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Thyroid cancer (TC) is the most common endocrine malignancy. Recently, the global incidence of TC has increased rapidly. Differentiated thyroid cancer includes papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma (FTC), which are the most common types of TC. Although PTCs and FTCs exert good prognoses and high survival rates, FTCs tend to be more aggressive than PTCs. There is an urgent need to improve patient outcomes by developing effective therapeutic agents for FTCs. Piperlongumine exerts anti-cancer effects in various human carcinomas, including human anaplastic TCs and PTCs. However, the anti-cancer effects of piperlongumine in FTCs and the underlying mechanisms are yet to be elucidated. Therefore, in the present study, we evaluated the effect of piperlongumine on cell proliferation, cell cycle, apoptosis, and autophagy in FTC cells with flowcytometry and Western blot. We observed that piperlongumine caused growth inhibition, cell cycle arrest, apoptosis induction, and autophagy elevation in FTC cells. Activities of reactive oxygen species and the downstream PI3K/Akt pathway were the underlying mechanisms involved in piperlongumine mediated anti-FTC effects. Advancements in our understanding of the effects of piperlongumine in FTC hold promise for the development of novel therapeutic strategies. [ABSTRACT FROM AUTHOR]

Simple Summary: There is no effective treatment currently available for patients with anaplastic, recurrent papillary, or follicular thyroid cancers. Reactive oxygen species (ROS) are believed to hold promise as a new therapeutic strategy for multiple human cancers. However, studies on ROS inducers for human thyroid cancer treatment are scarce. This study assesses the anticancer activity and the detailed downstream mechanisms of piperlongumine, a ROS inducer, in human thyroid cancer cells. We demonstrate that piperlongumine inhibits cell proliferation, regulates the cell cycle, and induces cellular apoptosis in various types of human thyroid cancer cells. The antihuman thyroid cancer activity of piperlongumine was through ROS induction, and it further suppressed the downstream Akt signaling pathway to elevate mitochondria-dependent apoptosis. A mouse xenograft study demonstrated that piperlongumine was safe and could inhibit tumorigenesis in vivo. The present study provides strong evidence that piperlongumine can be used as a therapeutic candidate for human thyroid cancers. Thyroid cancer (TC) is the most common endocrine malignancy, and its global incidence has steadily increased over the past 15 years. TC is broadly divided into well-differentiated, poorly differentiated, and undifferentiated types, depending on the histological and clinical parameters. Thus far, there are no effective treatments for undifferentiated thyroid cancers or advanced and recurrent cancer. Therefore, the development of an effective therapeutic is urgently needed for such patients. Piperlongumine (PL) is a naturally occurring small molecule derived from long pepper; it is selectively toxic to cancer cells by generating reactive oxygen species (ROS). In this study, we demonstrate the potential anticancer activity of PL in four TC cell lines. For this purpose, we cultured TC cell lines and analyzed the following parameters: Cell viability, colony formation, cell cycle, apoptosis, and cellular ROS induction. PL modulated the cell cycle, induced apoptosis, and suppressed tumorigenesis in TC cell lines in a dose- and time-dependent manner through ROS induction. Meanwhile, an intrinsic caspase-dependent apoptosis pathway was observed in the TC cells under PL treatment. The activation of Erk and the suppression of the Akt/mTOR pathways through ROS induction were seen in cells treated with PL. PL-mediated apoptosis in TC cells was through the ROS-Akt pathway. Finally, the anticancer effect and safety of PL were also demonstrated in vivo. Our findings indicate that PL exhibits antitumor activity and has the potential for use as a chemotherapeutic agent against TC. This is the first study to show the sensitivity of TC cell lines to PL. [ABSTRACT FROM AUTHOR]