Cancer cachexia has many symptoms but only one cause: anoxia
During nearly 100 years of research on cancer cachexia (CC), science has been reciting the same mantra: it is a multifactorial syndrome. The aim of this paper is to show that the symptoms are many, but they have a single cause: anoxia.
CC is a complex and devastating condition that affects a high proportion of advanced cancer patients. Unfortunately, it cannot be reversed by traditional nutritional support and it generally reduces survival time. It is characterized by significant weight loss, mainly from fat deposits and skeletal muscles. The occurrence of cachexia in cancer patients is usually a late phenomenon. The conundrum is why do similar patients with similar tumors, develop cachexia and others do not? Even if cachexia is mainly a metabolic dysfunction, there are other issues involved such as the activation of inflammatory responses and crosstalk between different cell types. The exact mechanism leading to a wasting syndrome is not known, however there are some factors that are surely involved, such as anorexia with lower calorie intake, increased glycolytic flux, gluconeogenesis, increased lipolysis and severe tumor hypoxia. Based on this incomplete knowledge we put together a scheme explaining the molecular mechanisms behind cancer cachexia, and surprisingly, there is one cause that explains all of its characteristics: anoxia. With this different view of CC we propose a treatment based on the physiopathology that leads from anoxia to the symptoms of CC. The fundamentals of this hypothesis are based on the idea that CC is the result of anoxia causing intracellular lactic acidosis. This is a dangerous situation for cell survival which can be solved by activating energy consuming gluconeogenesis. The process is conducted by the hypoxia inducible factor-1α. This hypothesis was built by putting together pieces of evidence produced by authors working on related topics. https://f1000research.com/articles/9-250
Great contribution Daniel!
The scheme proposed here:
Anoxia is difficult to attack. Vasodilators like nitrates and "hemodynamic enhancers" like pentoxifylline can improve circulation in the tumor by decreasing anoxia. Flunarizine is a vasodilator with the ability to block voltage-dependent sodium channels. Nitroglycerin is another vasodilator that has been tested on tumors. A combination of these medications could improve the oxygenation of the tumor. Any anti-angiogenic medication used must be discontinued.
HIF-1α, directly regulated by anoxia, is a targeted transcription factor. Although extensive and intensive research for an inhibitor has been carried out for many years, a suitable drug has not yet been developed. Emodin is a non-toxic HIF inhibitor and may produce some benefits 167-171 in CC.
Intracellular lactic acidosis-Cori-gluconeogenesis cycle: One of the mechanisms to decrease the Cori cycle is to damage the excessive production of lactic acid, either in anaerobic cancer cells or in the liver. In this sense, probably the drug of choice should be dichloroacetate (DCA).
Improved appetite: If the above problems have been medicated and controlled to some extent, then it makes sense to improve your appetite with megestrol and high-calorie nutritional supplements.