Lipoxygenases 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. After 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. 4-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. Thus, 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.

中文翻译：

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研究两种新型的4-MMPB类似物作为有效的脂氧合酶抑制剂对前列腺癌的治疗作用

脂氧合酶是可以靶向人类前列腺癌（PC）治疗的重要信号传导介质之一。在这项研究中，4-甲基-2-（4-甲基哌嗪基）嘧啶[4,5-b]苯并噻嗪（4-MMPB）及其两个类似物4-丙基-2-（4-甲基哌嗪基）嘧啶[4,5]有人提出将-b]苯并噻嗪（4-PMPB）和4-乙基-2-（4-甲基哌嗪基）嘧啶并[4,5-b]苯并噻嗪（4-EMPB）在前列腺癌中具有抗肿瘤特性。合成化合物后，用3- [4,5-二甲基噻唑-2-基] -2,5-二苯基四唑溴化物（MTT）研究了4-MMPB及其两种类似物对PC-3癌细胞和HDF正常细胞的细胞毒性作用。检测，然后通过流式细胞仪评估细胞死亡的机制。最后，在免疫受损的C57BL / 6小鼠模型中研究了上述化合物的抗肿瘤作用。与4-MMPB相比，4-PMPB和4-EMPB对PC-3细胞具有相似的抗癌作用，而对正常细胞却无作用。此外，凋亡和促肥大作用是这些癌细胞中诱导的细胞死亡的主要机制。此外，体内结果表明，两种类似物均具有与4-MMPB相似的抗癌作用，从而导致肿瘤生长延迟，并且在体重减轻和组织学研究中没有任何明显的副作用。因此，我们的结果表明，尽管需要进一步研究，但通过4-MMPB类似物特异性靶向脂氧合酶可被视为PC疗法的治疗选择。细胞凋亡和肥大症是这些癌细胞中诱导细胞死亡的主要机制。此外，体内结果表明，两种类似物均具有与4-MMPB相似的抗癌作用，从而导致肿瘤生长延迟，并且在体重减轻和组织学研究中没有任何明显的副作用。因此，我们的结果表明，尽管需要进一步研究，但通过4-MMPB类似物特异性靶向脂氧合酶可被视为PC疗法的治疗选择。细胞凋亡和肥大症是这些癌细胞中诱导细胞死亡的主要机制。此外，体内结果表明，两种类似物均具有与4-MMPB相似的抗癌作用，从而导致肿瘤生长延迟，并且在体重减轻和组织学研究中没有任何明显的副作用。因此，我们的结果表明，尽管需要进一步研究，但通过4-MMPB类似物特异性靶向脂氧合酶可被视为PC疗法的治疗选择。