Glutamine Addiction in Kidney Cancer Suppresses Oxidative Stress and Can Be Exploited for Real-Time Imaging

• Published in: Cancer research (Chicago, Ill.) Vol. 77; no. 23; pp. 6746 - 6758
• Main Authors: Abu Aboud, Omran, Habib, Samy L, Trott, Josephine, Stewart, Benjamin, Liang, Sitai, Chaudhari, Abhijit J, Sutcliffe, Julie, Weiss, Robert H
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research, Inc 01.12.2017; American Association for Cancer Research
• Subjects: 8-Hydroxy-2'-Deoxyguanosine; Addictions; Animals; Antineoplastic Agents - pharmacology; Antioxidants; Antioxidants - pharmacology; Apoptosis; Apoptosis - physiology; BASIC BIOLOGICAL SCIENCES; Benzeneacetamides - pharmacology; Carcinoma, Renal Cell - drug therapy; Carcinoma, Renal Cell - pathology; Cell lines; Clear cell-type renal cell carcinoma; Deoxyguanosine; Deoxyguanosine - analogs & derivatives; Deoxyguanosine - metabolism; DNA damage; Glutaminase; Glutaminase - antagonists & inhibitors; Glutamine; Glutamine - metabolism; Glutathione; Humans; Inhibitors; Kidney cancer; Kidney Neoplasms - drug therapy; Kidney Neoplasms - pathology; Metabolism; Mice; NF-E2 Transcription Factor - metabolism; Oxidants; Oxidative stress; Oxidative Stress - drug effects; Oxidizing agents; Reactive oxygen species; Reactive Oxygen Species - metabolism; Stress; Thiadiazoles - pharmacology; Tomography; Tumors; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-17-0930

Many cancers appear to activate intrinsic antioxidant systems as a means to counteract oxidative stress. Some cancers, such as clear cell renal cell carcinoma (ccRCC), require exogenous glutamine for growth and exhibit reprogrammed glutamine metabolism, at least in part due to the glutathione pathway, an efficient cellular buffering system that counteracts reactive oxygen species and other oxidants. We show here that ccRCC xenograft tumors under the renal capsule exhibit enhanced oxidative stress compared with adjacent normal tissue and the contralateral kidney. Upon glutaminase inhibition with CB-839 or BPTES, the RCC cell lines SN12PM-6-1 (SN12) and 786-O exhibited decreased survival and pronounced apoptosis associated with a decreased GSH/GSSG ratio, augmented nuclear factor erythroid-related factor 2, and increased 8-oxo-7,8-dihydro-2'-deoxyguanosine, a marker of DNA damage. SN12 tumor xenografts showed decreased growth when treated with CB-839. Furthermore, PET imaging confirmed that ccRCC tumors exhibited increased tumoral uptake of F-(2 ,4 )4-fluoroglutamine compared with the kidney in the orthotopic mouse model. This technique can be utilized to follow changes in ccRCC metabolism Further development of these paradigms will lead to new treatment options with glutaminase inhibitors and the utility of PET to identify and manage patients with ccRCC who are likely to respond to glutaminase inhibitors in the clinic. .