Department of Stomatology, Xuzhou Medical University Affiliated Hospital of Lianyungang, Lianyungang, 222000, Jiangsu, PR China.
Department of Stomatology, Xuzhou Medical University Affiliated Hospital of Lianyungang, Lianyungang, 222000, Jiangsu, PR China.
Mol Cell Probes. 2022 Aug;64:101821. doi: 10.1016/j.mcp.2022.101821. Epub 2022 Apr 29.
Oral squamous cell carcinoma (OSCC) represents an increasing problem in the global public health due to the high incidence and worsening prognosis. Traditional chemotherapy extends the limited benefit for OSCC patients because of acquired drug resistance. Carnosic acid is an important polyphenol and has attracted more interesting based on the indispensable role in the progression of several cancers. Nevertheless, its roles in OSCC remain elusive. In this study, carnosic acid dose-dependently inhibited OSCC cell viability while preserving normal oral keratinocytes. Importantly, carnosic acid application sensitized cisplatin-resistant CAL27-DDP and SCC9-DDP cells to cisplatin by decreasing cell viability and increasing cell death. Noticeably, SCC9-DDP and CAL27-DDP cells exhibited lower ferroptosis relative to the parental cells evident by the higher intracellular GSH levels and lower ROS and lipid peroxidation in cisplatin-resistant cells. Treatment with carnosic acid induced ferroptosis in cisplatin-resistant OSCC cells; however, this suppression was reversed following the application of ferroptosis antagonist liproxstatin-1 (Lip-1), indicating the involvement of ferroptosis for carnosic acid-mediated cisplatin resistance. Furthermore, compared with parental cells, stronger activation of the Nrf2/HO-1/xCT signaling was observed in cisplatin-resistant cells, which was inhibited by carnosic acid. Of interest, reactivating the Nrf2 signaling reversed carnosic acid-evoked ferroptosis in cisplatin-resistant cells and ultimately attenuated carnosic acid-mediated cell sensitivity to cisplatin. Together, the current findings highlight that carnosic acid may re-sensitize cisplatin-resistant cells to cisplatin by inducing ferroptosis, which involves the inactivation of Nrf2/HO-1/xCT pathway. Hence, this research may support a promising therapeutic approach to overcome chemoresistance in OSCC.
口腔鳞状细胞癌 (OSCC) 由于发病率高和预后恶化，成为全球公共卫生的一个日益严重的问题。由于获得性药物耐药性，传统化疗延长了 OSCC 患者的有限获益。迷迭香酸是一种重要的多酚，由于在几种癌症的进展中起着不可或缺的作用，因此引起了更多的关注。然而，其在 OSCC 中的作用仍不清楚。在这项研究中，迷迭香酸剂量依赖性地抑制 OSCC 细胞活力，同时保留正常的口腔角质形成细胞。重要的是，迷迭香酸的应用通过降低细胞活力和增加细胞死亡使顺铂耐药的 CAL27-DDP 和 SCC9-DDP 细胞对顺铂敏感。值得注意的是，与亲本细胞相比，SCC9-DDP 和 CAL27-DDP 细胞表现出较低的铁死亡，这表现在顺铂耐药细胞中细胞内 GSH 水平较高和 ROS 及脂质过氧化较低。用迷迭香酸处理诱导顺铂耐药 OSCC 细胞发生铁死亡；然而，在用铁死亡拮抗剂 liproxstatin-1（Lip-1）处理后，这种抑制作用被逆转，表明迷迭香酸介导的顺铂耐药与铁死亡有关。此外，与亲本细胞相比，顺铂耐药细胞中观察到更强的 Nrf2/HO-1/xCT 信号激活，而迷迭香酸可抑制该激活。有趣的是，重新激活 Nrf2 信号逆转了迷迭香酸引起的铁死亡，并最终减弱了迷迭香酸介导的细胞对顺铂的敏感性。总之，这些发现强调迷迭香酸通过诱导铁死亡使顺铂耐药细胞重新对顺铂敏感，其中涉及 Nrf2/HO-1/xCT 通路的失活。因此，这项研究可能为克服 OSCC 中的化疗耐药提供一种有前途的治疗方法。
