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Nsaid (aspirin) May Prevent Cancer Cachexia (wasting)

  1. Another study linking chronic inflammation to cancer and its signature muscle wasting condition known as cachexia. Yet another piece of the puzzle in how aspirin prevents and maybe even treats cancer.
    This study is also interesting b/c it found that that the current medical opinion vilifying fat deposits as bad and trying to burn them is actually the exact opposite of what should be done. It looks like, for cancer patients at least, regular white fat around the butt and belly is actually very beneficial.

    http://news.sciencemag.org/biology/2014 ... r-patients

    "In the mouse models, the researchers were able to link the process [cachexia] to the systemic inflammation that’s often seen in cancer patients. They implicated interleukin-6 (IL-6), a cell signaling protein involved in stimulating the body’s immune response to inflammation. They then showed that anti-inflammatory drugs may prevent the white fat browning that precedes cancer cachexia and the wasting syndrome itself, the team reports online this week in Cell Metabolism. Bruce Spiegelman, a cell biologist at the Dana-Farber Cancer Institute in Boston, recently reached a very similar conclusion in his own lab and published the result in Nature. Both papers, he says, “end any question that activation of fat browning is definitely part of cancer cachexia, at least in terms of animal models, and are pretty suggestive in people with cancer.” Spiegelman’s lab used a different mouse model of cancer cachexia and searched for genetic changes in tumor cell function, homing in on a distinct molecular factor, tumor-derived parathyroid-hormone-related protein (PTHrP). When his group neutralized this protein in mice, “muscle wasting and cachexia were alleviated but not stopped,” Spiegelman says. He says that means other factors are likely involved, possibly IL-6."
  2. Serotonin negatively regulates beige/brown fat - one of the mechanisms why germ free mice are lean. Less serotonin = more brown fat. I think a big piece of the puzzle here is increased inflammation & indoleamine dioxygenase (IDO) activity in cancer resulting in tryptophan depletion = loss of negative feedback on adipose tissue beiging/browning. It's possible some of those effects of serotonin are mediated through PTHrP and IL-6 - since both are increased by prolactin and serotonin.

    There's probably some mechanisms that helps to preserve brain/vital tissue serotonin levels under tryptophan depletion (accounting for the prolactin/PTHrP) - maybe the increased blood FFAs and reduced binding of tryptophan to albumin, maybe along with reduced levels of other aminos (increased use of some for gluconeogenesis?), maybe release of tryptophan from the muscles under catabolic stress...
  3. If serotonin is blocked at the receptor level, then cortisol will also be low and thus muscle breakdown would probably not occur as much leading to low tryptophan in blood and thus brain. This may be why serotonin antagonists have been shown to actually lower serotonin in blood unlike other receptor antagonists which raise the serum levels of the steroid they oppose (e.g. RU486 raises serum cortisol levels).
    Blocking serotonin and estrogen is likely the single most systemically beneficial approach in any cancer, which explains why cyproheptadine has shown so much promise in recent studies. If you look on Pubmed you will see that it is now considered for liver cancer, leukemia, lymphoma, glioblastoma, breast cancer, etc. Given that PTHrp is simply an abnormal PTH analogue subject to the same regulatory mechanisms, cyproheptadine may help there too as it has been shown to lower PTH and thus oppose the PTH-induced hypercalcemia. Cypro is also a calcium channel antagonist, so even is has a doubly protective action against calcium overload.