2. Academic Validation
  3. Inhibition of autophagy and induction of glioblastoma cell death by NEO214, a perillyl alcohol-rolipram conjugate

Inhibition of autophagy and induction of glioblastoma cell death by NEO214, a perillyl alcohol-rolipram conjugate

  • Autophagy. 2023 Dec;19(12):3169-3188. doi: 10.1080/15548627.2023.2242696.
Mengting Ou 1 2,  Hee-Yeon Cho 1 3,  Jie Fu 4,  Thu Zan Thein 1,  Weijun Wang 1,  Stephen D Swenson 1,  Radu O Minea 1,  Apostolos Stathopoulos 1,  Axel H Schönthal 5,  Florence M Hofman 1 6,  Liling Tang 2,  Thomas C Chen 1 6
Affiliations

Affiliations

  • 1 Department of Neurosurgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • 2 Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China.
  • 3 Department of Chemistry, Physics, and Engineering, Biola University, La Mirada, CA, USA.
  • 4 Department of Neurology, The Affiliated Hospital of Southwest Medical University, Luzhou, China.
  • 5 Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • 6 Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
PMID: 37545052 DOI: 10.1080/15548627.2023.2242696
Abstract

Glioblastoma (GBM) is the most aggressive primary brain tumor, exhibiting a high rate of recurrence and poor prognosis. Surgery and chemoradiation with temozolomide (TMZ) represent the standard of care, but, in most cases, the tumor develops resistance to further treatment and the patients succumb to disease. Therefore, there is a great need for the development of well-tolerated, effective drugs that specifically target chemoresistant gliomas. NEO214 was generated by covalently conjugating rolipram, a PDE4 (phosphodiesterase 4) inhibitor, to perillyl alcohol, a naturally occurring monoterpene related to limonene. Our previous studies in preclinical models showed that NEO214 harbors Anticancer activity, is able to cross the blood-brain barrier (BBB), and is remarkably well tolerated. In the present study, we investigated its mechanism of action and discovered inhibition of macroautophagy/Autophagy as a key component of its Anticancer effect in glioblastoma cells. We show that NEO214 prevents autophagy-lysosome fusion, thereby blocking autophagic flux and triggering glioma cell death. This process involves activation of mTOR (mechanistic target of rapamycin kinase) activity, which leads to cytoplasmic accumulation of TFEB (transcription factor EB), a critical regulator of genes involved in the autophagy-lysosomal pathway, and consequently reduced expression of autophagy-lysosome genes. When combined with chloroquine and TMZ, the Anticancer impact of NEO214 is further potentiated and unfolds against TMZ-resistant cells as well. Taken together, our findings characterize NEO214 as a novel Autophagy Inhibitor that could become useful for overcoming chemoresistance in glioblastoma.Abbreviations: ATG: Autophagy related; BAFA1: bafilomycin A1; BBB: blood brain barrier; CQ: chloroquine; GBM: glioblastoma; LAMP1: lysosomal associated membrane protein 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MGMT: O-6-methylguanine-DNA methyltransferase; MTOR: mechanistic target of rapamycin kinase; MTORC: mTOR complex; POH: perillyl alcohol; SQSTM1/p62: sequestosome 1; TFEB: transcription factor EB; TMZ: temozolomide.

Keywords

MTOR complex; NEO214; autophagic flux; chloroquine; glioblastoma; transcription factor EB.

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