Elucidating the Anticancer Mechanisms of Tetrahydroxycurcumin: A Comprehensive Review of Preclinical Studies

Abstract

ABSTRACT One significant reductive metabolite of curcumin, tetrahydroxycurcumin (THC), is a promising oncology candidate because of its multifunctional bioactivities. Preclinical data indicate that THC has a strong anti‐inflammatory, antioxidant, and anticancer profile, and as such, it is a better alternative to curcumin in treatment. Mechanistically, THC regulates important transcriptional factors that are involved in tumorigenesis, specifically nuclear factor‐kappa B (NF‐kB) and activator protein‐1 (AP‐1). Uncontrolled proliferation, inflammation, and resistance to apoptosis have been linked to aberrant activation of these pathways. Inhibition of NF‐kB and AP‐1 induced by THC suppresses cancer cell survival signaling and triggers apoptotic cell death. Simultaneously, THC inhibits the action of matrix metalloproteinases (MMPs), which are involved in the degradation of extra cells and metastatic spread, and promote tumor invasion and metastasis. Experimental research has also shown the effectiveness of THC in various cancers such as breast cancer, prostate cancer, colon cancer, and skin cancer. It is important to note that THC increases the therapeutic index of traditional chemotherapeutics, where they show synergistic interactions and counteract drug resistance mechanisms, which is a key obstacle in clinical oncology. THC has better physiological stability and bioavailability compared to its parent molecule, a characteristic that alleviates one of the greatest translational limitations of curcumin. This review highlights the molecular processes underlying the anticancer action of THC, its possible use as a single agent and as an adjuvant to already established chemotherapeutic protocols, and the translational issues that need to be overcome to achieve clinical acceptance. Together, the existing evidence supports THC as an attractive future cancer therapeutic with the potential to improve treatment outcomes and overcome drug resistance.