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Synthesis of a novel non‐diuretic, brain‐penetrating, ethacrynic acid analog and demonstration of its potent efficacy in orthotopic glioblastoma (GBM) models
Author(s) -
Madala Hanumantha Rao,
Punganuru Surendra Reddy,
KALKUNTE SRIVENUGOPAL
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.178.1
Subject(s) - pharmacology , unfolded protein response , brain tumor , oxidative stress , cancer research , downregulation and upregulation , temozolomide , apoptosis , medicine , chemistry , pathology , biochemistry , glioblastoma , gene
The incidence of pediatric and adult brain tumors has continued to rise in the USA and the alkylating agent temozolomide has remained the sole choice in the chemotherapy of these lethal malignancies. Therefore, there is a very urgent need to design new, more effective brain‐penetrating drugs that can significantly advance the survival brain tumor patients. We are highly interested in exploiting the elevated oxidative stress present in gliomas and have synthesized a hydrophobic, non‐diuretic analog of ethacrynic acid (EA) called KSS72 by removing the carboxylate side chain. KSS72 was selectively cytotoxic to cancer cells and pharmacokinetics following intravenous or oral administrations in mice showed its excellent penetrance through the blood‐brain‐barrier, accumulating at levels equivalent to (TMZ) in the brain. In vitro assays measuring protein carbonyl content, GSH content, ROS generation, GSTpi enzyme activity and others showed that KSS72 triggers a redox imbalance by inhibiting GSTpi and by lowering the antioxidant (GSH) and reducing equivalent (NADPH) levels, leading to a significant elevation of ROS levels. We also showed the upregulation of endoplasmic reticulum (ER) stress‐responsive proteins, activation of MAPK, autophagy and apoptotic pathways by KSS72 in several cell lines. In view of its excellent brain penetrance and multiple cytocidal events mediated by ROS, we tested the antitumor efficacy of KSS72 in human GBM cell lines and intracranial GBM xenografts. SF‐188 human GBM cells expressing firefly luciferase were injected into the brain just left of bregma for the development of orthotopic GBM in nude mice. These mice were given 25 mg/kg/day of KSS72 intraperitoneally for 2 weeks. The animals when imaged by IVIS after luciferin injections showed a complete lack of intracranial tumors in all KSS72 administered animals. H&E staining of mouse brain sections confirmed the total elimination of GBM by KSS72. KSS72 did not exert any toxicity on host tissues and serum ALT and AST levels were not altered. In summary, we conclude that KSS72 acting through multiple pathways of oxidative stress is a hugely promising non‐toxic anti‐glioma drug with potential to enter clinical trials. Support or Funding Information CPRIT grant RP130266 to KSS.