ALLICIN IN HEPATOCELLULAR CARCINOMA: MECHANISTIC INSIGHTS INTO ROS-MEDIATED APOPTOSIS AND POTENTIAL P53-INDEPENDENT ANTICANCER EFFECTS

Hepatocellular carcinoma (HCC) is a significant health problem and a leading cause of cancer-related deaths worldwide, mainly because of delayed diagnosis and the presence of multiple clones and a lack of effective treatment. Targeted therapies and immunotherapy offer limited survival gains, and often result in drug resistance, toxicity and high expense. One of the major factors that contributes to therapeutic failure is the inactivity of the tumor suppressor p53 which leads to resistance and apoptosis. Natural compounds have proven to be multi-targeted agents of interest in this context. The bioactive compound of Allium sativum, allicin (diallyl thiosulfinate), has been noted for its p53-independent anticancer properties. This review compiles the current evidence of allicin’s anticancer activities related to its ability to generate ROS, to disrupt mitochondrial functions, to activate caspases, and to regulate key signaling pathways in HCC. It underscores studies suggesting that some of these mechanisms can act without p53 signaling, but there is a lack of direct evidence from the HCC models that have been validated in p53 deficient cells, and the redox modulating, mitochondrial dysfunction, caspase activation and endoplasmic reticulum (ER) stress effects of allicin in HCC are highlighted. Furthermore, allicin can modulate key pathways, such as PI3K/Akt, MAPK, and NF-κB, which are involved in the crosstalk between apoptosis and autophagy, thus further stimulating the killing of tumour cells even in resistant phenotypes. “Importantly, this review provides a ROS-metabolic cell-centric mechanism that elucidates how allicin may be selectively pro-apoptotic to HCC cells, bypassing p53-resistant cells, thereby providing support for the hypothesis that resistance in HCC is correlated with p53 dysfunction. Further research is still required to confirm and provide direct evidence of the selective targeting of p53-resistant HCC.” Although there is promising preclinical evidence potential bioavailability, pharmacokinetics, and clinical validation issues are large hurdles. In conclusion, allicin is a promising therapeutic agent for HCC, and further research is needed using advanced drug delivery systems and clinical trials to establish its efficacy.