Mitochondria-Targeted Honokiol Confers a Striking Inhibitory Effect on Lung Cancer via Inhibiting Complex I Activity

Jing Pan, Yongik Lee, Gang Cheng, Jacek Zielonka, Qi Zhang, Martina Bajzikova, Donghai Xiong, Shirng-Wern Tsaih, Micael Hardy, Michael Flister, Christopher M. Olsen, Yian Wang, Ole Vang, Jiri Neuzil, Charles R. Myers, Balaraman Kalynaraman, Ming You

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

We synthesized a mitochondria-targeted honokiol (Mito-HNK) that facilitates its mitochondrial accumulation; this dramatically increases its potency and efficacy against highly metastatic lung cancer lines in vitro, and in orthotopic lung tumor xenografts and brain metastases in vivo. Mito-HNK is >100-fold more potent than HNK in inhibiting cell proliferation, inhibiting mitochondrial complex ǀ, stimulating reactive oxygen species generation, oxidizing mitochondrial peroxiredoxin-3, and suppressing the phosphorylation of mitoSTAT3. Within lung cancer brain metastases in mice, Mito-HNK induced the mediators of cell death and decreased the pathways that support invasion and proliferation. In contrast, in the non-malignant stroma, Mito-HNK suppressed pathways that support metastatic lesions, including those involved in inflammation and angiogenesis. Mito-HNK showed no toxicity and targets the metabolic vulnerabilities of primary and metastatic lung cancers. Its pronounced anti-invasive and anti-metastatic effects in the brain are particularly intriguing given the paucity of treatment options for such patients either alone or in combination with standard chemotherapeutics.
Original languageEnglish
JournaliScience
Volume3
Pages (from-to)192-207
Number of pages16
DOIs
Publication statusPublished - 22 Apr 2018

Cite this