Redox dyshomeostasis-driven prodrug strategy for enhancing camptothecin-based chemotherapy: Selenization of SN38 as a...

Harnessing the modulation of redox homeostasis represents a promising anticancer strategy. Here, we design and evaluate Se-SN38, a prodrug of the camptothecin (CPT) derivative 7-ethyl-10-hydroxycamptothecin (SN38) with a cyclic five-membered diselenide moiety for redox-triggered activation. We demonstrate that Se-SN38 exhibits superior cytotoxicity in various cancer cell lines over the parent drug SN38 or the control prodrug S-SN38, a sulfur analogue of Se-SN38. This increased potency is attributed to the efficient release of SN38 and induction of oxidative stress, as demonstrated by a significant rise in reactive oxygen species production, along with a marked depletion of cellular total thiols and a decreased GSH/GSSG ratio. Furthermore, Se-SN38 treatment leads to inhibition of thioredoxin reductase activity, disruption of mitochondrial membrane potential, and induction of DNA damage, culminating in apoptosis. These findings suggest that Se-SN38 represents a promising strategy to enhance the therapeutic efficacy of CPT derivatives by exploiting the unique redox-active properties of cyclic five-membered diselenide to induce oxidative stress and apoptosis.