Abstract
Knocking down delta-5-desaturase (D5D) by siRNA or shRNA is a promising strategy to achieve 8-hydroxyoctanoic acid (8-HOA) production for cancer inhibition. However, the RNAi-based strategy to stimulate 8-HOA is restricted due to endonucleases mediated physiological degradation and off-target effects. Thus, to get persistent 8-HOA in the cancer cell, we recognized a D5D inhibitor Iminodibenzyl. Here, we have postulated that Iminodibenzyl, by inhibiting D5D activity, could shift the di-homo-gamma-linolenic acid (DGLA) peroxidation from arachidonic acid to 8-HOA in high COX-2 microenvironment of 4T1 and MDA-MB-231 breast cancer cells. We observed that Iminodibenzyl stimulated 8-HOA caused HDAC activity reduction resulting in intrinsic apoptosis pathway activation. Additionally, reduced filopodia and lamellipodia, and epithelial-mesenchymal transition markers give rise to decreased cancer cell migration. In the orthotopic breast cancer model, the combination of Iminodibenzyl and DGLA reduced tumor size. From in vitro and in vivo studies, we concluded that Iminodibenzyl could reprogram COX-2 induced DGLA peroxidation to produce anti-cancer activity.
Highlights
Breast cancer is the most commonly occurring cancer among females in developed countries
It is well established that ω-6-PUFAs such as di-homo-gamma-linolenic acid (DGLA) upon metabolism by D5D forms arachidonic acid (AA), which further peroxidized by
From DGLA peroxidation resulting in cancer growth inhibitory effect. c Cell viability analysis by different dose combination of DGLA and Iminodibenzyl in 4T1 and MDA-MB-231 cancer cells. d GC/MS analysis of 4T1 and MDA-MB-231 cancer cells treated with 100 μM DGLA, 10 μM Iminodibenzyl, and combination of 100 μM DGLA + 10 μM Iminodibenzyl. n = 6–10 for (c) and n = 3 for (d)
Summary
Breast cancer is the most commonly occurring cancer among females in developed countries. As per the National Institute of Statistics, 90% of women are diagnosed with advanced-stage breast cancer, which significantly reduces their survival and quality of life[1]. Multiple predisposing factors are responsible for mammary cancer induction and growth, including overconsumption of ω-6 polyunsaturated fatty acid (ω-6-PUFAs)[2,3]. Scientific reports have suggested that cancer-promoting effects of ω-6-PUFAs are due to cyclooxygenase-2 (COX-2) induced increased levels of procarcinogenic eicosanoids, such as prostaglandin E2 (PGE2)[3]. COX-2 is involved in the growth of various epithelial cancers including breast cancer[4]. An immunohistochemistry study evaluating more than 1500 breast cancer specimens for COX-2 reported moderate to strong COX-2 expression in 37% of the samples[5]
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