LAUSR

Simple Summary The aim of this study was to determine the antitumor activity of nerolidol, a naturally occurring sesquiterpene alcohol, in two bladder carcinoma cell lines and to elucidate the possible cell death pathway. Bladder carcinoma is one of the most common malignancies worldwide, with a high recurrence rate and low survival. In our study, we observed multiple cellular mechanisms of nerolidol with two distinct modes of cell death. Its specific induction of cell death, which does not depend on apoptotic factors, is a potential therapeutic approach to overcome the inherent resistance of tumors to apoptosis. Abstract 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 cis-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 cis-nerolidol induces DNA damage and ER stress. A mechanistic study identified a common cAMP, Ca2+, 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. cis-Nerolidol shows promising antitumor activity through an unorthodox mechanism of action that could help target resistant forms of malignancies, such as bladder cancer.