Premium
New Delta‐5‐Desaturase Inhibitor Suppress Lung Cancer Progression: A Paradigm Shift on COX‐2 Biology in Lung Cancer Treatment
Author(s) -
Pang Lizhi,
Shah Harshit,
Zhao Pinjing,
Qian Steven,
Sathish Venkatachalem
Publication year - 2020
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.2020.34.s1.09700
Subject(s) - lung cancer , cancer , in vivo , arachidonic acid , cancer research , cancer cell , pharmacology , medicine , lipid peroxidation , chemistry , biology , biochemistry , enzyme , oxidative stress , microbiology and biotechnology
Objective As the first leading cause of cancer deaths in the United States, lung cancer still attracts much research attention. Cyclooxygenase‐2 (COX‐2) is considered a classic target due to overexpression in nearly 80% non‐small‐cell lung cancer (NSCLC, major type) patients. The traditional concept of the COX‐2 inhibitor was designed to limit the COX‐2‐catalyzed arachidonic acid (AA) peroxidation and the formation of the PGE2 (subsequent cancer promoter). However, many COX‐2 inhibitors have failed to show clinical efficacy. Instead of inhibiting COX‐2, our previous studies have demonstrated that the genetically knocking down the delta‐5‐desaturase (D5D) by siRNA in cancer cells can lead to the inhibition of AA and PGE2 formation. This phenomenon promotes the COX‐2 catalyzed DGLA peroxidation to form 8‐hydroxyoctanoic acid (8‐HOA), which could be served as an anti‐cancer free radical byproduct in cancer therapy. However, the application of siRNA is still hindered by its in vivo instability and off‐target effect. Therefore, continued research into a new D5D small molecule inhibitor for lung cancer is required to expand the clinical benefit to the patient and to improve outcomes in NSCLC. In this study, we have first proposed the 10,11‐Dihydro‐5H‐dibenz[b,f]azepine as a newly synthesized D5D inhibitor and evaluated its effect on lung cancer by both in vitro and in vivo model. Method After the treatment of novel D5D inhibitor in vitro , the DGLA, AA, PGE2, and 8‐HOA profile was measured by LC/MS or GC/MS to assess the D5D activity in A549 NSCLC cells. Colony formation assay, wound‐healing assay, transwell assay, flow cytometry analysis, and western blot analysis was performed on A549 cells to evaluate the effect of D5D inhibitor on cancer cell proliferation, migration, and apoptosis. The in vivo effect of the D5D inhibitor was determined by xenograft mouse models in a 4 weeks treatment period along with supplementation of DGLA. Results The fatty acid profile results indicated that the treatment of D5D inhibitor (10 μM) significantly suppressed the AA and PGE2 but promoted 8‐HOA formation in A549 cells. The cell survival, migration, and proliferation of A549 cells were improved by the DGLA (100 μM) and D5D inhibitor treatment. Consistent with our in vitro data, the in vivo results suggested that the D5D inhibitor (15 mg/kg) along with DGLA supplementation could promote 8‐HOA formation to a threshold level, resulting in significant tumor reduction in both A549 and LLC xenograft mouse (nu/nu or C57B6) models. D5D inhibitor also suppressed the metastasis of LLC cells from the site of injection to the lung. Additionally, western blotting and immunohistochemistry results indicated that the D5D inhibitor also promoted apoptosis in tumor tissues. Conclusion Our new concept makes active use of the commonly overexpressed COX‐2 in cancer cells (no longer to be considered a problem, but instead a benefit), and concurrently targets D5D to also elicit DGLA’s anti‐cancer effect; these two efforts will act in concert to result in more effective and safer therapeutic outcomes for lung cancer treatment. Support or Funding Information NIHR15CA195499