Background Mycosis fungoides (MF) and Sézary syndrome (SS) are subtypes of primary cutaneous lymphomas and represent complex diseases regarding their physiopathology and management. Depending on the stage of the disease, different treatment regimens are applied, but there is no consensus on an optimal approach. Prognosis for patients with early stage MF is favorable, but significantly worsens in advanced disease and in SS, where patients frequently relapse and require multiple therapies. Methods We investigated the potential anticancer effects of NEO212, a novel compound generated by covalently conjugating perillyl alcohol (a natural monoterpene) to temozolomide (an alkylating agent), on MF and SS cell lines in vitro. HUT-78, HUT-102, and MyLa cells were treated with NEO212 under different conditions, and drug effects on proliferation, viability, and apoptosis were characterized. Results NEO212 inhibited proliferation, diminished viability, and stimulated apoptosis in all cell lines, although with varying degrees of potency in the different cell lines. It down-regulated c-myc and cyclin D1 proteins, which are required for cell proliferation, but triggered endoplasmic reticulum stress and activation of caspases. Pretreatment of cells with antioxidants ascorbic acid and beta-mercaptoethanol prevented these NEO212-induced effects. Conclusions NEO212 exerted promising anticancer effects on SS and MF cell lines. The generation of reactive oxygen species (ROS) appears to play a key role in the NEO212-induced cell death process, because the blockage of ROS with antioxidants prevented caspase activation. We propose that NEO212 should be investigated further toward clinical testing in these tumor types.

中文翻译：

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紫苏醇-替莫唑胺偶联物 NEO212 对体外皮肤 T 细胞淋巴瘤的细胞毒性影响。

背景 蕈样肉芽肿 (MF) 和 Sézary 综合征 (SS) 是原发性皮肤淋巴瘤的亚型，代表了关于其生理病理学和治疗的复杂疾病。根据疾病的阶段，采用不同的治疗方案，但没有就最佳方法达成共识。早期 MF 患者的预后良好，但在晚期疾病和 SS 中显着恶化，患者经常复发并需要多种治疗。方法 我们在体外研究了 NEO212 对 MF 和 SS 细胞系的潜在抗癌作用，NEO212 是一种由紫苏醇（一种天然单萜）与替莫唑胺（一种烷化剂）共价结合产生的新型化合物。HUT-78、HUT-102 和 MyLa 细胞在不同条件下用 NEO212 处理，药物对增殖、活力、和细胞凋亡进行了表征。结果 NEO212 在所有细胞系中抑制增殖、降低活力并刺激细胞凋亡，尽管在不同细胞系中具有不同程度的效力。它下调了细胞增殖所需的 c-myc 和 cyclin D1 蛋白，但引发了内质网应激和半胱天冬酶的激活。用抗氧化剂抗坏血酸和β-巯基乙醇预处理细胞可防止这些 NEO212 诱导的作用。结论 NEO212对SS和MF细胞系具有良好的抗癌作用。活性氧 (ROS) 的产生似乎在 NEO212 诱导的细胞死亡过程中起关键作用，因为抗氧化剂对 ROS 的阻断阻止了半胱天冬酶的活化。