Cinnamaldehyde-Containing Organoarsenic Prodrug with Synergistic Anticancer Activity via Redox Dyshomeostasis

The severe occurrence and mortality of cancer and the gradually increasing failure rate of traditional chemotherapeutic agents call for the search for alternative strategies for cancer therapy. Herein, we report the development of a small-molecule prodrug TAO-CA by conjugating a trivalent organoarsenical (TAO) with a natural product cinnamaldehyde (CA) via an acetal linkage. This prodrug is able to be activated under the mildly acidic environment of the tumor to release the two parent drugs for simultaneously inhibiting the activity of thioredoxin reductase (TrxR) and reducing the cellular level of glutathione (GSH), resulting in intracellular redox dyshomeostasis and consequent cancer cell apoptosis for effective inhibition of tumor growth. The mechanism and efficacy of this prodrug have been validated by a series of in vitro and in vivo experiments, demonstrating the promising potential of our strategy, the integration of the prodrug approach, and synergistic redox dyshomeostasis induction for effective cancer therapy.