Recent advances of potential antitumor agents from natural sesquiterpenoids

Sesquiterpenoids, a major class of plant-derived secondary metabolites known for their structural diversity and biological activities, have gained significant attention for their cytotoxic effects against cancer cells, suggesting their potential as promising anticancer agents. Given the rapid advancements and increasing volume of research, there is a crucial need to compile and summarize the latest developments to fully understand their mechanisms and therapeutic potential.

This review aims to elucidate the diverse antitumor effects of sesquiterpenoids and their potential therapeutic applications. It seeks to provide a comprehensive framework for understanding the key signaling pathways and proteins involved in their antitumor mechanisms, highlight the extensive research conducted from January 2020 to September 2024, and to guide future research directions for translating these findings into clinical applications.

We performed extensive searches in electronic databases, including Web of Science and PubMed, from 2020 onward, using keywords such as 'antitumor', 'sesquiterpenes', 'mechanism', 'signaling pathways', and various combinations of these terms.

A total of 112 natural sesquiterpenoids were systematically characterized. Their antitumor effects primarily involved: (1) ROS overproduction, (2) inhibition of key signaling pathways (PI3K/Akt, NF-κB, and STAT3), and (3) modulation of apoptosis-related proteins-upregulating executioner caspase-3 and pro-apoptotic BAX while downregulating anti-apoptotic Bcl-2. These collective actions synergistically enhanced programmed cell death in malignant cells.

Recently discovered sesquiterpenoids, whether isolated or derived from extracts, have demonstrated antitumor activities. Although these compounds display lower toxicity, fewer adverse effects, and the ability to act on multiple biological targets to combat drug resistance, their effectiveness remains weaker than first-line antitumor agents, limiting their primary use to adjuvant therapeutic roles. The clinical translation of sesquiterpenoids is hindered by inherent pharmacokinetic limitations, particularly poor aqueous solubility and low bioavailability. To overcome these issues, two complementary approaches appear effective: (1) structural modification to develop hydrophilic derivatives through rational drug design, and (2) advanced delivery systems utilizing tumor-targeting nanoparticles to enhance biodistribution and treatment efficacy.