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

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer 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.
OriginalsprogEngelsk
TidsskriftiScience
Vol/bind3
Sider (fra-til)192-207
Antal sider16
DOI
StatusUdgivet - 22 apr. 2018

Emneord

  • Mitochondria
  • Complex I
  • Cancer
  • Honokiol

Citer dette

Pan, J., Lee, Y., Cheng, G., Zielonka, J., Zhang, Q., Bajzikova, M., Xiong, D., Tsaih, S-W., Hardy, M., Flister, M., Olsen, C. M., Wang, Y., Vang, O., Neuzil, J., Myers, C. R., Kalynaraman, B., & You, M. (2018). Mitochondria-Targeted Honokiol Confers a Striking Inhibitory Effect on Lung Cancer via Inhibiting Complex I Activity. iScience, 3, 192-207. https://doi.org/10.1016/j.isci.2018.04.013