Terpenoids as modulators of autophagy-senescence crosstalk in lung cancer

Lung cancer (LC) is ranked among the top causes of cancer death in the world, with little success achieved by currently available therapies due to late diagnoses, resistance, and side effects. Terpenoids, which are secondary metabolites produced by plants, have been extensively investigated for their anticancer activities. Preclinical studies demonstrate that terpenoids affect important cellular mechanisms like autophagy and cellular senescence (CS), which have both tumor-suppressive and tumor-progressive effects. The present study summarizes the effects of 46 structurally diverse terpenoids including monoterpenoids, diterpenoids, triterpenoids, sesquiterpenoids, and their analogs on autophagy and CS in pulmonary cancer cells. Interestingly, most of these agents were reported to affect both pathways by targeting central nodes of signaling pathway, which include AMP-activated protein kinase (AMPK), Nuclear factor-kappa B (NF-κB), mitogen-activated protein kinase (MAPK)/Extracellular signal-regulated kinase (ERK)/c-Jun N-terminal kinase (JNK), phosphoinositide 3-kinase (PI3K)/alpha serine/threonine kinase (AKT)/ mechanistic target of rapamycin (mTOR), reactive oxygen species (ROS) and tumor protein (p53), retinoblastoma proteins (Rb), Cell Cycle Arrest, and Senescence-associated secretory phenotype (SASP) factors. The review highlighted that autophagy and CS can be exploited in lung cancer treatment to provide an improved benefit to patients. Although preclinical studies provide promising evidence for the anticancer potential of terpenoids, their clinical translation is limited by poor solubility, low bioavailability, and challenges in targeted delivery.