TY - JOUR
T1 - Mitochondria-Targeted Honokiol Confers a Striking Inhibitory Effect on Lung Cancer via Inhibiting Complex I Activity
AU - Pan, Jing
AU - Lee, Yongik
AU - Cheng, Gang
AU - Zielonka, Jacek
AU - Zhang, Qi
AU - Bajzikova, Martina
AU - Xiong, Donghai
AU - Tsaih, Shirng Wern
AU - Hardy, Micael
AU - Flister, Michael
AU - Olsen, Christopher M.
AU - Wang, Yian
AU - Vang, Ole
AU - Neuzil, Jiri
AU - Myers, Charles R.
AU - Kalyanaraman, Balaraman
AU - You, Ming
N1 - Funding Information:
We are grateful to Dr. Joan Massage (Memorial Sloan Kettering Cancer Center) for providing the H2030-BrM3 and PC9-BrM3 cells, to O.V. (Roskilde University) for providing the 143B and 143B ρ0 cells, and to M.B. (Czech Academy of Sciences) for providing the B16 and B16 ρ0 cells. This work was funded by the NIH grant R01CA208648 .
Funding Information:
We are grateful to Dr. Joan Massage (Memorial Sloan Kettering Cancer Center)for providing the H2030-BrM3 and PC9-BrM3 cells, to O.V. (Roskilde University)for providing the 143B and 143B ρ0 cells, and to M.B. (Czech Academy of Sciences)for providing the B16 and B16 ρ0 cells. This work was funded by the NIH grant R01CA208648. M.Y. B.K. J.P. and J.Z. were responsible for the overall experimental design with input from Y.L. G.C. D.X. M.F. C.M.O. and C.R.M. The project was supervised by M.Y. B.K. J.P. and J.Z. M.H. synthesized and characterized the mito-honokiols. C.M.O. J.P. and Q.Z. assessed the animal toxicity of Mito-HNK. G.C. J.P. and Y.L. did the cell proliferation and transwell invasion studies. J.P. and Y.L. did the tyrosine kinase assays, western blots, and STAT3 knockout and knockdown experiments. J.P. Y.L. Q.Z. and Y.W. conducted the orthotopic lung cancer and brain metastasis animal studies. M.F. D.X. and S.-W.T. did the RNA-seq analysis. J.P. and G.C. conducted the experiments with ρ0 cells. G.C. and J.Z. analyzed respiratory enzyme activity and intracellular oxidants. C.R.M. did the peroxiredoxin experiments. M.B. O.V. and J.N. provided rho0 or ρ0 cells. M.Y. and B.K. acquired the funding. The following were largely responsible for writing, reviewing, and editing the manuscript: J.P. G.C. J.Z. M.H. M.F. C.R.M. B.K. and M.Y. The authors declare that there are no financial or other conflicts of interest.
Publisher Copyright:
© 2018 The Authors
PY - 2018/5/25
Y1 - 2018/5/25
N2 - 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.
AB - 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.
KW - Immunology
KW - Medicinal and Aromatic Plants
KW - Natural Product Chemistry
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UR - http://www.scopus.com/inward/citedby.url?scp=85063413951&partnerID=8YFLogxK
U2 - 10.1016/j.isci.2018.04.013
DO - 10.1016/j.isci.2018.04.013
M3 - Article
AN - SCOPUS:85063413951
VL - 3
SP - 192
EP - 207
JO - iScience
JF - iScience
SN - 2589-0042
ER -