It has been widely reported that cancer, along with its treatment regimens, cause severe toxicity in the host. A suitable agent having chemopreventive properties as well as capabilities of ameliorating tumor- and drug-induced toxicities is of imminent need. Pomegranate has been projected as an excellent anti-tumor, anti-inflammatory and anti-oxidant agent. In this study, for the first time, we delineated the exact signaling cascade by which dietary supplementation of pomegranate fruit extract (PFE) protects tumor-bearing mice from tumor-induced hepatotoxicity. Increased activities of serum Alanine transaminase, Aspartate transaminase, Lactate dehydrogenase and Alkaline phosphatase, as well as histological studies confirmed the establishment of a state of hepatic dysfunction in tumor-bearers. Further investigations revealed that increased hepatic reactive oxygen species content and glutathione depletion-initiated apoptosis in these hepatocytes as we observed an alteration in the apoptotic proteins. PFE supplementation in tumor-bearing mice, on the other hand, differentially modulated redox-sensitive transcription factors Nrf2 and NF-κB, ultimately decreasing tumor-induced hepatic oxidative damage and cell death. siRNA-mediated inhibition of Nrf2 and NF-κB completely abolished the hepato-protective activities of PFE while pre-treatment of tumor-conditioned hepatocytes with N-acetyl cysteine augmented the cyto-protective properties of PFE. The present study clearly identified Nrf2/NF-κB/glutathione axis as the key factor behind the hepatoprotective potential of PFE. These findings would add to the existing knowledge about cancer chemoprevention by dietary polyphenols and might lead to the application of pomegranate polyphenols as supplement to escalate the effectiveness of cancer therapy by protecting normal cells from cancer related toxicities.

据广泛报道，癌症及其治疗方案会对宿主造成严重的毒性。迫切需要具有化学预防特性以及改善肿瘤和药物引起的毒性的能力的合适药剂。石榴被认为是一种优秀的抗肿瘤、抗炎和抗氧化剂。在这项研究中，我们首次描述了饮食中补充石榴果实提取物（PFE）可保护荷瘤小鼠免受肿瘤诱导的肝毒性的确切信号级联反应。血清丙氨酸转氨酶、天冬氨酸转氨酶、乳酸脱氢酶和碱性磷酸酶活性增加，以及组织学研究证实肿瘤携带者存在肝功能障碍状态。进一步的研究表明，当我们观察到凋亡蛋白的变化时，肝脏活性氧含量的增加和谷胱甘肽的消耗引发了这些肝细胞的凋亡。另一方面，在荷瘤小鼠中补充 PFE 可以差异调节氧化还原敏感转录因子 Nrf2 和 NF-κB，最终减少肿瘤诱导的肝氧化损伤和细胞死亡。 siRNA 介导的 Nrf2 和 NF-κB 抑制完全消除了 PFE 的肝保护活性，而用 N-乙酰半胱氨酸预处理肿瘤条件肝细胞则增强了 PFE 的细胞保护特性。本研究明确确定 Nrf2/NF-κB/谷胱甘肽轴是 PFE 保肝潜力的关键因素。 这些发现将增加关于膳食多酚化学预防癌症的现有知识，并可能导致石榴多酚作为补充剂的应用，通过保护正常细胞免受癌症相关毒性来提高癌症治疗的有效性。