Abstract
BackgroundLipoxygenases are one of the critical signaling mediators which can be targeted for human prostate cancer (PC) therapy. In this study, 4-methyl-2-(4-methylpiperazinyl)pyrimido[4,5-b]benzothiazine (4-MMPB) and its two analogs, 4-propyl-2-(4-methylpiperazinyl)pyrimido[4,5-b]benzothiazine (4-PMPB) and 4-ethyl-2-(4-methylpiperazinyl)pyrimido[4,5-b]benzothiazine (4-EMPB), were proposed to have anti-tumor properties in prostate cancer.MethodsAfter synthesizing the compounds, cytotoxic effects of 4-MMPB and its two analogs against PC-3 cancerous and HDF normal cells were investigated by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay and then mechanism of cell death was assessed by flow cytometry. Finally, the anti-tumor effects of the mentioned compounds were investigated in an immunocompromised C57BL/6 mouse model.Results4-PMPB and 4-EMPB had similar anti-cancer effects on PC-3 cells as compared with 4-MMPB, while they were not effective on normal cells. Moreover, apoptosis and ferroptosis were the main mechanisms of induced cell death in these cancerous cells. Furthermore, in vivo results indicated that both analogs had similar anti-cancer effects as 4-MMPB, leading to delayed tumor growth without any noticeable side effects in weight loss and histological investigations.ConclusionThus, our results suggest that specific targeting of lipoxygenases via 4-MMPB analogs can be considered as a treatment of choice for PC therapy, although it requires further investigations.
Highlights
Lipoxygenases are one of the critical signaling mediators which can be targeted for human prostate cancer (PC) therapy
Enzyme activity assay Lipoxygenase inhibitory activity of 4-MMPB and its analogs was assessed on soybean LOX-1 and the inhibitory potencies (IC50 values) of the mentioned compounds were calculated from their sigmoidal dose–response curves (Fig. 2)
4-EMPB decreased lipoxygenase activity by IC50 value of 14.3 μM, which falls between inhibitory potencies of 4-PMPB (IC50 = 8.6 μM) and 4-MMPB (Half maximal inhibitory concentration (IC50) = 17.1 μM)
Summary
Lipoxygenases are one of the critical signaling mediators which can be targeted for human prostate cancer (PC) therapy. Human lipoxygenases (LOXs) are a family of non-heme iron based enzymes that are involved in the metabolism of AA and other PUFAs into biologically active metabolites [15]. 15-LOX-1 is involved in both tumor promotion and suppression depending on the type of cancer. This enzyme predominantly metabolizes linoleic acid (LA) to 13S-hydroperoxyoctadecadienoic acid (13S-HpODE), and metabolizes AA to 12S- and 15S-hydroperoxyeicosatetraenoic acid (15S-HpETE) [25]. The inhibitory activities of stylosin and its derivatives have been shown on soybean LOX-1 [36] These compounds exerted their anti-cancer effects in PC cells via induction of apoptosis. Recent studies have demonstrated that ferroptotic pathway as another type of programmed cell death can be mediated via LOXs in some contexts to eradicate cancers [44, 45]
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