Iminodibenzyl redirected cyclooxygenase-2 catalyzed dihomo-γ-linolenic acid peroxidation pattern in lung cancer.
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| Abstract |
Cyclooxygenase-2 (COX-2) is up-regulated by redox imbalance and is considered a target for cancer therapy. The rationale of the COX-2 inhibitor lies in suppressing COX-2 catalyzed peroxidation of omega-6 polyunsaturated fatty acids (PUFAs), which are essential and pervasive in our daily diet. However, COX-2 inhibitors fail to improve cancer patients' survival and may lead to severe side effects. Here, instead of directly inhibiting COX-2, we utilize a small molecule, iminodibenzyl, which could reprogram the COX-2 catalyzed omega-6 PUFAs peroxidation in lung cancer by inhibiting delta-5-desaturase (D5D) activity. Iminodibenzyl breaks the conversion from dihomo-γ-linolenic acid (DGLA) to arachidonic acid, resulting in the formation of a distinct byproduct, 8-hydroxyoctanoic acid, in lung cancer cells and solid tumors. By utilizing COX-2 overexpression in cancer, the combination of DGLA supplementation and iminodibenzyl suppressed YAP1/TAZ pathway, decreasing the tumor size and lung metastasis in nude mice and C57BL/6 mice. This D5D inhibition-based strategy selectively damaged lung cancer cells with a high COX-2 level, whereas it could avoid harassing normal lung epithelial cells. This finding challenged the COX-2 redox basis in cancer, providing a new direction for developing omega-6 (DGLA)-based diet/regimen in lung cancer therapy.
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| Authors | Lizhi Pang, Harshit Shah, Steven Qian, Venkatachalem Sathish |
| Journal | Free radical biology & medicine (Free Radic Biol Med) Vol. 172 Pg. 167-180 (08 20 2021) ISSN: 1873-4596 [Electronic] United States |
| PMID | 34102280 (Publication Type: Journal Article, Research Support, N.I.H., Extramural) |
| Copyright | Copyright © 2021 Elsevier Inc. All rights reserved. |
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