Is the Autophagy Induced by Thiopurines Beneficial or Deleterious?

Abstract

Thiopurines (azathioprine, 6-mercaptopurine and 6-thioguanine), are drugs useful in the treatment of leukemia, autoimmune diseases, as well as in organ transplantation. After many years of use is still not well understood their mode of action. Recently, several groups have found that thiopurines can activate autophagy by different mechanisms. Autophagy is a process of auto-digestion. After an infection, radiation, injury, oxidative stress, or after drug treatment, the cellular organelles may be damaged. In those cases the damaged structures are recognized by the cell, isolated in a double-membrane vacuole and finally degraded in autolysosomes. The digestion gives rise to biosynthetic precursors needed to regenerate partially destroyed structures, so as to produce the energy essential in the anabolic process. During fasting, the protein aggregates, lipid droplets and glycogen deposits are degraded by this pathway for releasing nutrients to the blood. Therefore this process is of vital importance in the maintaining of cellular functions and in the systemic homeostasis of whole organism. The therapy with thiopurines leads to adverse effects such as myelosuppression and hepatotoxicity whose mechanism is not well understood today. Autophagy is also involved in liver degeneration induced by drugs, alcohol or viruses. Therefore, seems to be very attractive know whether the autophagy induced by thiopurines is the cause of the hepatotoxicity associated with these drugs, or rather, autophagy is a compensatory response that protects the liver against the deleterious effects of the thiopurines. Our results and previous data suggest that autophagy is beneficial for the liver because protects it against the deleterious effects of thiopurines.

Role of autophagy in the pathogenesis of inflammatory bowel disease

“…Thiopurines, including azathioprine and 6-mercaptopurine, are immunosuppressant drugs used to maintain remission in patients with IBD[78]. Thiopurines and autophagy have also been shown to be correlated by the adverse effects of treatment.…”

“…It was shown that autophagy might represent an important route for the clearance of TPMT*3A aggregates and/or aggregate precursors[84]. Due to the severe adverse effects of thiopurines, a potential protective role for autophagy in hepatocytes has been investigated; it has been shown that autophagy has a protective role in hepatocytes during thiopurine therapy[78]. …”

Autophagy and haematopoietic stem cell transplantation

“…Silencing of ULK1 , Atg5 or Atg7 contributes to increased apoptosis in response to CsA, further supporting a protective role of autophagy following CsA treatment 91 . Similar to CsA, thiopurine can activate autophagy and also appears to serve as a compensatory protective mechanism to counter cytotoxicity 92 . Thus, the strategic use of immunosuppressants that also promote autophagy might serve to decrease the intrinsic cytotoxic effects of these agents.…”

Inflammatory Bowel Disease Drugs: A Focus on Autophagy

“…73 They have a relatively slow onset but can maintain remission in moderate to severe cases of CD and have also shown some effectiveness for the induction of remission. 3,74 The commonly used pro-drug azathioprine is converted to 6-mercaptopurine [6-MP] by glutathione in the intestinal wall.…”

“…Autophagy is activated in hepatocytes treated with thiopurines, possibly as a secondary response to the hepatotoxic effects of the drug [Figure 3]; however, it could also indicate that autophagy is directly modulated to balance immune responses in patients. 73,78 Despite the lack of understanding of the mechanism of action of thiopurines, it has been shown that autophagy has a protective role in hepatocytes during thiopurine therapy, 73 suggesting that a combination treatment of thiopurines with drugs that induce autophagy may reduce their adverse effects, enhancing their efficacy and safety.…”