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DHODH Inhibition –Ensuring the Safety of Pluripotent Stem Cell-based Regenerative Approaches

Review of “Selective eradication of pluripotent stem cells by inhibiting DHODH activity” from STEM CELLS by Stuart P. Atkinson

To abolish the risk of tumorigenesis associated with the transplantation of pluripotent stem cell (PSC)-derived therapeutically-relevant cell types, we require an efficient means of eliminating any undifferentiated self-renewing cells. The dihydroorotate dehydrogenase (DHODH) enzyme represents an attractive therapeutic target for many types of cancer [1-5], whose inhibition can interrupt vital cellular functions by preventing the modification of crucial transcription factors and thereby inducing their nuclear export [5, 6]. Therefore, the inhibition of DHODH activity may represent an efficient approach to the elimination of undifferentiated cells that persist throughout a given differentiation protocol.

Writing in a recent STEM CELLS article [7], Toru Kondo (Hokkaido University, Japan) now provides evidence for the utility of DHODH inhibitors such as brequinar in the development of safe and effective PSC‐based therapies.

This fascinating new study revealed that treatment with the DHODH inhibitor brequinar eliminated undifferentiated mouse PSCs while displaying significantly lower cytotoxicity to tissue-specific adult stem cells or differentiated somatic cells in vitro, which included neural stem cells, astrocytes, and myoblasts. Specifically, brequinar exposure prompted cell cycle arrest, pluripotency loss, and cell death in mouse PSCs. Interestingly, the author linked the brequinar-induced loss of pluripotency to the nuclear export of the Oct4 and Nanog pluripotency factors in a manner that required chromosomal maintenance 1 (Crm1, also known as Exportin 1), which is the major mammalian export protein that facilitates the transport of large macromolecules (e.g., RNA and protein) across the nuclear membrane to the cytoplasm.

Finally, the study shifted to study the potential of brequinar in vivo, where the authors provided evidence that DHODH inhibition could prevent the formation of teratomas and reduce the levels of pluripotency-associated marker expression following the transplantation of mouse PSCs into immunodeficient mice. Furthermore, brequinar treatment failed to induce any evident toxic side-effects.

Successful PSC-based regenerative medicine outcomes require the exclusion or elimination of potentially dangerous undifferentiated cells from the transplanted population, and these findings support the inhibition of DHODH through brequinar treatment as a potentially exciting means to achieve this goal.

For more on new strategies to ensure the safety and efficacy of PSC-derived regenerative therapies, stay tuned to the Stem Cells Portal!

References

  1. White RM, Cech J, Ratanasirintrawoot S, et al., DHODH modulates transcriptional elongation in the neural crest and melanoma. Nature 2011;471:518-522.
  2. Sykes DB, Kfoury YS, Mercier FE, et al., Inhibition of Dihydroorotate Dehydrogenase Overcomes Differentiation Blockade in Acute Myeloid Leukemia. Cell 2016;167:171-186.e15.
  3. Brown KK, Spinelli JB, Asara JM, et al., Adaptive Reprogramming of De Novo Pyrimidine Synthesis Is a Metabolic Vulnerability in Triple-Negative Breast Cancer. Cancer Discovery 2017;7:391.
  4. Koundinya M, Sudhalter J, Courjaud A, et al., Dependence on the Pyrimidine Biosynthetic Enzyme DHODH Is a Synthetic Lethal Vulnerability in Mutant KRAS-Driven Cancers. Cell Chemical Biology 2018;25:705-717.e11.
  5. Echizenya S, Ishii Y, Kitazawa S, et al., Discovery of a new pyrimidine synthesis inhibitor eradicating glioblastoma-initiating cells. Neuro-Oncology 2020;22:229-239.
  6. Yang WH, Park SY, Nam HW, et al., NFkappaB activation is associated with its O-GlcNAcylation state under hyperglycemic conditions. Proc Natl Acad Sci U S A 2008;105:17345-50.
  7. Kondo T, Selective eradication of pluripotent stem cells by inhibiting DHODH activity. STEM CELLS 2021;39:33-42.