Two-Photon Photodegradation of E3 Ubiquitin Ligase Cereblon by a Ru(II) Complex: Inducing Ferroptosis in Cisplatin-Resistant Tumor Cells

Using photodynamic therapy (PDT) to trigger nonconventional
cell
death pathways has provided a new scheme for highly efficient and
non-side effects to drug-resistant cancer therapies. Nonetheless,
the unclear targets of available photosensitizers leave the manner
of PDT-induced tumor cell death relatively unpredictable. Herein,
we developed a novel Ru(II)-based photosensitizer, Ru-Poma. Possessing the E3 ubiquitin ligase CRBN-targeting moiety and high
singlet oxygen yield of 0.96, Ru-Poma was demonstrated
to specifically photodegrade endogenous CRBN, increase lipid peroxide,
downregulate GPX4 and GAPDH expression, and consequently induce ferroptosis
in cisplatin-resistant cancerous cells. Furthermore, with the deep
penetration of two-photon excitation, Ru-Poma achieved
drug-resistant circumvention in a 3D tumor cell model. Thus, we describe
the first sample of the CRBN-targeting Ru(II) complex active in PDT.