Discovery of a Novel Stilbene Derivative as a Microtubule Targeting Agent Capable of Inducing Cell Ferroptosis

Microtubule targeting agents (MTAs)
are used as clinically effective
chemotherapies for cancer treatment but might be limited by the acquired
or intrinsic resistance of cancer cells to apoptosis. The vulnerability
of therapy-resistant cancers to ferroptosis provides an alternative
way to overcome drug resistance. In this study, on the basis of the
MTAs obtained in our previous studies, a series of MTAs were synthesized,
and detailed structure–activity relationships were obtained
through extensive molecular dynamics studies. Among them, a diphenylethene
derivative, compound 33, displayed the most potent activity
in vitro and in vivo, with IC50 values of 10–50
nM toward six cancer cell lines and a 78.6% tumor growth inhibition
in vivo. Interestingly, although it acted as the MTA, compound 33 triggered cell death mainly
through cell ferroptosis rather than apoptosis, which might provide
an alternative way to eradicate apoptosis-related drug resistance.