) produced from enteral eNOS will complex with heme's inner Fe³⁺ atom, forming ligated Fe²⁺–N=O which can nitrosylate amino acids such as phenylalanine, proline, and cysteine. The fact that it can nitrosylate thiols and aromatic rings makes the oft-used term 'N-nitroso' seem totally inadequate to describe the carnage; the heme–nitric oxide can also form S-nitroso and C-nitroso adducts, making it appropriate to simply drop the 'N' unless there is something especially carcinogenic about N-nitroso adducts.


'We report herein that nitric oxide is indeed redox activated by iron (III) porphyrins and heme proteins to a nitrosating species having the character of nitrosonium ion.'―Wade

The 'enormously stable' heme–ṄO complex apparently has to make direct contact with the soon-to-be nitrosylated molecule since there is considerable variation in capability among heme enzymes. Myoglobin will form C-nitrosophenyl at a 100% yield yet cytochrome C fails to nitrosylate just one. These of course represent the extremes, and other heme enzymes have intermediate capacities. But due to the stochastic nature of digestion and damning epidemiological and experimental evidence you'd almost have to assume that free heme has the capacity to: (1) form the Fe²⁺–N=O complex from nitric oxide, (2) donate its nitroso group to a molecule, and (3) accept yet another ṄO to and repeat steps 1 & 2.

'However, gassing the chloroiron (III) porphyrin with nitric oxide in methanol/toluene resulted in the iron(II)-NO complex.' ―Wade

This could be a protein independent event, as the colon has two endogenous sources of nitric oxide: endothelial nitric oxide synthase (eNOS) is normally expressed and produces nitric oxide from arginine (shown below); inducible nitric oxide synthase (iNOS) is similar in function yet differs in provenance and incidence, being induced by cytokines (i.e. TNFα) and expressed only in inflamed areas (not shown).

eNOS.png


Although nitrites are often added to meat and no-doubt contribute to nitrosylation, this species is not necessary because this process will occur in simple systems containing heme, nitric oxide, water, and a suitable amino acid.

Inositol hexaphosphate (IP₆) has a high affinity for iron that could perhaps pull-it-out of the heme complex. Almost unbelievably, there had actually been a study performed involving heme, iron, nitic oxide, and inositol hexaphosphate:

Maxwell, J. "An infrared study of nitric oxide bonding to heme B and hemoglobin A. Evidence for inositol hexaphosphate induced cleavage of proximal histidine to iron bonds." Biochemistry (1976)


'The “pulling away” of the proximal histidine would weaken the histidine to iron bonding and thereby render the iron(II) less attractive as a 7 donor to dioxygen. [...] The IHP [inositol hexaphosphate] effect observed here may be explained solely in terms of a “pulling away” of proximal histidines in the manner strongly favored by Perutz et al. (1976) in discussions of these hemoglobin reactions in terms of R and T forms. Such an effect is supported by numerous examples of trans effects in metal porphyrin systems and has been proposed as a mechanistic possibility for heme-heme interactions and related allosteric phenomena. However, other factors which can be highly significant, but are as yet unevaluated, include changes in donor-acceptor (T) interactions between the porphyrin aromatic ring system (and the highly polarizable vinyl groups) and the protein environment, and changes in the environment about the nitrosyl ligand.' ―Maxwell
They had found that inositol hexaphosphate will bind heme's iron. Although IP₆ will not remove it from the complex, it can: break two Fe³⁺–histidine bonds, change the infrared spectra, and pull it slightly out-of-plane.
 
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TreasureVibe

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They had found that inositol hexaphosphate will bind heme's iron. Although IP₆ will not remove it from the complex, it can: break two Fe³⁺–histidine bonds, change the infrared spectra, and pull it slightly out-of-plane.
Is this comparable to the conventional cancer drug Deferoxamine? And is this effect of IP6 therapeutically relevant for cancer? Wouldn't this somehow make the Fe(II)-NO-complex more susceptible to be created?
 
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Travis

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(Oxytocin is a potent uterine stimulator whose clinical use in labor and delivery is well documented. Researchers have shown that oxytocin's clinical effectiveness is due to the activation of phospholipase C to produce inositol-1,4,5-triphosphate which releases calcium from intracellular stores and stimulates uterine contractions. The activation of the phosphatidylinositol signaling system by calcium agonists is also supported by the work of other researchers).

Source: Inositol, IP3 and IP6

This also is kind of confusing, genistein and quercetin lower IP3 in tumors, causing differentiation apoptosis. I thought IP3 was good? Or is this book not correct:

It's a good iron and calcium chelator, but intracellular calcium levels are also determined by cAMP. Genistein is also a ligand for the estradiol receptor (ERβ) where it represses transcription, making it an estrogen reverse agonist.

'Compared with ERα, ERβ exhibits a 7–30-fold greater binding affinity for genistein, whereas E₂ binds to ERα and ERβ with equal affinity (38, 39)' ―Lomri

'However, isoflavones are about 10–300-fold more potent at triggering transcriptional repression compared with transcriptional activation with ERβ.' ―Lomri

Alpha tocopherol succinate can complex with calcium and bring it into the cell. This represses the growth of hormone dependent cancers in two ways: (2) The androgen receptor binds calmodulin only in the presence of calcium; and (2) the CREB transcription factor is activated by calcium and competes with the androgen receptor for dNA and CREB binding protein, a satellite transcription factor. The estrogen receptor also binds to calmodulin in the presence of calcium, but I'm not sure if it competes with CREB.

[1] Lomri, N. "Estrogen receptor β-selective transcriptional activity and recruitment of coregulators by phytoestrogens." Journal of Biological Chemistry (2001)
 

Travis

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Is this comparable to the conventional cancer drug Deferoxamine? And is this effect of IP6 therapeutically relevant for cancer? Wouldn't this somehow make the Fe(II)-NO-complex more susceptible to be created?

I don't know what effect this has, but since inorganic iron doesn't nitrosylate proteins you'd be forced to think the heme–Fe³⁺ complex, together, is the active agent. The electrons in the heme–Fe³⁺ complex are delocalized over the entire porphyrin heterocycle, and the iron atom in the center can use these electrons. Since inositol hexaphosphate breaks two histidine–Fe³⁺ bonds and pulls it out of plane, I think logic would dictate this event would lower heme's nitrosylation potential by partially-severing iron's link to the electron pool in the porphyrin ring.
 

Travis

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@Travis your presence on this forum continues to give me confidence. When you were MIA last week I missed you!

I was working on this article, and it's brutal to write. I'll make sure to link you a copy when I'm done; the topic should be relevant for everybody (although it may not seem that way at first glance).
 

Obi-wan

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Alpha tocopherol succinate is a hit with Travis. I should get my order today. Hope my PSA is down next week since it only takes 8 hours to lower it. Shouldn't it be taking calcium out of the cell as calcium and bulk water makes the cell swell. Estrogen comes in to dismantle the microtubules getting the whole process ready for proliferation...Magnesium should be inside the cell.
 
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Obi-wan

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