Investigating the effects of two novel 4-MMPB analogs as potent lipoxygenase inhibitors for prostate cancer treatment

Abstract

Background 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. Methods 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. Results 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. Conclusion 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.

Tumour induction in BALB/c mice for imaging studies: An improved protocol

“…Fayzullin et al used a combination of CsA (30 mg/kg) and ketoconazole (10 mg/kg) to induce immunosuppression in BALB/c mice 20 . Iranpour et al suppressed the immune system of male C57BL/6 mice by combination of CsA, itraconazole and co‐amoxiclav 21 . Cunha et al reported xenotransplantation (cross‐species transplantation) of human cells of glioblastoma in rats by CsA treatment (5 mg/kg, daily) until the final step of experiments 8 .…”

“…20 Iranpour et al suppressed the immune system of male C57BL/6 mice by combination of CsA, itraconazole and co-amoxiclav. 21 23 Akhter et al reported successful induction of human colon adenocarcinoma cells in rats using daily CsA administration. 6 In this study, CsA, ketoconazole and CP drugs were used to improve an immunosuppression protocol in order to induct human tumour xenografts in mice.…”

“… 20 Iranpour et al suppressed the immune system of male C57BL/6 mice by combination of CsA, itraconazole and co‐amoxiclav. 21 Cunha et al reported xenotransplantation (cross‐species transplantation) of human cells of glioblastoma in rats by CsA treatment (5 mg/kg, daily) until the final step of experiments. 8 Du et al used CsA (10 mg/kg, daily) to develop xenografts of human hepatocarcinoma cells in C57BL/6 mice.…”

A potent multifunctional ZIF-8 nanoplatform developed for colorectal cancer therapy by triple-delivery of chemo/radio/targeted therapy agents

“…An immunosuppression protocol was carried out on male C57BL/6 mice (4-6 weeks old) as described previously. 40 The xenograft tumor model was developed by subcutaneous injection of 8 Â 10 6 HT-29 cells (suspended in 1 : 1; PBS: Matrigel) into the back of immunocompromised C57BL/6 mice. 2.9.1.…”

Ferroptosis landscape in prostate cancer from molecular and metabolic perspective

“…Besides, scientists have artificially synthesized some ferroptosis inducers. 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) are synthetic compounds thought to have antineoplastic properties in PCa, which is achieved by promoting ferroptosis [ 151 ]. Qin et al synthesized isothiocyanate-modified AR antagonists, which showed synergistic activity when combined with buthionine sulfoximine to treat CRPC cells, and resulted in the downregulation of AR/AR-V7 and ferroptosis [ 152 ].…”