Ingenol mebutate in cancer therapy: mechanisms, clinical applications and future directions

Ingenol mebutate (IM), a diterpene ester derived from Euphorbia species, has demonstrated promising anticancer properties through direct cytotoxicity and immune modulation. Despite initial clinical success, its therapeutic use has been curtailed due to safety concerns, including potential links to increased skin cancer risk. This review evaluates the mechanisms of action, preclinical and clinical efficacy, safety, and limitations of IM as an anticancer agent, identifying areas for further development. A comprehensive literature review was performed using Google Scholar to identify English-language articles published from 2010 to 2023. Keywords included “Ingenol mebutate,” “PEP005,” and “cancer therapy.” Articles focusing on IM’s pharmacological properties, therapeutic mechanisms, clinical studies, and safety profile were included. IM exerts anticancer effects through dual mechanisms: mitochondrial dysfunction leading to necrosis and immune-mediated cytotoxicity via protein kinase C activation. Preclinical studies show efficacy against pancreatic, colorectal, and epithelial cancers and clinical studies have reported success in treating actinic keratosis and nonmelanoma skin cancers. Challenges include intense local skin reactions and safety concerns, particularly its potential association with increased skin malignancy risk. IM represents a promising therapeutic agent due to its rapid and potent anticancer effects. However, optimizing its safety profile and exploring advanced delivery methods are critical to expanding its clinical applications. Further studies are required to establish its long-term efficacy and potential for broader use in oncology.