| dc.description.abstract | Breast cancer arises from the culmination of complex process enclosing multiple gene modifications such as cyclooxygenase-2 (COX-2). It catalyzes arachidonic acid (AA, downstream ω-6 polyunsaturated fatty acid (ω-6 PUFA)) metabolism to cancer-promoting prostaglandin E2 (PGE2). Hence, COX-2 inhibition was considered an ideal strategy to inhibit the cancer progression. However, COX-2 inhibitors are no longer advised for cancer management due to life threatening cardiovascular adverse events. Recently, we found that inhibition of delta-5-desaturase (D5D, enzyme catalyzing di homo-gamma-linolenic acid (DGLA) metabolism to AA) in breast cancer cells by siRNA/shRNA caused the diversion of DGLA metabolism from PGE2 to anticancer metabolite 8-hydroxyoctanoic acid (8-HOA). But, the approach of using siRNA/shRNA was limited by endonucleases mediated physiological degradation and inability to cross the cell membrane. Therefore, to overcome the limitation and to stimulate DGLA metabolism towards anti-cancer activity, small molecule D5D activity inhibitor Iminodibenzyl was identified. Here, we have hypothesized that Iminodibenzyl could inhibit the DGLA metabolism by inhibiting the D5D activity, and simultaneously overexpressed COX-2 in breast cancer cells would peroxidize the accumulated DGLA to an anti-cancer metabolite 8-HOA. To achieve the research goal, we have performed various in vitro and in vivo studies (orthotopic breast cancer model). From these studies, we noted that Iminodibenzyl could alter DGLA metabolism to anti-cancer metabolite 8-HOA in 4T1 and MDA-MB-231 breast cancer cells. After treating cancer cells with the combination of Iminodibenzyl and DGLA, a significant increase in apoptosis was observed through the caspasedependent mechanism, which was validated by pretreating cells with nonspecific caspase inhibitor Z-VAD-FMK. Additionally, a significant reduction in HDAC activity and β-Catenin was observed, which might have reduced cancer cell survival fraction and proliferation. We believe that all the above mechanisms affected by the combination might have reduced the cancer growth resulting in significant reduction in tumor size. Additionally, combination treatment also reduced lamellipodia and filopodia, and EMT markers resulting in reduction in cancer cell migration as visible from larger wound size and less number of metastatic nodules. Hence, all the above findings provide evidence about the efficacy of Iminodibenzyl to shift the DGLA metabolism producing anti-cancer activity in breast cancer cells. | en_US |
