Glumac Mateo, Čikeš Čulić Vedrana, Marinović-Terzić Ivana, Radan Mila
Department of Immunology and Medical Genetics, School of Medicine, University of Split, 21000 Split, Croatia.
Department of Medicinal Chemistry and Biochemistry, School of Medicine, University of Split, 21000 Split, Croatia.
Cancers (Basel). 2023 Feb 3;15(3):981. doi: 10.3390/cancers15030981.
Nerolidol is a naturally occurring sesquiterpene alcohol with multiple properties, including antioxidant, antibacterial, and antiparasitic activities. A few studies investigating the antitumor properties of nerolidol have shown positive results in both cell culture and mouse models. In this study, we investigated the antitumor mechanism of -nerolidol in bladder carcinoma cell lines. The results of our experiments on two bladder carcinoma cell lines revealed that nerolidol inhibited cell proliferation and induced two distinct cell death pathways. We confirmed that -nerolidol induces DNA damage and ER stress. A mechanistic study identified a common cAMP, Ca, and MAPK axis involved in signal propagation and amplification, leading to ER stress. Inhibition of any part of this signaling cascade prevented both cell death pathways. The two cell death mechanisms can be distinguished by the involvement of caspases. The early occurring cell death pathway is characterized by membrane blebbing and cell swelling followed by membrane rupture, which can be prevented by the inhibition of caspase activation. In the late cell death pathway, which was found to be caspase-independent, cytoplasmic vacuolization and changes in cell shape were observed. -Nerolidol shows promising antitumor activity through an unorthodox mechanism of action that could help target resistant forms of malignancies, such as bladder cancer.
橙花叔醇是一种天然存在的倍半萜醇，具有多种特性，包括抗氧化、抗菌和抗寄生虫活性。一些研究调查了橙花叔醇的抗肿瘤特性，在细胞培养和小鼠模型中均显示出阳性结果。在本研究中，我们调查了β-橙花叔醇在膀胱癌细胞系中的抗肿瘤机制。我们对两种膀胱癌细胞系进行的实验结果表明，橙花叔醇抑制细胞增殖并诱导两种不同的细胞死亡途径。我们证实β-橙花叔醇会诱导DNA损伤和内质网应激。一项机制研究确定了一个共同的环磷酸腺苷（cAMP）、钙（Ca）和丝裂原活化蛋白激酶（MAPK）轴参与信号传播和放大，导致内质网应激。抑制该信号级联反应的任何部分都能阻止两种细胞死亡途径。这两种细胞死亡机制可通过半胱天冬酶的参与来区分。早期发生的细胞死亡途径的特征是细胞膜起泡和细胞肿胀，随后细胞膜破裂，这可以通过抑制半胱天冬酶激活来预防。在晚期细胞死亡途径中，发现其不依赖半胱天冬酶，观察到细胞质空泡化和细胞形状改变。β-橙花叔醇通过一种非传统的作用机制显示出有前景的抗肿瘤活性，这可能有助于靶向恶性肿瘤的耐药形式，如膀胱癌。
