This administrative supplement is in response to notice NOT-CA-20-019 on Dementia or Alzheimer?s Disease (AD) and is within the scope of parent grant funded by NCI R01 CA221813-03. Doxorubicin (DOX) is one of the most effective anti-cancer drugs that causes muscle weakness and atrophy as we have proposed in the parent grant. A recent surge in cancer survivors following DOX treatment shows cognitive deficit and developed dementia also called ?chemo brain?. Patients with chemo brain experience oxidative stress, inflammation, fog like symtoms, and finally show DOX-induced cognitive dysfunction and dementia (DICD). It remains unknown whether the inflammation induced cell death, known as pyroptosis (a distinct form of cell death, from apoptosis and necrosis), occurs as a result of DICD. Our supporting preliminary data shows that treatment with DOX shows an increase in pro-inflammatory M1 macrophages, presence of inflammatory cytokines TNF-? and IL-6 and pyroptotic specific marker IL-1? in the DICD. We also observed a significant decrease in brain weight and size, suggesting presence of atrophy in the chemo brain. Furthermore, our histological data shows a significant positive pathological marker of cognitive dysfunction and dementia such as decrease in thickness of pyramidal layer, formation of neurofibrillary tangles, Hirano bodies and cytoplasmic vacuolization in the chemo brain. Our preliminary data shows a significant increase in AD markers (BACE1 and S100B) and brain dysfunction in chemo brain. Therefore, we hypothesize that DOX treatment enhances infiltration of monocytes that polarizes into M1 macrophages, which triggers inflammation causing pyroptosis, brain atrophy, vacuolization which ultimately enhances DICD and AD. Our unpublished studies as proposed in the parent grant shows ES-exos attenuate inflammation, pyroptosis and improving muscle function. However, it is completely unknown whether ES-Exos ameliorate DOX-induced pyroptosis and associated adverse cerebral cortex as well as hippocampal remodeling by increasing anti-inflammatory M2 macrophages, thereby improving brain function. We propose to test these hypotheses in two specific Aims; 1) To determine if increased presence of monocytes polarized into M1 macrophages following DOX treatment induces pyroptosis leading to cognitive dysfunction with a potential to develop AD. 2) To demonstrate whether treatment with ES-exos cause phenoswitching of M1 macrophages into M2 macrophages, resulting in amelioration of pyroptosis, reduced cognitive dementia and decreased severity of AD. This application will have unique novelty to establish a link between DOX-induced muscle dysfunction and cognitive dysfunction and dementia with a potential to develop AD while testing a potential therapy to prevent DICD and AD.
Doxorubicin is a wonderful anti-cancer drug. Unfortunately, a major side effect of this drug is causing a muscle dysfunction, cognitive impairment and dementia in patients suffering from cancer in the U.S. and around the world. Recently, chemotherapy survival rate is significant; however, the suffer from major side effects as mentioned above. Doxorubicin induces inflammation by attracting monocytes that polarizes into M1 macrophages is now becoming a considerable cause of development and progression of muscular dysfunction and fatigue. However, nothing is known how cognitive dysfunction progresses whether this also involves M1macrophages. We report as a preliminary data that presence of M1 macrophages causing immune mediated cell death called pyroptosis, brain remodeling, cognitive dysfunction and dementia. We have generated ES-Exosome from ES cells which could be an excellent therapeutic option as these cell free components don?t form teratoma and are capable to attenuate pyroptosis and brain remodeling and dysfunction is proposed in the grant. Overall if successful, ES-Exos will provide protection in DOX induced brain toxicity by inhibiting pyroptosis and adverse brain remodeling, atrophy and dysfunction
| Merino, Hilda; Singla, Dinender K (2018) Secreted Frizzled-Related Protein-2 Inhibits Doxorubicin-Induced Apoptosis Mediated through the Akt-mTOR Pathway in Soleus Muscle. Oxid Med Cell Longev 2018:6043064 |
