Induction of monoamine oxidase A-mediated oxidative stress and impairment of NRF2-antioxidant defence response by polyphenol-rich fraction of Bergenia ligulata sensitizes prostate cancer cells in vitro and in vivo

• Published in: Free radical biology & medicine Vol. 172; pp. 136 - 151
• Main Authors: Ghosh, Suvranil, Dutta, Naibedya, Banerjee, Pinaki, Gajbhiye, Rahul L., Sareng, Hossainoor Rahaman, Kapse, Prachi, Pal, Srabani, Burdelya, Lyudmila, Mandal, Narayan C., Ravichandiran, Velyutham, Bhattacharjee, Ashish, Kundu, Gopal C., Gudkov, Andrei V., Pal, Mahadeb
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 20-08-2021
• Subjects: Antioxidant response; Bergenia ligulata; GSK-3β; Monoamine oxidase-A; NOD-SCID xenograft; NRF2; Paclitaxel; Polyphenolic compounds; Prostate cancer; Splenocyte; NOD-SCID xenograft; GSK-3β; Antioxidant response; NRF2; Bergenia ligulata; Monoamine oxidase-A; Paclitaxel; Polyphenolic compounds; Splenocyte; Prostate cancer
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2021.05.037

Prostate cancer (PCa) is a major cause of mortality and morbidity in men. Available therapies yield limited outcome. We explored anti-PCa activity in a polyphenol-rich fraction of Bergenia ligulata (PFBL), a plant used in Indian traditional and folk medicine for its anti-inflammatory and antineoplastic properties. PFBL constituted of about fifteen different compounds as per LCMS analysis induced apoptotic death in both androgen-dependent LNCaP and androgen-refractory PC3 and DU145 cells with little effect on NKE and WI38 cells. Further investigation revealed that PFBL mediates its function through upregulating ROS production by enhanced catalytic activity of Monoamine oxidase A (MAO-A). Notably, the differential inactivation of NRF2-antioxidant response pathway by PFBL resulted in death in PC3 versus NKE cells involving GSK-3β activity facilitated by AKT inhibition. PFBL efficiently reduced the PC3-tumor xenograft in NOD-SCID mice alone and in synergy with Paclitaxel. Tumor tissues in PFBL-treated mice showed upregulation of similar mechanism of cell death as observed in isolated PC3 cells i.e., elevation of MAO-A catalytic activity, ROS production accompanied by activation of β-TrCP-GSK-3β axis of NRF2 degradation. Blood counts, liver, and splenocyte sensitivity analyses justified the PFBL safety in the healthy mice. To our knowledge this is the first report of an activity that crippled NRF2 activation both in vitro and in vivo in response to MAO-A activation. Results of this study suggest the development of a novel treatment protocol utilizing PFBL to improve therapeutic outcome for patients with aggressive PCa which claims hundreds of thousands of lives each year.
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•Polyphenol-rich fraction of Bergenia ligulata (PFBL) kills androgen-dependent and independent prostate cancer (PCa) cells.•PFBL exerts its function through upregulation of ROS level mediated by Monoamine oxidase- A in PCa cells.•PFBL inactivates NRF2 antioxidant response by activation of GSK-3β activity in PCa cells.•PFBL kills PC3-tumor xenograft in NOD-SCID mice alone and in synergy with Paclitaxel with high efficacy.