Scheit Katrin, Bauer Georg
Department of Medical Microbiology and Hygiene, Institute of Virology, University Medical Center, Freiburg, 79104, Germany Present address: Klinik Immenstadt, 87509 Immenstadt, Germany.
Department of Medical Microbiology and Hygiene, Institute of Virology, University Medical Center, Freiburg, 79104, Germany
Carcinogenesis. 2015 Mar;36(3):400-11. doi: 10.1093/carcin/bgv010. Epub 2015 Feb 3.
Salicylic acid and anthocyanidins are known as plant-derived antioxidants, but also can provoke paradoxically seeming prooxidant effects in vitro. These prooxidant effects are connected to the potential of salicylic acid and anthocyanidins to induce apoptosis selectively in tumor cells in vitro and to inhibit tumor growth in animal models. Several epidemiological studies have shown that salicylic acid and its prodrug acetylsalicylic acid are tumor-preventive for humans. The mechanism of salicylic acid- and anthocyanidin-dependent antitumor effects has remained enigmatic so far. Extracellular apoptosis-inducing reactive oxygen species signaling through the NO/peroxynitrite and the HOCl signaling pathway specifically induces apoptosis in transformed cells. Tumor cells have acquired resistance against intercellular reactive oxygen species signaling through expression of membrane-associated catalase. Here, we show that salicylic acid and anthocyanidins inactivate tumor cell protective catalase and thus reactive apoptosis-inducing intercellular reactive oxygen species signaling of tumor cells and the mitochondrial pathway of apoptosis Salicylic acid inhibits catalase directly through its potential to transform compound I of catalase into the inactive compound II. In contrast, anthocyanidins provoke a complex mechanism for catalase inactivation that is initiated by anthocyanidin-mediated inhibition of NO dioxygenase. This allows the formation of extracellular singlet oxygen through the reaction between H(2)O(2) and peroxynitrite, amplification through a caspase8-dependent step and subsequent singlet oxygen-mediated inactivation of catalase. The combination of salicylic acid and anthocyanidins allows for a remarkable synergistic effect in apoptosis induction. This effect may be potentially useful to elaborate novel therapeutic approaches and crucial for the interpretation of epidemiological results related to the antitumor effects of secondary plant compounds.
水杨酸和花青素被认为是植物来源的抗氧化剂，但在体外也可能引发看似矛盾的促氧化作用。这些促氧化作用与水杨酸和花青素在体外选择性诱导肿瘤细胞凋亡以及在动物模型中抑制肿瘤生长的潜力有关。多项流行病学研究表明，水杨酸及其前药乙酰水杨酸对人类具有肿瘤预防作用。迄今为止，水杨酸和花青素依赖性抗肿瘤作用的机制仍不清楚。通过NO/过氧亚硝酸盐和HOCl信号通路诱导细胞外凋亡的活性氧信号特异性地诱导转化细胞凋亡。肿瘤细胞通过表达膜相关过氧化氢酶获得了对细胞间活性氧信号的抗性。在此，我们表明水杨酸和花青素可使肿瘤细胞保护性过氧化氢酶失活，从而激活肿瘤细胞的细胞间活性氧凋亡诱导信号和凋亡的线粒体途径。水杨酸通过将过氧化氢酶的化合物I转化为无活性的化合物II直接抑制过氧化氢酶。相比之下，花青素引发了一种复杂的过氧化氢酶失活机制，该机制由花青素介导的NO双加氧酶抑制引发。这允许通过H(2)O(2)与过氧亚硝酸盐之间的反应形成细胞外单线态氧，通过半胱天冬酶8依赖性步骤进行放大，随后单线态氧介导过氧化氢酶失活。水杨酸和花青素的组合在诱导凋亡方面具有显著的协同作用。这种效应可能对开发新的治疗方法具有潜在的用途，并且对于解释与次生植物化合物抗肿瘤作用相关流行病学结果至关重要。
