Abstract
Breast cancer is one of the most important causes of cancer death in the world, and chemically induced breast cancers with 7,12-dimethylbenz anthracene (DMBA) or N-methyl-N-nitrosourea (MNU) are a good model of the histopathology and molecular features of human mammary carcinogenesis. Thymoquinone (TQ), the major bioactive compound of Nigella sativa (NS) and gallic acid (GA), a widely found plant phenolic, have shown anticancer effects individually. The scientific justification for combining these two phytochemicals, however, is that these two compounds can target complementary oncogenic pathways and are likely to be synergistically effective with reduced toxicity of individual compounds. This review critically examines the available evidence for the synergy of TQ and GA specifically in chemically-induced breast cancer models on in silico, in vitro and in vivo experimental platforms. The high affinity of TQ and GA to target a variety of driving breast cancer targets, such as nuclear factor kappa B (NF-κB), signal transducer and activator of transcription 3 (STAT3) and estrogen receptor alpha (ERα) in the molecular docking studies, indicates that they may exert their effects through a polypharmacological mechanism. In vitro studies in DMBA-transformed mammary epithelial cell lines have shown that the co-administration of TQ and GA results in a combination index below 1.0, representing a true synergy, with higher levels of reactive oxygen species generation, mitochondrial membrane depolarization and caspase-dependent apoptosis than either agent alone. In vivo, rodent models of mammary carcinogenesis induced by DMBA demonstrate that TQ-GA combination significantly lowers the incidence, multiplicity, and volume of murine mammary tumors and inhibits the pulmonary metastasis when compared to monotherapies. Overall, the scientific and mechanistic underpinning of the TQ-GA synergy is sound, but the dosing ratios, bioavailabilisation and comprehensive pharmacokinetic interaction studies remain as critical prerequisites before clinical translation could be responsibly pursued.