Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Resource and Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
IMPDH inhibitors for antitumor therapy in tuberous sclerosis complex
Alexander J. Valvezan, … , Elizabeth P. Henske, Brendan D. Manning
Alexander J. Valvezan, … , Elizabeth P. Henske, Brendan D. Manning
Published April 9, 2020
Citation Information: JCI Insight. 2020;5(7):e135071. https://doi.org/10.1172/jci.insight.135071.
View: Text | PDF
Research Article Metabolism Therapeutics

IMPDH inhibitors for antitumor therapy in tuberous sclerosis complex

  • Text
  • PDF
Abstract

Recent studies in distinct preclinical tumor models have established the nucleotide synthesis enzyme inosine-5′-monophosphate dehydrogenase (IMPDH) as a viable target for antitumor therapy. IMPDH inhibitors have been used clinically for decades as safe and effective immunosuppressants. However, the potential to repurpose these pharmacological agents for antitumor therapy requires further investigation, including direct comparisons of available compounds. Therefore, we tested structurally distinct IMPDH inhibitors in multiple cell and mouse tumor models of the genetic tumor syndrome tuberous sclerosis complex (TSC). TSC-associated tumors are driven by uncontrolled activation of the growth-promoting protein kinase complex mechanistic target of rapamycin (mTOR) complex 1 (mTORC1), which is also aberrantly activated in the majority of sporadic cancers. Despite eliciting similar immunosuppressive effects, the IMPDH inhibitor mizoribine, used clinically throughout Asia, demonstrated far superior antitumor activity compared with the FDA-approved IMPDH inhibitor mycophenolate mofetil (or CellCept, a prodrug of mycophenolic acid). When compared directly to the mTOR inhibitor rapamycin, mizoribine treatment provided a more durable antitumor response associated with tumor cell death. These results provide preclinical support for repurposing mizoribine, over other IMPDH inhibitors, as an alternative to mTOR inhibitors for the treatment of TSC-associated tumors and possibly other tumors featuring uncontrolled mTORC1 activity.

Authors

Alexander J. Valvezan, Molly C. McNamara, Spencer K. Miller, Margaret E. Torrence, John M. Asara, Elizabeth P. Henske, Brendan D. Manning

×

Figure 1

Mizoribine is the most selective IMPDH inhibitor for reducing the viability of TSC2-deficient cells in culture.

Options: View larger image (or click on image) Download as PowerPoint
Mizoribine is the most selective IMPDH inhibitor for reducing the viabil...
(A) Littermate-derived Tsc2+/+ and Tsc2–/– mouse embryonic fibroblasts (MEFs) or (B) Tsc2–/– 105K renal tumor–derived cells stably reconstituted with empty vector or wild-type TSC2 were treated with vehicle or given concentrations of the indicated IMPDH inhibitors for (A) 72 hours or (B) 48 hours. Viable cells were counted by trypan blue exclusion and graphed as percentage of vehicle-treated cells. n = 3 independent experiments. (C) Cells in A were treated for 24 hours with vehicle, mizoribine (Miz: 1, 2, or 3 μM), mycophenolic acid (MPA: 125, 250, or 500 nM), ribavirin (Rib: 10, 20, or 30 μM), or AVN-944 (AVN: 100 or 250 nM) followed by immunoblotting for indicated proteins. Results are representative of at least 2 independent experiments. S6K, S6 kinase. (D) Annexin V (Ann V)/propidium iodide (PI) staining on cells in A treated for 72 hours with vehicle, 3 μM mizoribine, or 250 nM MPA. n = 3 independent experiments. Graphical data are presented as mean of indicated replicates ± SEM. *P < 0.05, #P < 0.01 by 2-tailed Student’s t test.

Copyright © 2022 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts