SR9011 is a research drug that was developed by Professor Thomas Burris of Scripps as an agonist of Rev-ErbA with a half-maximum inhibitory concentration (IC50) = 790 nM for Rev-Erb and IC50 = 560 nM for Rev-ErbA . It has been used in the study of the regulation of the circadian rhythm and its links to immune system function, inflammation, and cancer.
The biological clock controls a variety of physiological functions, such as metabolism, cell proliferation, and inflammation. Now, Sulli et al. Write on nature. It is reported that the biological clock component Rev-erb (also known as nr1d1) and Reverb (also known as nr1d2), are nuclear hormone receptors that inhibit several pathways related to tumorigenesis, maybe a new anticancer strategy.
Two recently developed Rev-erb agonists sr9009 and sr9011 show obesity-reducing activity in mouse models by changing the expression of enzymes involved in fatty acid metabolism and transport. These observations led Sulli et al. To study whether enhancing the inhibitory function of Reverb can also inhibit the expression of abnormally activated genes in cancer cells. Satchidananda Panda, the lead author of the study, explained: Cancer cells thrive in changes in metabolic homeostasis. Therefore, reactivating biological clock components may be a new method to make cancer cells lose the metabolic state that promotes tumor growth.
SR9009 and SR9011 induce apoptosis in a series of cancer cell lines, including melanoma, leukemia, brain cancer, breast cancer, and colon cancer, and cells driven by different oncogenes, including HRAS, KRAS, BRAF, and CTNNB1 encoding. - Catenin) or PTEN deficiency, with little toxicity to normal cells. This selectivity suggests that sr9009 and sr9011 may affect processes specific to cancer cell survival, such as autophagy and de novo lipogenesis, which are strictly regulated by Reverb. No matter where or how cancer starts, all cancer cells need more nutrition and more recycled materials to build new cells, the panda said. In fact, the number of autophagy treated with sr9009 and sr9009 increased. It also reduced the expression of lipogenic enzymes fatty acid synthase (FAS) and stearoyl COA desaturase 1 (SCD1).
Next, taking advantage of the fact that sr9009 can cross the blood-brain barrier and evaluating whether activation of Rev-erb may be a treatment, the authors tested sr9009 in vivo in two mouse models of glioblastoma. Sr9009 reduces the growth of glioblastoma, induces apoptosis, and downregulates the expression of the autophagy gene. The efficacy of sr9009 is similar to that of temozolomide, which is the current standard treatment for glioblastoma, although it is not toxic.
This study suggests that drug development for the biological clock may provide an effective tool for cancer treatment.
This study shows that the development of drugs targeting the biological clock may provide effective tools for cancer treatment and improve the possibility of developing drugs to manipulate the biological clock. These drugs can not only treat cancer but also treat other diseases that may be related to circadian rhythm disorders.