(5R)-5-hydroxytriptolide (LLDT-8), a novel immunosuppressant in clinical trials, exhibits potent antitumor activity via transcription inhibition.

(5R)-5-hydroxytriptolide (LLDT-8), a triptolide derivative, is a low-toxicity immunosuppressant in Phase I clinical trials. Here, we demonstrate that LLDT-8 displays broad-spectrum, potent (nanomolar level IC(50)s) antitumor activity, and induces S-phase cell-cycle arrest and apoptosis in vitro. Notably, LLDT-8 effectively overcomes multidrug resistance mediated by P-glycoprotein. In vivo, LLDT-8 demonstrates potent antitumor activity, particularly against human ovarian cancer 3AO and prostate cancer PC-3 xenografts in nude mice. The antitumor activity of LLDT-8 is achieved by virtue of its general inhibition of gene transcription. Our results indicate that LLDT-8 is a novel transcription inhibitor with potential for cancer therapy, particularly for cancers with drug resistance mediated by P-glycoprotein.